Achievable accuracies reported in the literature categorized by body site and immobilization/repositioning device.(AAPM TG101)
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"4625",leadTitle:null,fullTitle:"Complementary Therapies for the Body, Mind and Soul",title:"Complementary Therapies for the Body, Mind and Soul",subtitle:null,reviewType:"peer-reviewed",abstract:"Complementary Therapies (CT) refers to the practices, products, or health systems that are outside the realm of conventional medicine, used to treat disease or to promote health and well-being. Defining CT is difficult, because the field is very broad and constantly changing. The title of this book includes the words body, mind, and soul. The body and the mind (and their reciprocal relations) have been extensively studied scientifically. What about the soul? The book brings some points about this new ground in CT. We hope you find in the present work the sincere desire to collaborate with the dissemination of knowledge. May this book be useful and pleasant to you.",isbn:null,printIsbn:"978-953-51-2158-9",pdfIsbn:"978-953-51-7250-5",doi:"10.5772/59418",price:119,priceEur:129,priceUsd:155,slug:"complementary-therapies-for-the-body-mind-and-soul",numberOfPages:296,isOpenForSubmission:!1,isInWos:1,hash:"48cd88cd7a6ffb4ade0088448e5ac56b",bookSignature:"Marcelo Saad",publishedDate:"September 2nd 2015",coverURL:"https://cdn.intechopen.com/books/images_new/4625.jpg",numberOfDownloads:16232,numberOfWosCitations:10,numberOfCrossrefCitations:6,numberOfDimensionsCitations:17,hasAltmetrics:1,numberOfTotalCitations:33,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 21st 2014",dateEndSecondStepPublish:"November 11th 2014",dateEndThirdStepPublish:"February 7th 2015",dateEndFourthStepPublish:"March 9th 2015",dateEndFifthStepPublish:"April 8th 2015",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"51991",title:"Prof.",name:"Marcelo",middleName:null,surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad",profilePictureURL:"https://mts.intechopen.com/storage/users/51991/images/system/51991.png",biography:"Marcelo Saad, MD, PhD (Brazil), is a physician, board certified in acupuncture. He has a doctorate in the Sciences of Rehabilitation from the Federal University of S. Paulo. He is also current director member of the Spiritist-Medical Association of S. Paulo.\nHe has been invited to the upcoming postgraduate course in Interfaith Hospital Chaplaincy, Santa Marcelina Medical School. Besides his work as a medical acupuncturist in private practice,\nhe is also engaged in scientific publications, editorial collaborations with journals and books, medical lectures, and participation in scholarly tasks. His main interests are religiosity in \nhealthcare, acupuncture, and complementary therapies.",institutionString:"Spiritist Medical Association of Sao Paulo",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"Universidade de Santo Amaro",institutionURL:null,country:{name:"Brazil"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"992",title:"Pharmacology",slug:"complementary-medicine-pharmacology"}],chapters:[{id:"48438",title:"Complementary Therapy with Traditional Chinese Medicine for Treating Atherosclerosis-Related Diseases",doi:"10.5772/60704",slug:"complementary-therapy-with-traditional-chinese-medicine-for-treating-atherosclerosis-related-disease",totalDownloads:1391,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Yu-Chiang Hung, Chun-Ting Liu and Wen-Long Hu",downloadPdfUrl:"/chapter/pdf-download/48438",previewPdfUrl:"/chapter/pdf-preview/48438",authors:[{id:"49804",title:"Dr.",name:"Yu-Chiang",surname:"Hung",slug:"yu-chiang-hung",fullName:"Yu-Chiang Hung"},{id:"49848",title:"Dr.",name:"Wen-Long",surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu"},{id:"175558",title:"Dr.",name:"Chun-Ting",surname:"Liu",slug:"chun-ting-liu",fullName:"Chun-Ting Liu"}],corrections:null},{id:"48326",title:"Acupuncture in Treatment of Chronic Functional Constipation",doi:"10.5772/60521",slug:"acupuncture-in-treatment-of-chronic-functional-constipation",totalDownloads:1431,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Shuqing Ding, Xun Jin, Yijiang Ding, Lingling Wang and Huifeng\nZhou",downloadPdfUrl:"/chapter/pdf-download/48326",previewPdfUrl:"/chapter/pdf-preview/48326",authors:[{id:"173903",title:"Prof.",name:"Shuqing",surname:"Ding",slug:"shuqing-ding",fullName:"Shuqing Ding"}],corrections:null},{id:"49027",title:"Patients Suffering from Intractable Diseases Treated Effectively with Medicines of Kampo and TCM",doi:"10.5772/60573",slug:"patients-suffering-from-intractable-diseases-treated-effectively-with-medicines-of-kampo-and-tcm",totalDownloads:1339,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Yasuyo Hijikata",downloadPdfUrl:"/chapter/pdf-download/49027",previewPdfUrl:"/chapter/pdf-preview/49027",authors:[{id:"68766",title:"Dr.",name:"Yasuyo",surname:"Hijikata",slug:"yasuyo-hijikata",fullName:"Yasuyo Hijikata"}],corrections:null},{id:"49034",title:"Low Back Pain from the Perspective of Traditional Iranian Medicine (TIM)",doi:"10.5772/61170",slug:"low-back-pain-from-the-perspective-of-traditional-iranian-medicine-tim-",totalDownloads:989,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Mohammad Reza Vaez Mahdavi, Mohsen Naseri, Nafiseh Hoseini\nYekta, Younes Roohany, Fatemeh Emadi and Soghrat Faghihzadeh",downloadPdfUrl:"/chapter/pdf-download/49034",previewPdfUrl:"/chapter/pdf-preview/49034",authors:[{id:"73334",title:"Prof.",name:"Mohamad Reza",surname:"Vaez Mahdavi",slug:"mohamad-reza-vaez-mahdavi",fullName:"Mohamad Reza Vaez Mahdavi"},{id:"174289",title:"Prof.",name:"Mohammad Reza",surname:"Vaez Mahdavi",slug:"mohammad-reza-vaez-mahdavi",fullName:"Mohammad Reza Vaez Mahdavi"}],corrections:null},{id:"48746",title:"Anticancer Plants in Islamic Traditional Medicine",doi:"10.5772/61111",slug:"anticancer-plants-in-islamic-traditional-medicine",totalDownloads:1657,totalCrossrefCites:5,totalDimensionsCites:12,signatures:"Behjat Javadi, Milad Iranshahy and Seyed Ahmad Emami",downloadPdfUrl:"/chapter/pdf-download/48746",previewPdfUrl:"/chapter/pdf-preview/48746",authors:[{id:"46265",title:"Dr.",name:"Seyed Ahmad",surname:"Emami",slug:"seyed-ahmad-emami",fullName:"Seyed Ahmad Emami"},{id:"177141",title:"Dr.",name:"Behjat",surname:"Javadi",slug:"behjat-javadi",fullName:"Behjat Javadi"},{id:"177142",title:"Dr.",name:"Milad",surname:"Iranshahy",slug:"milad-iranshahy",fullName:"Milad Iranshahy"}],corrections:null},{id:"48731",title:"Animal Assisted Intervention for Rehabilitation Therapy and Psychotherapy",doi:"10.5772/61117",slug:"animal-assisted-intervention-for-rehabilitation-therapy-and-psychotherapy",totalDownloads:2447,totalCrossrefCites:1,totalDimensionsCites:3,signatures:"Okjin Kim, Sunhwa Hong, Hyun-A Lee, Yung-Ho Chung and Si-Jong\nLee",downloadPdfUrl:"/chapter/pdf-download/48731",previewPdfUrl:"/chapter/pdf-preview/48731",authors:[{id:"174303",title:"Prof.",name:"Okjin",surname:"Kim",slug:"okjin-kim",fullName:"Okjin Kim"},{id:"174309",title:"Prof.",name:"Sunhwa",surname:"Hong",slug:"sunhwa-hong",fullName:"Sunhwa Hong"},{id:"174310",title:"Prof.",name:"Hyun-A",surname:"Lee",slug:"hyun-a-lee",fullName:"Hyun-A Lee"},{id:"175622",title:"Prof.",name:"Yung-Ho",surname:"Chung",slug:"yung-ho-chung",fullName:"Yung-Ho Chung"},{id:"175623",title:"Prof.",name:"Si-Jong",surname:"Lee",slug:"si-jong-lee",fullName:"Si-Jong Lee"}],corrections:null},{id:"48659",title:"Kampo, a Traditional Japanese Medicine, for the Body, Mind, and Soul",doi:"10.5772/60702",slug:"kampo-a-traditional-japanese-medicine-for-the-body-mind-and-soul",totalDownloads:1073,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Shin Takayama, Takehiro Numata, Natsumi Saito, Soichiro Kaneko\nand Tetsuharu Kamiya",downloadPdfUrl:"/chapter/pdf-download/48659",previewPdfUrl:"/chapter/pdf-preview/48659",authors:[{id:"57951",title:"Dr.",name:"Shin",surname:"Takayama",slug:"shin-takayama",fullName:"Shin Takayama"}],corrections:null},{id:"48608",title:"Yoga & Qigong — A Self-reliant Practice for Health of Body & Mind",doi:"10.5772/60568",slug:"yoga-qigong-a-self-reliant-practice-for-health-of-body-mind",totalDownloads:1520,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Ping-chung Leung",downloadPdfUrl:"/chapter/pdf-download/48608",previewPdfUrl:"/chapter/pdf-preview/48608",authors:[{id:"58131",title:"Prof.",name:"Ping-Chung",surname:"Leung",slug:"ping-chung-leung",fullName:"Ping-Chung Leung"}],corrections:null},{id:"48527",title:"Role of Acupuncture in the Treatment of Drug Addiction",doi:"10.5772/60655",slug:"role-of-acupuncture-in-the-treatment-of-drug-addiction",totalDownloads:1210,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Anfeng Xiang, Boyuan Zhang and Sheng Liu",downloadPdfUrl:"/chapter/pdf-download/48527",previewPdfUrl:"/chapter/pdf-preview/48527",authors:[{id:"173908",title:"Dr.",name:"Sheng",surname:"Liu",slug:"sheng-liu",fullName:"Sheng Liu"},{id:"175883",title:"Dr.",name:"Sheng",surname:"Liu",slug:"sheng-liu",fullName:"Sheng Liu"}],corrections:null},{id:"48500",title:"Distant Healing Techniques and Distant Intercessory Prayer – A Tentative Scientific Conciliation",doi:"10.5772/60722",slug:"distant-healing-techniques-and-distant-intercessory-prayer-a-tentative-scientific-conciliation",totalDownloads:1491,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Marcelo Saad and Roberta de Medeiros",downloadPdfUrl:"/chapter/pdf-download/48500",previewPdfUrl:"/chapter/pdf-preview/48500",authors:[{id:"51991",title:"Prof.",name:"Marcelo",surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad"},{id:"62007",title:"Dr.",name:"Roberta",surname:"De Medeiros",slug:"roberta-de-medeiros",fullName:"Roberta De Medeiros"}],corrections:null},{id:"48662",title:"Why is Qi-Invigorating Therapy in Chinese Medicine Suitable for Mitochondrial Diseases? A Bioenergetic Perspective",doi:"10.5772/60675",slug:"why-is-qi-invigorating-therapy-in-chinese-medicine-suitable-for-mitochondrial-diseases-a-bioenergeti",totalDownloads:1693,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Xing-Tai Li, Hai-Xue Kuang and Jia Zhao",downloadPdfUrl:"/chapter/pdf-download/48662",previewPdfUrl:"/chapter/pdf-preview/48662",authors:[{id:"44740",title:"Prof.",name:"Haixue",surname:"Kuang",slug:"haixue-kuang",fullName:"Haixue Kuang"},{id:"73821",title:"Dr.",name:"Xing-Tai",surname:"Li",slug:"xing-tai-li",fullName:"Xing-Tai Li"},{id:"122689",title:"Dr.",name:"Jia",surname:"Zhao",slug:"jia-zhao",fullName:"Jia Zhao"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"2975",title:"Complementary Therapies for the Contemporary Healthcare",subtitle:null,isOpenForSubmission:!1,hash:"604c4ba43197c3ba1506c55c763d4ca7",slug:"complementary-therapies-for-the-contemporary-healthcare",bookSignature:"Marcelo Saad and Roberta de Medeiros",coverURL:"https://cdn.intechopen.com/books/images_new/2975.jpg",editedByType:"Edited by",editors:[{id:"51991",title:"Prof.",name:"Marcelo",surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1316",title:"Acupuncture",subtitle:"Clinical Practice, Particular Techniques and Special Issues",isOpenForSubmission:!1,hash:"60c42faaae3504a330936fc3ff4456ee",slug:"acupuncture-clinical-practice-particular-techniques-and-special-issues",bookSignature:"Marcelo Saad",coverURL:"https://cdn.intechopen.com/books/images_new/1316.jpg",editedByType:"Edited by",editors:[{id:"51991",title:"Prof.",name:"Marcelo",surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"386",title:"Acupuncture",subtitle:"Concepts and Physiology",isOpenForSubmission:!1,hash:"a1b327d1a93e8dfd07289ab0a701aa39",slug:"acupuncture-concepts-and-physiology",bookSignature:"Marcelo Saad",coverURL:"https://cdn.intechopen.com/books/images_new/386.jpg",editedByType:"Edited by",editors:[{id:"51991",title:"Prof.",name:"Marcelo",surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7910",title:"Acupuncture",subtitle:"Resolving Old Controversies and Pointing New Pathways",isOpenForSubmission:!1,hash:"8ee244050594f166365bb63ec51a447a",slug:"acupuncture-resolving-old-controversies-and-pointing-new-pathways",bookSignature:"Marcelo Saad and Roberta de Medeiros",coverURL:"https://cdn.intechopen.com/books/images_new/7910.jpg",editedByType:"Edited by",editors:[{id:"51991",title:"Prof.",name:"Marcelo",surname:"Saad",slug:"marcelo-saad",fullName:"Marcelo Saad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5222",title:"Cannabinoids in Health and Disease",subtitle:null,isOpenForSubmission:!1,hash:"d684a703afd17dc97d18480a982e5316",slug:"cannabinoids-in-health-and-disease",bookSignature:"Rosaria Meccariello and Rosanna Chianese",coverURL:"https://cdn.intechopen.com/books/images_new/5222.jpg",editedByType:"Edited by",editors:[{id:"143980",title:"Prof.",name:"Rosaria",surname:"Meccariello",slug:"rosaria-meccariello",fullName:"Rosaria Meccariello"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"68990",slug:"erratum-application-of-design-for-manufacturing-and-assembly-development-of-a-multifeedstock-biodies",title:"Erratum - Application of Design for Manufacturing and Assembly: Development of a Multifeedstock Biodiesel Processor",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/68990.pdf",downloadPdfUrl:"/chapter/pdf-download/68990",previewPdfUrl:"/chapter/pdf-preview/68990",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/68990",risUrl:"/chapter/ris/68990",chapter:{id:"63204",slug:"application-of-design-for-manufacturing-and-assembly-development-of-a-multifeedstock-biodiesel-proce",signatures:"Ilesanmi Afolabi Daniyan and Khumbulani Mpofu",dateSubmitted:"March 15th 2018",dateReviewed:"July 9th 2018",datePrePublished:"November 5th 2018",datePublished:"January 3rd 2019",book:{id:"7460",title:"Applications of Design for Manufacturing and Assembly",subtitle:null,fullTitle:"Applications of Design for Manufacturing and Assembly",slug:"applications-of-design-for-manufacturing-and-assembly",publishedDate:"January 3rd 2019",bookSignature:"Ancuţa Păcurar",coverURL:"https://cdn.intechopen.com/books/images_new/7460.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"184794",title:"Dr.",name:"Ancuta Carmen",middleName:null,surname:"Păcurar",slug:"ancuta-carmen-pacurar",fullName:"Ancuta Carmen Păcurar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"11921",title:"Prof.",name:"Khumbulani",middleName:null,surname:"Mpofu",fullName:"Khumbulani Mpofu",slug:"khumbulani-mpofu",email:"mpofuk@tut.ac.za",position:null,institution:{name:"Tshwane University of Technology",institutionURL:null,country:{name:"South Africa"}}},{id:"260269",title:"Dr.",name:"Ilesanmi Afolabi",middleName:null,surname:"Daniyan",fullName:"Ilesanmi Afolabi Daniyan",slug:"ilesanmi-afolabi-daniyan",email:"afolabiilesanmi@yahoo.com",position:null,institution:null}]}},chapter:{id:"63204",slug:"application-of-design-for-manufacturing-and-assembly-development-of-a-multifeedstock-biodiesel-proce",signatures:"Ilesanmi Afolabi Daniyan and Khumbulani Mpofu",dateSubmitted:"March 15th 2018",dateReviewed:"July 9th 2018",datePrePublished:"November 5th 2018",datePublished:"January 3rd 2019",book:{id:"7460",title:"Applications of Design for Manufacturing and Assembly",subtitle:null,fullTitle:"Applications of Design for Manufacturing and Assembly",slug:"applications-of-design-for-manufacturing-and-assembly",publishedDate:"January 3rd 2019",bookSignature:"Ancuţa Păcurar",coverURL:"https://cdn.intechopen.com/books/images_new/7460.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"184794",title:"Dr.",name:"Ancuta Carmen",middleName:null,surname:"Păcurar",slug:"ancuta-carmen-pacurar",fullName:"Ancuta Carmen Păcurar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"11921",title:"Prof.",name:"Khumbulani",middleName:null,surname:"Mpofu",fullName:"Khumbulani Mpofu",slug:"khumbulani-mpofu",email:"mpofuk@tut.ac.za",position:null,institution:{name:"Tshwane University of Technology",institutionURL:null,country:{name:"South Africa"}}},{id:"260269",title:"Dr.",name:"Ilesanmi Afolabi",middleName:null,surname:"Daniyan",fullName:"Ilesanmi Afolabi Daniyan",slug:"ilesanmi-afolabi-daniyan",email:"afolabiilesanmi@yahoo.com",position:null,institution:null}]},book:{id:"7460",title:"Applications of Design for Manufacturing and Assembly",subtitle:null,fullTitle:"Applications of Design for Manufacturing and Assembly",slug:"applications-of-design-for-manufacturing-and-assembly",publishedDate:"January 3rd 2019",bookSignature:"Ancuţa Păcurar",coverURL:"https://cdn.intechopen.com/books/images_new/7460.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"184794",title:"Dr.",name:"Ancuta Carmen",middleName:null,surname:"Păcurar",slug:"ancuta-carmen-pacurar",fullName:"Ancuta Carmen Păcurar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"6184",leadTitle:null,title:"Applications in Water Systems Management and Modeling",subtitle:null,reviewType:"peer-reviewed",abstract:"With the growth of urbanization, industrialization, and intensive agricultural practices, all superficial, inland, and marine water bodies have become the repository for large quantities of every type of substance extraneous to the natural aquatic environment. The knowledge of hydrodynamics becomes crucial in this context, as it is the driving mechanism for the movement and transport of these matters and of sediments that become collectors of these substances, in a surface water system. The best way to understand these natural processes is via examples and case studies. This book deals with practical studies of hydrodynamic processes through physical and numerical models. Researchers, together with practicing engineers, will find this book useful in making a rapid assessment of different environmental water body problems.",isbn:"978-1-78923-045-1",printIsbn:"978-1-78923-044-4",pdfIsbn:"978-1-83881-321-5",doi:"10.5772/intechopen.68457",price:119,priceEur:129,priceUsd:155,slug:"applications-in-water-systems-management-and-modeling",numberOfPages:140,isOpenForSubmission:!1,hash:"fba712d6246fe9d253e35b1cdb8cd972",bookSignature:"Daniela Malcangio",publishedDate:"May 2nd 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6184.jpg",keywords:null,numberOfDownloads:5107,numberOfWosCitations:4,numberOfCrossrefCitations:7,numberOfDimensionsCitations:14,numberOfTotalCitations:25,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 13th 2017",dateEndSecondStepPublish:"May 4th 2017",dateEndThirdStepPublish:"July 31st 2017",dateEndFourthStepPublish:"October 29th 2017",dateEndFifthStepPublish:"December 28th 2017",remainingDaysToSecondStep:"4 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"205577",title:"Dr.",name:"Daniela",middleName:null,surname:"Malcangio",slug:"daniela-malcangio",fullName:"Daniela Malcangio",profilePictureURL:"https://mts.intechopen.com/storage/users/205577/images/7230_n.jpg",biography:"Daniela Malcangio is an academic researcher (assistant professor with tenure) in Hydraulics at the Department of Civil, Environmental, Land, Building Engineering and Chemistry (DICATECh), Polytechnic University of Bari, Italy, since May 2012.\nShe graduated in Civil Engineering at the same university in April 2000 with highest grade (110/110). \nIn 2004, she obtained her PhD degree in Waste Disposal and Environmental Protection from the same university.\nHer main research interests include:\nTurbulent jets and plumes\nHydrodynamic interaction between jets and plumes and vegetation\nCirculation of marine currents offshore and onshore\nDiffusion and dilution of discharges in the sea\nShe is the author or coauthor of publications on these topics published in international, peer-reviewed ISI-JCR journals, book chapters, and conference proceedings and reviewer for some ISI-JCR journals.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Polytechnic University of Bari",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"872",title:"Water Resources",slug:"water-resources"}],chapters:[{id:"60379",title:"Introductory Chapter: Applications in Water Systems",slug:"introductory-chapter-applications-in-water-systems",totalDownloads:475,totalCrossrefCites:0,authors:[{id:"205577",title:"Dr.",name:"Daniela",surname:"Malcangio",slug:"daniela-malcangio",fullName:"Daniela Malcangio"}]},{id:"58856",title:"The Effects of Climate Change on Rural-Urban Migration in Sub-Saharan Africa (SSA)—The Cases of Democratic Republic of Congo, Kenya and Niger",slug:"the-effects-of-climate-change-on-rural-urban-migration-in-sub-saharan-africa-ssa-the-cases-of-democr",totalDownloads:1195,totalCrossrefCites:2,authors:[{id:"148090",title:"Dr.",name:"Gurudeo",surname:"Tularam",slug:"gurudeo-tularam",fullName:"Gurudeo Tularam"},{id:"208956",title:"Mr.",name:"Omar",surname:"Moalin Hassan",slug:"omar-moalin-hassan",fullName:"Omar Moalin Hassan"}]},{id:"57637",title:"Identifying Water Network Anomalies Using Multi Parameters Random Walk: Theory and Practice",slug:"identifying-water-network-anomalies-using-multi-parameters-random-walk-theory-and-practice",totalDownloads:469,totalCrossrefCites:0,authors:[{id:"208877",title:"Dr.",name:"Eyal",surname:"Brill",slug:"eyal-brill",fullName:"Eyal Brill"},{id:"209006",title:"MSc.",name:"Barak",surname:"Brill",slug:"barak-brill",fullName:"Barak Brill"}]},{id:"58415",title:"Segmentation of Water Body and Lakeshore Changes behind an Island Owing to Wind Waves",slug:"segmentation-of-water-body-and-lakeshore-changes-behind-an-island-owing-to-wind-waves",totalDownloads:667,totalCrossrefCites:1,authors:[{id:"13491",title:"Dr.",name:"Takaaki",surname:"Uda",slug:"takaaki-uda",fullName:"Takaaki Uda"},{id:"122917",title:"Dr.",name:"Masumi",surname:"Serizawa",slug:"masumi-serizawa",fullName:"Masumi Serizawa"},{id:"208350",title:"Ms.",name:"Shiho",surname:"Miyahara",slug:"shiho-miyahara",fullName:"Shiho Miyahara"}]},{id:"59309",title:"Assessing the Hydrodynamic Pattern in Different Lakes of Malaysia",slug:"assessing-the-hydrodynamic-pattern-in-different-lakes-of-malaysia",totalDownloads:509,totalCrossrefCites:2,authors:[{id:"186369",title:"Dr.",name:"Zati",surname:"Sharip",slug:"zati-sharip",fullName:"Zati Sharip"},{id:"220302",title:"Mr.",name:"Shahirwan",surname:"Aman Shah",slug:"shahirwan-aman-shah",fullName:"Shahirwan Aman Shah"},{id:"220303",title:"Mr.",name:"Aminuddin",surname:"Jamin",slug:"aminuddin-jamin",fullName:"Aminuddin Jamin"},{id:"220304",title:"Mr.",name:"Juhaimi",surname:"Jusoh",slug:"juhaimi-jusoh",fullName:"Juhaimi Jusoh"}]},{id:"60177",title:"Application of a Hydrodynamic and Water Quality Model for Inland Surface Water Systems",slug:"application-of-a-hydrodynamic-and-water-quality-model-for-inland-surface-water-systems",totalDownloads:1245,totalCrossrefCites:2,authors:[{id:"169118",title:"Dr.",name:"Lubo",surname:"Liu",slug:"lubo-liu",fullName:"Lubo Liu"}]},{id:"58244",title:"Optical Methods Applied to Hydrodynamics of Cohesive Sediments",slug:"optical-methods-applied-to-hydrodynamics-of-cohesive-sediments",totalDownloads:551,totalCrossrefCites:0,authors:[{id:"207783",title:"Dr.",name:"Juan Antonio",surname:"Garcia Aragon",slug:"juan-antonio-garcia-aragon",fullName:"Juan Antonio Garcia Aragon"},{id:"207868",title:"Dr.",name:"Humberto",surname:"Salinas Tapia",slug:"humberto-salinas-tapia",fullName:"Humberto Salinas Tapia"},{id:"207869",title:"Dr.",name:"Victor",surname:"Diaz Palomarez",slug:"victor-diaz-palomarez",fullName:"Victor Diaz Palomarez"},{id:"216620",title:"MSc.",name:"Klever",surname:"Izquierdo-Ayala",slug:"klever-izquierdo-ayala",fullName:"Klever Izquierdo-Ayala"}]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"220806",firstName:"Julian",lastName:"Virag",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/220806/images/6089_n.jpg",email:"julian@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6886",title:"Water and Sustainability",subtitle:null,isOpenForSubmission:!1,hash:"f01b34abf4b3d3329dda4921c461fcf4",slug:"water-and-sustainability",bookSignature:"Prathna Thanjavur Chandrasekaran",coverURL:"https://cdn.intechopen.com/books/images_new/6886.jpg",editedByType:"Edited by",editors:[{id:"167917",title:"Dr.",name:"Prathna",surname:"Thanjavur Chandrasekaran",slug:"prathna-thanjavur-chandrasekaran",fullName:"Prathna Thanjavur Chandrasekaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8098",title:"Resources of Water",subtitle:null,isOpenForSubmission:!1,hash:"d251652996624d932ef7b8ed62cf7cfc",slug:"resources-of-water",bookSignature:"Prathna Thanjavur Chandrasekaran, Muhammad Salik Javaid, Aftab Sadiq",coverURL:"https://cdn.intechopen.com/books/images_new/8098.jpg",editedByType:"Edited by",editors:[{id:"167917",title:"Dr.",name:"Prathna",surname:"Thanjavur Chandrasekaran",slug:"prathna-thanjavur-chandrasekaran",fullName:"Prathna Thanjavur Chandrasekaran"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"45395",title:"Curative Radiotherapy in Metastatic Disease: How to Develop the Role of Radiotherapy from Local to Metastases",doi:"10.5772/56556",slug:"curative-radiotherapy-in-metastatic-disease-how-to-develop-the-role-of-radiotherapy-from-local-to-me",body:'Metastasis is the leading cause of cancer death and in patients with proven distant metastases from solid tumors, it has been a notion that the condition is incurable and the treatment is usually conducted with palliative intent, with rare exceptions. Treatment predominantly involves the use of systemic chemotherapy, targeted radiotherapy or local measures typically reserved for symptom relief (Argiris, 2004; Escudier, 2007; Hurwits, 2004). Chemotherapy is delivered without expectation of long term survival, except for highly chemosensitive malignancies, such as leukemia, lymphoma, and germ cell tumors. According to the conventional treatment strategy for solid tumors, the presence of metastatic disease is a contraindication for local therapy because it is believed that these tumor cells have already spread systemically. However, from the viewpoint of reducing tumor burden, local therapy may be an adequate strategy when the target lesions account for the major portion of the total tumor volume. The local therapies are metastasectomy, heating or cooling, and radiotherapy.
In a subset of patients with a limited number of metastases or oligometastases, local ablative therapy, such as surgical resection, can potentially yields favorable outcomes. For instance, in surgical literature, it has been demonstrated that surgical resection of limited lung and liver metastases has results in prolonged survival and possibly cure in a significant proportion of patients with oligometastases (Fong, 1999; Friedel, 1994). International registry of lung metastases reported that lung metastasectomy is a safe and curative procedure in selected patients with disease free interval (DFI) ≥ 3 years, single lesion and germ cell tumor (Pastorino, 1997). And the lung and liver metastasectomy is a surgical approach used in colon and breast cancers, with upto 22% of colon cancer patients surviving 10 years and 35-46% of breast cancer patients surviving upto 5 years (Fong et al, 1999; Friedel et al, 1994; Pocard et al, 2001). However, resection may not be feasible in patients of extremely advanced age or with poor cardiopulmonary function or multiple comorbidities because of the risk of significant morbidity and mortality in these settings. In such patients, external radiotherapy is often the treatment of choice. However, this treatment also has its drawbacks, including the potential to damage adjacent or nearby structures and its association with a local failure rate that is higher than that was seen in resection. To minimize collateral injury to normal tissues, adequate fractionation (e.g. 1.8-2.0 Gy/fraction) over 6 to 7 weeks is commonly used. The use of radioablative treatment such as using stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) to overcome problems with normal tissue injury in patients with medically inoperable metastatic tumor has now been actively studied at many institutions.
In 1889, Paget’s “seed and soil” hypothesis stated that the development of a metastasis depends on cross talk between selected cancer cells (the seed) and a specific organ microenvironment (the soil) (Paget, 1889). This means that successfully establishing a distant metastasis depends on certain properties of the host organ as well as those of tumor cells. Dissemination of tumor cells in general circulation does not necessarily mean that wide spread metastatic disease will always develop. This hypothesis is still widely accepted. Observing the natural history of breast cancer, Hellmann and Weichselbaum hypothesized the existence of an intermediate state between widespread metastatic disease and locally confined disease and coined the term “oligometastases” (Hellman & Weichselbaum, 1995). Thus, local control of oligometastatic disease may allow better systemic control. In addition, thanks to the evolution of radiologic imaging technique, detection of metastasis at a size previously impossible to be detected may result in under treatment and an effective chemotherapy may downstage these metastatic diseases to oligometastases.
Clinically, there are two types of oligometastases. The De novo type is the tumor early in the evolution of metastatic progression producing metastasis that are limited in number and location, and the induced type is generated when effective systemic chemotherapy eradicates the majority of metastatic deposits in a patients with wide spread metastatic disease (MacDermed, 2008).
In a retrospective study, Mehta et al tracked the number of individual metastatic sites and the number of organs involved using serial computerized tomography of the body in 38 patients with stage IIIb or IV non small cell lung cancer treated with chemotherapy. Seventy four percent of patients (n=28) had a metastatic disease limited to 1-2 organs and 50% (n=29) had a disease limited to the primary tumor and three or less metastatic lesions at presentation. Fifty percent (n=19) had stable (n=12) or progressive (n=7) disease in initially involved site without development of new metastatic lesion. Among the 17 patients with four or fewer metastatic sites with no pleural effusions, 65% (n=11) had stable or progressive disease in initially involved sites without development of new metastatic lesions (Mehta, 2004). The results of this study suggest that a subset of patients with oligometastases from lung cancer may benefit from a combination of systemic chemotherapy and local aggressive therapy. In another study, records of 387 patients with advanced non small cell lung cancer were reviewed and 64 patients with measurable advanced stage non small cell lung cancer who received first line systemic chemotherapy and follow up were identified. Thirty four patients were deemed theoretically SBRT eligible. Disease in the lung and liver was limited to ≤ 3 sites each. Among the 34 SBRT eligible patients, the pattern of failure were local only in 68%, distant only in 14%, and mixed in 18%. The time to first progression was 3.0 months in those with local only failure (Rusthoven, 2009). The results of this study suggest that SBRT may improve the time to first progression in a significant proportion of patients with metastatic non small cell lung cancer. After all, because any patient with oligometastatses may exist in a spectrum between orderly metastatic progressions and wide spread occult disease, the role of the local modality to ablate oligometastases need to be determined.
The scientific study and clinical practice of oncology have progressed remarkably in recent years. Insights into molecular interactions occurring within a cancer cell have been translated into novel medical treatments, and a variety of technological advances have allowed new surgical and radiotherapeutic techniques. Within the discipline of radiation oncology in particular, the fusion of state-of the-art tumor imaging with precision radiation treatment delivery systems has created an opportunity to shift from the classic radiation therapy paradigm of administering thirty or more individual allow-dose treatments toward briefer, more intense, and more potent regimens in which a much higher dose per treatment is used for greater clinical effect. Stereotactic body radiation therapy (SBRT) refers to an emerging radiotherapy procedure that is highly effective in controlling early stage primary and oligometastatic cancers at locations throughout the abdominopelvic and thoracic cavities, and at spinal and paraspinal sites. The major feature that separates SBRT from conventional radiation treatment is the delivery of large doses in a few fractions, which results in a high biological effective dose (BED). In order to minimize the normal tissue toxicity, conformation of high doses to the target and rapid fall-off doses away from the target is critical. The practice of SBRT therefore requires a high level of confidence in the accuracy of the entire treatment delivery process.
In SBRT, radiation is targeted almost exclusively to the tumor, while tissues not grossly involved with the tumor are spared. However, unique radiobiology of SBRT that ensures maximal tumor control but minimal normal tissue complication is what really sets SBRT apart from other radiotherapy techniques. Additional defining characteristics of SBRT include the abilities to securely immobilize the patient for the typically long treatment sessions; to accurately duplicate patient position between simulation and treatment; to minimize normal tissue exposure through the use of multiple- or large angle, arcing, small-aperture fields; to rigoursly account for organ motion; to stereoctactically register tumor target and normal tissue structures; and to deliver ablative dose fractions with subcentimeter accuracy to the patient (Timmerman, 2007).
Immobilization and repositioning devices include the Elekta Stereotactic Body Frame™ (Elekta, Norcross, Ga., USA), the Leibinger stereotactic body fixation system (Stryker, Kalamazoo, Mich., USA), and the Medical Intelligence Bodyfix™ system (Medical Intelligence, Schwabmuenchen, Germany).
Several systems provide one or another solution to the problem of respiratory motion. A breath-hold device is the Active Breathing Coordinator™ (Elekta), which allows coordination of beam-on time during a fixed level of inspiration; a respiratory gating system is the RPMTM (Varian, Palo Alto, USA) which tracks inspiration and expiration and turns the accelerator off when indicators predict that the tumor position is outside of an acceptable range of distance from baseline; a another gating system is the ANZAI (Anzai, Japan).
Various system of Stereotactic Body Radiation Therapy (SBRT)
Also now available for purchase are specialized SBRT-ready linear accelerators that combine capacity for image-guided radiotherapy with compatibility with modern immobilization and respiratory motion solution technology. The Novalis™ (BrainLAB, Inc.), Elekta Synergy™, Varian Trilogy™, Siemens Atiste™ System, Tomotherapy HiArt™ System (TomoTherapy, Madison, Wisc., USA), and Cyberknife™ (Accuray, Sunnyvale, Calif., USA) are linear accelerators for SBRT (Fig. 1).
The most prevalent method of radiotherapy in the past 100 years of radiation oncology has been a strategy known as protracted fractionation in which daily small doses of radiation (e.g. 1.8~4 Gy) are delivered repeatedly over many days. The basis of this method of radiotherapy was that normal tissue repairs sublethal injury between fractions better than does tumor tissue. With the advent of SRS to treat intracranial tumors, an alternatively strategy of giving an ablative dose (e.g. 12~30 Gy) was born. A SBRT is an extension of this technique to deliver ablative radiotherapy (8~30 Gy) to extracranial sites. When alternate fractionation schemes are considered, we need some model for calculating isoeffect doses and a linear quadratic (LQ) formalism is most commonly used for quantitative prediction of dose/fractionation dependencies. The LQ model approximates clonogenic survival data with a truncated power series (second order polynomial) expansion of natural log of S (surviving proportion) as follows (see Equation 1).
The d is daily dose and α & β are expansion parameters: α is the slope of the survival curve at the limit d→0, and β is the parameter determining the relative contribution from the quadratic component (Fig. 2A). This model was initially derived to fit experimental observation of the effects of dose and fractionation on cell survival, chromosomal damage, and acute radiation effects. Later, some ascribed underlying biological mechanism to the mathematical terms, primarily the formation of single- and double-strand break in DNA. The LQ model has been useful for predicting and understanding the effects of conventional fractionated radiotherapy. The biological effective dose (BED) is a characteristic dose value that facilitated comparisons between the effects of different dose fractionation schemes. The BED is defined as the total dose delivered in an infinite number of infinitesimally small dose fractions that has the same biologic effect as the dose fractionation scheme in question and described as BED=D*[1+d/(α/β)].
This BED based on LQ model is known reasonably predictive of dose response relation, both in vivo and vitro, in the dose per fractions range of 2 to 15 Gy (Brenner, 2008), however, the LQ model predicts a continuously bending curve in the high dose range and experimentally measured data have decidedly shown a linear relationship between the dose and log of the proportion of surviving clonogen. In addition, in the early phase of its development, one of the developers of the LQ model stated that “LQ is not intended for doses higher than 8-10 Gy. In any case, LQ is simply a loose dose approximation to equation
Shape of survival curve for mammalian cells exposed to radiation. The fraction of cells surviving is plotted on a logarithmic scale against on a linear scale. For α-particles or low energy neutrons (said to be densly ionizing), the dose-response curve is a straight line from the origin (i.e., survival is an exponential function of dose). The survival curve can be described by just one parameter, the slope. For X- or γ-rays (said to be sparsely ionizing), the dose-response curve has an initial slope, followed by a shoulder; at higher dose, the curve tends to become straight again. A: The linear quadratic model. The experimental data are fitted to a linear quadratic function. There are two components of cell killing: One is proportional to dose (αD); the other is proportional to the square of the dose (βD2). The dose at which the linear and quadratic components are equal is the ratio α/β. The linear quadratic curve bends continuously but is a good fit to experimental data for the first few decades of survival. B: The multitarget model. The curve is described by the initial slope (D1), the final slope (D0), and a parameter that represents the width of the shoulder, either n or Dq (Hall, 2006).
that do become straight exponential at higher dose” (Hall, 1993). Thus, LQ model overestimates the effect of radiation on clonogenicity in the high dose commonly used in SBRT and inappropriate to apply at the high doses per fraction encountered in radiosurgery because it (1) does not accurately explain the observed (in vivo) data; (2) was derived largely from, in vitro, rather than in vivo, observations and, thus, does not consider the impact of ionizing radiation on the supporting tissues; (3) does not consider the impact of subpopulation of radioresistant clonogens (ie, the “cancer stem cell” response); and (4) creates a “false belief” that this simplified model represent an absolute truth (Kirkpatrick, 2008). Substantial modifications are needed to apply the LQ model to the SBRT regimen; at which point the model loses its simplicity and natural appeal (Guerrero & Li, 2004). The multitarget model (Fig. 2B) provides an alternative description of the clonogenic survival as a function of radiation dose and is still valuable because it fits the empirical data well, especially in the high dose range. In a study of University of Texas, Park et al proposed a new model, universal survival curve (USC), to reconcile the strengths of these LQ model and multitarget model into single, unifying model and stressed that the proposed survival curve model (Fig. 3) (Park, 2008).
Universal survival curve (USC) and transition between dose range at which linear quadratic (LQ) model is valid and dose range at which multitarget model is valid. Below transition dose DT, USC curve is identical with LQ model curve and above DT, USC curve is identical with terminal linear portion of multitarget model curve.
The USC model can be used to derive isoeffective relations (equivalent dose function) of any arbitrarily fractionated RT. For SBRT, a novel concept of the single fraction equivalent dose (SFED) can serve as an alternative and more intuitive way to compare different dose fractionation schemes. SFED was defiend as the dose delivered in a single fraction that would have the same biologic effects as the dose fractionation scheme in question. For total dose D given in n fractions, each fraction with the dose, d, SFED is determined by the intersection line crossing the effective survival curve at D=d*n (Fig. 4) (Park, 2008).
Graphic representation of stereotactic body radiotherapy (SBRT) and conventionally fractionated radiotherapy (CFRT) effective survival curves compared with single fraction equivalent dose (SFED) and biological effective dose (BED). Note, DCFRTand DSBRT are always situated between biologically equivalent dose parameters of SFED and BED.
The definition of BED and SFED using the USC curve remain applicable for any fractionation regimen. The ln S in fractionated conventional fractionated radiation therapy (CFRT) and SBRT is calculated (see Equation 2A and 2B).
Thus, Equations. 2A and 2B are arranged to reflect the common clinical practice in designing dose fraction scheme in which dCFRT and nCFRT is varied for CFRT, and nSBRT is fixed and dSBRT is varied for SBRT. By letting dCFRT=2 Gy, the equation for DCFRT can be used to calculated the standard effective dose (SED), total dose in 2 Gy fractions with equivalent effect (see Equation 3A and 3B).
From the report of 12 non small cell lung cancer cell lines from National Cancer Institute, the value for α, D0 or Dq was obtained by determining the arithmetic mean values of each parameter. The range of Dq was wide, between 1.5 Gy and 2.5 Gy. The mean value for α, D0, and Dq was 0.33 Gy-1, 1.25 Gy and 1.8 Gy, respectively (Carmichael, 1989; Morstyn, 1984). The transition dose, DT was calculated to be 6.2 Gy, reassuring results, because the dose per fraction used in CFRT is < 6.2 Gy and SBRT regimens commonly use a dose per fraction > 6.2 Gy. This USC is a new model that may offer a superior description of the mammalian cell survival curve in the ablative dose range beyond the shoulder, on the same time, preserving all the strengths of the LQ model in the low dose range (around the shoulder). However, the true survival of in vivo tumors depends on multiple factors that cannot possibly be contained in simplified mathematical formulas. The only way to truly know the tumor control rates or the tolerance of different fractionation schemes is through performing prospectively designed trial.
In delivering SBRT, many commercially available units can be utilized. Sophisticated image guidance is a common feature to these treatment units. Units equipped with online image-guided radiation therapy (IGRT) capability minimize the uncertainty associated with tumor localization. In-house developed systems such as RT-RT and CT-on-rails were employed prior to the widespread availability of in-treatment-room imaging. Recent developments have spread the availability of in-treatment-room imaging to many facilities.
The first commercially available cone beam CT (CBCT) IGRT system was the Elekta Synergy™ (Elekta, Crawley, UK), the other medical linear accelerator (linac) manufacturers have also now embraced the IGRT concept and have either produced their own version of an IGRT linac, Varian Trilogy™ (Varian Medical Systems, Palo Alto, Calif., USA), or are in the process of such developments, Siemens ARTÍSTE™ (Siemens Medical Solutions USA, Inc., Malvern, Pa.,USA). The Synergy and Trilogy consists of a retractable kV X-ray source, an amorphous silicon flat panel imager mounted on the linear accelerator perpendicular to the radiation beam direction, and a software module (referred to as the XVI system). The system provides planar, motion, and volumetric images.
For CBCT image acquisitions, the gantry is rotated around the patient for a preset angle (between 180° and 360° to allow sufficient data acquisition) and images are acquired via an amorphous silicon panel. Volumetric image reconstruction is performed simultaneously with the acquisition to expedite the process. The reconstructed three-dimensional geometry is subsequently registered with the reference geometry planning image, either manually or automatically (using either soft tissue or bone mode). For some disease sites, such as prostate cancer, the soft tissue mode is conceptually ideally suited, since the prostate often moves relative to the bones. However, at present, it is difficult to visualize the prostate in all cases, and thus implanted radiopaque seeds are used to make the registration process more efficient. Based on the registration, the difference between the data sets is calculated and displayed as translation along and rotation about the three axes. Subsequent treatment table adjustments are made and the patient treated. One can clearly appreciate that CBCT-based IGRT shows great potential for objective, precise positioning of patients for treatment, matching the treatment setup image model to that of the planning image model. It remains to be determined exactly which imaging features on the integrated CBCT linacs (i.e., kVp CBCT, planar, motion, and MV electronic portal imaging device) are best suited for a particular disease site.
Helical tomotherapy was first proposed by Mackie et al. in 1993 and is now commercially available as the TomoTherapy HI -ART system (TomoTherapy, Inc., Madison, Wisc., USA). A short in-line 6-MV linac (Siemens Oncology Systems, Concord, Calif., USA) rotates on a ring gantry at a source-axis distance of 85 cm. The IMRT treatment is delivered while the patient support couch is translated in the y-direction (toward the gantry) through the gantry bore, in the same way as a helical CT study is conducted. In the patíent’s reference frame, the treatment beam is angled inwards along a helix with the midpoint of fan beam passing through the center of the bore. Similar to helical CT, the treatment beam pitch is defined as the distance traveled by the couch per gantry rotation, divided by the field width in the y-direction. The width of the beam in the y-direction is defined by a pair of jaws that is fixed, for any particular patient treatment, to one of three selectable values (1, 2.5 or 5 cm). Laterally, the treatment beam is modulated by a 64 leaf binary multileaf collimator, whose leaves transition rapidly between open and closed states providing a maximum possible open lateral field length of 40 cm at the bore center. Highly modulated treatments can achieve great conformality, though they inevitably take longer to deliver. A helical MV CT image is acquired prior to treatment each day using the on-board xenon CT detector system and the 6-MV linac (detuned to 3.6 MV). Registration software is provided to compare the daily patient setup image with the stored prescription CT planning image. After image registration, table adjustments are then automatically made and the patient is then treated.
The only MV Cone Beam CT (CBCT) system currently available is the most recent addition to the family of in-room 3D systems designed for IGRT. The MV CBCT imaging system consists of a 6-MV x-ray beam produced by a conventional linear accelerator (Oncor, Siemens AG, Erlangen, Germany) equipped with an amorphous-silicon EPID (AG9-ES, PerkinElmer Optoelectronics, Waltham, MA., USA) flat panel detector. The system is controlled by a computer workstation (Syngo Coherence RTT, Siemens AG, Erlangen, Germany) that is responsible for all tasks related to portal or MV CBCT imaging, including calibration of the system, quality assurance, image acquisition, and image registration (2D or 3D) for patient alignment. The use of MV photons for imaging is a departure from conventional preferences of using kilovoltage (kV) photons, which have resulted in superior image quality for diagnostic purposes. The MV CBCT system is capable of measuring setup errors of fiducials in an anthropomorphic head phantom with submillimeter accuracy and reproducibility. The gantry rotates in a continuous 200° arc (270° to 110°) while acquiring one low-dose portal image per degree. The 200 projection images acquired are then used for MV CBCT reconstruction, which is completed approximately 2 minutes after the starts with an automatic registration, based on a maximization of mutual information algorithm, which utilizes all information in both 3D images to maximize the alignment of similar structures.
Routine quality assurance on the system has also demonstrated that the calibrated MV CBCT imaging isocenter remained within 1 mm to the machine treatment isocenter over a period of 1 year. As for the field-of-view, anatomical information situated in a 27 X 27 X 27 cm3 volume centered at isocenter is reconstructed in the MV CBCT system with a half-beam acquisition mode should increase the reconstruction size in the axial plane by up to 40 cm.
Vero SBRT is specifically designed for IGRT and a new type of 6 MV linac with attached MLC is mounted on an O-ring gantry. The MLC consists of sixty 5-mm-leaves and produces a maximum field size of 150 x 150 mm2. The gantry rotates 360 degree and the horizontal axis, similar to a C-arm linac platform, but additionally allows rotation about the vertical axis. The system incorporates the MHI-TM2000 linear accelerator and sophisticated software to deliver radiation therapy. The system is equipped with a dual orthogonal kV imaging systems attached to the O-ring at 45 from the MV beam. This imaging system allows simultaneous acquisition of orthogonal X-rays images and fluoroscopy. Also kV CBCT imaging is available. Vero SBRT dynamically contours the treatment beam exactly to the tumor from every angle as the machine moves around the patient. Furthermore, Vero’s technology allows clinicians to dynamically treat with a moving beam in order to spare surrounding healthy tissue and organs while maximizing such as x-ray, CT and fluoroscopy, so that clinicians can modify their plans during treatment as needed. The targeted beam adapts to breathing and other body movements to maintain safe, complete and accurate dose delivery.
One of the earliest applications of electromagnetic tracking in RT was for the nonradiographic localication of interstitial abdominal implants for intraoperative high-dose-rate (HDR). In this application a then-commercially available 3SPACE-FASTRAK system (Polhemus Inc, Colchester, VT., USA) was configured to fit in the lumen of a catheter. The system was then used to measure the spatial path of all catheters by inserting the wired sensor sequentially into each catheter. This information was then used by the planning system to accurately determine and calculate dwell positions and times. The stated accuracy of the system was a root mean square (RMS) of 0.8 mm, but measurements in the operating environment found the RMS accuracy to be 0.38 mm in the absence of metallic surgical retractors and 0.70 mm in the presence of three retractors, with maximum absolute errors of 2.1 mm or less.
In 2000, the Paul Scherrer Institute reported on an electromagnetic tracking system they had developed for real-time (50 Hz) target volume tracking during proton therapy with continuous spot scanning delivery. This system consisted of an external magnetic field generator, a wired implantable sensor, and the associated signal processing electronics. When compared with an optical tracking device with 30 μm accuracy, the RMS spatial accuracy was reported to be 1 mm to 2 mm, whereas the RMS angular accuracy of determining the orientation of the dipole was 0.5 to 1 degree. The system’s ability to track and gate was tested in a moving phantom and qualitatively shown to very nearly restore the dose distribution to the planned static distribution when a 3-mm gating window was implemented. The technology for this system was developed by a spin-off company from the Paul Scherrer Institute called Mednetix AG, which was acquired by Northern Digital Inc (Waterloo, ON, Canada). Further development efforts have focused on a wired electromagnetic tracking system for guidance of medical instruments, which is commercially available in the Aurora system.
The use of a small X-band linear accelerator mounted on an industrial robot was first developed for radiosurgery. The robot provides the capability of aiming beamlets with any orientation relative to the target volume. The system uses two ceiling-mounted diagnostic X-ray sources, and amorphous silicon image detectors mounted flush to the floor. The treatment is specified by the trajectory of the robot and by the number of monitor units delivered at each robotic orientation. During the patient\'s treatment, the Cyberknife System correlates live radiographic images with preoperative CT or MRI scans in real time to determine patient and tumor position repeatedly over the course of treatment. More details are provided by users of this system in subsequent articles in this volume.
SBRT requires precise delineation of patient anatomy, targets for planning, and clear visualization for localization during treatment delivery. Three-dimensional data sets assembled from CT or 4DCT for visualizations and dose calculation and/or MRI and positron emission tomography (PET) images assist in target and visualization for SBRT.
Respiratory correlated 4DCT was developed over the past several years to address the issues of respiratory motion in radiotherapy targeting (Rietzel, 2005). Respiration-correlated CT uses a surrogate signal, such as the abdominal surface, respiratory air flow, or internal anatomy to provide a signal that permits resorting of the reconstructed image data, resulting in multiple coherent spatiotemporal data sets at different respiratory phases. The scan time for 4DCT with multi-slice scanners is on the order of a few minutes, and post-processing takes an additional 30 min if manual phase selection is required. The output of this process is typically 10 CT volumes, each with a temporal resolution of approx. 1/10 of the respiratory period. 4DCT uses multi-slice CT scanners combined with a respiratory surrogate to develop a series of 3DCT scans each representing the patient in a different respiratory phase. The entire 4DCT dataset can be used to determine an envelope of tumor motion which can be expanded to include areas of subclinical disease resulting in an internal target volume (ITV) (ICRU 1999) which can be used as the treatment target. Alternatively, select phases from the 4DCT can be used to determine an ITV that only covers a select range of respiratory phases (i.e. 40%-60% corresponding to a ± 10% window around end exhalation) that would be the target for gated treatments. The most common form of motion management used in RTOG studies to date and also at many experienced centers using SBRT across the world has been chest wall breathing with abdominal compression. Chest wall breathing exerts forces on the intrathoracic tissues in multiple opposing directions in contrast to the mostly craniocaudal force vectors associated with diaphragmatic breathing. As a result, the amplitude of tumor motion with chest wall breathing can be significantly decreased. With this technique, the patient is first coached to expand the lungs using their upper chest wall rather than by moving their diaphragm toward their abdomen.
The 4DCT implementation relies on sensing the respiratory phase by using the Varian RPM system or Anzai system. 4DCT provides an imaging tool to quantify and characterize tumor and normal tissue shape and motion as a function of time. This provides the radiation oncologist and treatment planner with information essential in the design of an aperture that more adequately covers the internal target volume (assuming respiration during treatment is reproducible to that during CT simulation). 4DCT data can also be used as input in making treatment decisions on when to intervene with gating or other motion management strategies. In addition, the 4DCT data can be used as direct input into four-dimensional treatment planning, and to generate time-varying dose-volume histograms or isodose distributions. An effective method of conveying the utility of 4DCT is through computer animation. Dr. Choi et al. [pers. commun., 2005] have found that approximately one half of patients with early-stage disease have motion of less than 10 mm during quiet breathing (in approx. 100 cases). Seppen woolde et al. reported on the motion of 21 lesions in 20 patients and found a mean motion of 5.5 mm in the craniocaudal direction (data ranged from 0 to 2.5 cm). Average periodicity was observed to be 3.5 s, and ranged from 2.8 to over 6 s. The clinical importance of 4DCT is that it provides insight into patient-specific organ motion.
Overview of respiratory phase “bin” generation from four-dimensional computed tomography data.
SBRT treatments do not use invasive external frames. A body frame system has been developed that incorporates several features to ensure reproducible setup, including a vacuum bag that is fit to the patient at the time of simulation, a scale that facilitates reproducible positioning of the patient in the frame, an abdominal compression paddle to restrict abdominal motion, and external fiducial markers to improve setup accuracy (Lohr, 1999; Hadinger, 2002). This system is particularly useful when the patient is to be imaged in one room and the entire patient/body frame system is moved to the treatment room. Without a body frame, either implanted fiducial markers or in-room volumetric imaging is required for accurate internal soft tissue-based setup.
One technique for minimizing the effects of respiratory motion is to activate the radiation beam only when the tumor is at a predetermined location in the respiratory cycle. This is referred to as respiratory gating (Shirato, 2000; Starkschall, 2004; Nelson, 2005; Underberg, 2005). The use of gating requires some measure of the tumor location within the respiratory cycle, which can be done directly but is more often done through some respiratory surrogate such as abdominal height or diameter. Spirometry has also been used to gate based on tidal volume (Zhang, 2003).
Alternative motion management techniques include dynamic gating and breath-hold techniques. During dynamic gating the patient is allowed to breath normally with or without audio or visual coaching and the radiation beam is activated only when the patient reaches the planned points in their respiratory cycle. Breath-hold gating requires the patient to hold their breath at a given abdominal height or tidal volume generally with the aid of visual feedback and the radiation beam is activated only when the patient is holding their breath in this target position. The breath-hold can either be voluntary or assisted with an occlusion valve. Breath-hold has several benefits over dynamic gating including the ability to do volumetric imaging over a series of breath holds, longer irradiation times to allow radiotherapy beams to stabilize, and the ability to expand the lungs and give more fall-off distance between the target and nearby critical structures.
Gating is performed with real time or near time verification of the target position in the gate with in-treatment-room imaging. An early example of in-treatment-room imaging was developed by Shirato et al. (Shirato, 1999) who developed a real-time tumor tracking method in which four sets of x-ray tubes and fluoroscopic imagers are used to measure the position of four implanted radiopaque markers relative to the isocenter. The linear accelerator was configured so that it irradiated the tumor only when the markers were within certain coordinates. This system is effective for the treatment of lung tumors but requires the invasive implantation of fiducial markers. In addition this system has not become commercially available. A similar method is used by two commercially available stereotactic systems, Novalis®/Exactrac® (BrainLAB, Feldkirchen, Germany) (Yin, 2002) and Cyberknife® (Accuray, Sunnyvale, CA) (Adler, 1997). These systems both have room mounted orthogonal x-ray systems that can observe the patient’s anatomy in the treatment position. Implanted fiducial markers are required for all lung tumors on the Novalis® system but the Cyberknife® can use either fiducial markers or direct imaging depending on the tumor location. The Novalis® system does not employ real-time tumor tracking but rather relies on a relationship between external surrogates and the tumor position developed immediately prior to treatment. Cyberknife® can either confirm the position of the target at regular intervals during treatment or utilize a respiratory tracking system that continuously synchronizes beam delivery to the motion of the target.
Non-radiographic localization was investigated by Balter et al. (Balter, 2005) who studied the use of the Calypso™ 4D system for patient positioning based on real-time localization of implanted electromagnetic transponders (beacons). This study demonstrated the accuracy of the system before clinical trials were conducted. The system consists of 5 major components: wireless transponders, a console, a detector array, a tracking station and infrared cameras. The array emits electromagnetic radiation that excites the implanted transponders. Due to the resonance response the array can locate the 3D coordinates of the wireless transponders. The infrared cameras allow the registration of the position of the array relative to the isocenter of the linear accelerator. This system offers the potential for real-time tracking and is commercially available for prostate but not yet for other body sites including the lungs
An important goal of a quality assurance (QA) program is to instill confidence that patients are receiving their prescribed treatments accurately. The goal should not be simply getting through some mandatory tests as quickly and painlessly as possible. Unfortunately, many catastrophic events are produced by failures happening at a moment that cannot be predicted or caught by routine quality control (QC) procedures. As there are built-in interlocks in treatment devices, most failures occur in human processes rather than in equipment. Finding the proper balance between effort spent on specific QC procedures and effort spent on an overall quality management program is major challenge at most institutions.
The QA program for an SBRT process based on IGRT system must evaluate the entire treatment process, including patient immobilization, setup, simulation imaging, treatment planning (including the production of reference images to guide corrections), verification imaging, image registration, patient position correction, and treatment. Tests that assess the entire process from beginning to end inspire confidence that the overall process is accurate and robust. In such as study, planning images of a phantom are acquired and transferred to the treatment planning system. A treatment plan is designed and reference images are produced. The phantom is then taken to the treatment unit and positioned for treatment. A verification images is acquired and registered to the reference image. Any necessary corrections to the position are made. Treatment is then delivered and measured by using an ion chamber and/or film. The dosimeter readings are compared with the expected values from the treatment plan. The frequency of such tests should be based upon an analysis of system stability during the initial operation of the SBRT system. Also, the image-guidance procedures should be reviewed on a regular basis to ensure that the procedures are consistent with the initial design and to initiate appropriate changes if necessary. The review results and any new changes must be communicated among staff. The review of the guidance elements of a patient’s treatment can be integrated into the institutional chart rounds and quality control programs to verify that the image guidance procedure is operating correctly.
Conventional linear accelerator-based IGRT consists of imaging in the treatment room during a course of radiotherapy. Planar (two-dimensional [2D]) and volumetric (three-dimensional [3D]) imaging are used for repositioning the patient immediately prior to treatment. The common elements of a QA program include: (1) safety and functionality, (2) geometric accuracy (agreement of MV and kV beam isocenters), (3) image quality, (4) registration and correction accuracy, and (5) dose to patient and doseimetric stability.
Helical Tomotherapy requires synchrony of gantry rotation, couch translation, linear accelerator pulsing, and opening and closing of the binary MLC leaves used to modulate the radiation beam. The accuracy of this highly dynamic treatment process depends on the correct performance of the radiation source, MLC, gantry, and couch table. The dose delivered to the patient depends on the static beam dosimetry, system geometry, system dynamics, and system synchrony. Systematic QA of the system dynamics and synchrony has been suggested, which includes jaw width constancy, actual fraction of time leaves are open, couch drive distance, speed and uniformity, linear accelerator pulsing and gantry synchrony, leaf opening and gantry synchrony, and couch drive and gantry synchrony.
Quality assurance programs for IGRT are not easy to implement. Rapid development of new IGRT techniques and devices is quickly making traditional QA guidelines outdated. Because of the diversity of IGRT, it is extremely difficult to develop industry-wide specific QA guidelines, forcing a conversion to process-centered quality management guidelines, which each institution can tailor to its individual needs. An optimal QA program is always a balance between available resources, manpower, and time to perform the work.
Patient-specific QA procedures for SRS/SBRT should be developed as an integrated part of a comprehensive ongoing QA program in the clinic. Therefore, before implementing an SBRT program, the clinic first needs to determine which system(s) will be used and develop QA procedures to match. SBRT-enabled systems often have specialized equipment such as immobilization systems, localization systems, and on-board imaging systems which are not always found in the clinic. In other cases, the entire system is specialized for SBRT (e.g. the Accuray Cyberknife). For example, Table 1 summarizes the stereotactic localization and image guidance strategies used by commercially-available systems. These specialized components require detailed and specialized QA procedures, over and beyond the general guidelines for external beam radiotherapy as specified in the AAPM Reports of TG 40, 142, and 45
Author | Site | Immobilization/repositioning | Reported accuracy |
Lax, 1994 | Abdomen | Wood frame/stereotactic coordinates on box to skin marks | 3.7 mm Lat. 5.7 mm Long |
Hamilion, 1995 | Spine | Screw fixation of spinous processes to box | 2 mm |
Murphy, 1997 | Spine | Frameless/implanted fiducial markers with real-time imaging and tracking | 1.6 mm radial |
Lohr, 1999 | Spine | Body cast with stereotactic coordinate | ≤ 3.6 mm mean vector |
Yenice, 2003 | Spine | Custom stereotactic frame and in-room CT guidance | 1.5 mm system accuracy, 2-3 mm positioning accuracy |
Chang, 2004 | Spine | MITM BodyFix with stereotactic frame/linac/CT on rails with 6D robotic couch | 1 mm system accuracy |
Tokuuye, 1997 | Liver | Prone position jaw and arm straps | 5 mm |
Nakagawa, 2000 | Thoracic | MVCT on linac | Not reported |
Wulf, 2000 | Lung, liver | ElektaTM body frame | 3.3 mm Lat. 4.4 mm long |
Fuss, 2004 | Lung, liver | MITM Body Fix | Bony anatomy translation 0.4, 0.1, 1.6 mm (mean X, Y, Z); tumor translation before image guidance 2.9, 2.5, 3.2 mm (mean X, Y, Z) |
Herfarth 2001 | Liver | Leiginger body frame | 1.8 – 4.4 mm |
Nagata, 2002 | Lung | ElektaTM body frame | 2 mm |
Fukumoto, 2002 | Lung | ElektaTM body frame | Not reported |
Hara, 2002 | Lung | Custom bed transferred to treatment unit after confirmatory scan | 2 mm |
Hof, 2003 | Lung | Leibinger body frame | 1.8 – 4 mm |
Timmerman, 2003 | Lung | ElektaTM body frame | Approx. 5 mm |
Wang, 2006 | Lung | Medical Intelligence body frame stereotactic coordinates/CT on rails | 0.3±1.8 mm AP. -1.8±3.2 mm Lat. 1.5±3.7 mm SI |
Achievable accuracies reported in the literature categorized by body site and immobilization/repositioning device.(AAPM TG101)
Source | Purpose | Proposed test | Reported achievable | Proposed frequency |
Ryu et al., 2001 | End-to-end localization accuracy | Stereo x ray/DRR fusion | 1.0 to 1.2 mm root mean square | Initial commissioning and annually thereafter |
Ryu et al., 2001 | Intrafraction targeting variability | Stereo x ray/DRR fusion | 0.2 mm average, 1.5 mm maximum | Daily (during treatment) |
Verellen et al., 2003 | End-to-end localization accuracy | Hidden target (using stereo x ray/DRR fusion) | 0.41 ± 0.92 mm | Initial commissioning and annually thereafter |
Verellen et al., 2003 | End-to-end localization accuracy | Hidden target (using implanted fiducials) | 0.28 ± 0.36 mm | Initial commissioning and annually thereafter |
Yu et al., 2004 | End-to-end localization accuracy | Dosimetric assessment of hidden target (using implanted fiducials) | 0.68 ± 0.29 mm | Initial commissioning and annually thereafter |
Sharpe et al., 2006 | CBCT mechanical stability | Constancy comparison to MV imaging isocenter (using hidden targets) | 0.50 ± 0.5 mm | Baseline at commissioning and monthly thereafter |
Galvin et al., 2008 | Overall positioning accuracy, including image registration (frame-based systems) | Wiston-Lutz test modified to make use of the in-room imaging system | ≤ 2 mm for multiple couch angles | Initial commissioning and monthly thereafter |
Palta et al., 2008 | MLC accuracy | Light field, radiographic film or EPID | < 0.5 mm (especially for IMRT delivery) | Annually |
Solberg et al., 2008 | End-to-end localization accuracy | Hidden target in anthropomorphic phantom | 1.0 ± 0.42 mm | Initial commissioning and annually thereafter |
Jiang et al., 2008 | Respiratory motion tracking and gating in 4D CT | Phantoms with cyclical motion | N/A | N/A |
Bissonnette et al., 2008 | CBCT geometric accuracy | Portal image vs CBCT image isocenter coincidence | 2 mm | daily |
Summary of published QA recommendations for SBRT and SBRT-related techniques..(AAPM TG101)
The most important goal of SBRT in oligometastases is to achieve local control, however, whether obtaining local control of the metastasis would translate into clinical or survival benefit of the patients is dependent on multiple factors, including age, performance status, medical comorbidities and histology of malignancies. Therefore, the patients’ whole condition should be fully considered. In general, patients with younger age, high performance status, controlled primary sites, limited number of metastases from three to five or fewer, metachronous occurrence of primary disease and metastatic disease, histologies, such as colorectal carcinoma, breast cancer and radioresistant cancer including renal cell ca, melanoma and sarcoma, are most likely to benefit from SBRT of their oligometastases (Carey-Sampson et al, 2006). In addition, SBRT delivers the individual ablative radiation doses to a planning target volume with a steep dose gradient outside the lesion treated and it is crucial that the lesions to be treated must be easily delineated on diagnostic imaging.
type | No of pts /targets | Dose(Gy/fx) | FU (mo) | LC (%) | Survival | |
Blomgren et al, 1995a | retrospective | 10/14 | 7.7-45Gy/1-4fx | 8 | 92 | Med.S 11.3mo |
Uematsu et al, 1995b | retrospective | 22/43 | 33-71Gy/5-15fx | 9 | 98 | |
Nakagawa et al, 2000 | retrospective | 14/21 | 16-24Gy/1fx | 10 | 95 | 2YOS 35% |
Wulf et al, 2001 | retrospective | 41/51 | 30-37.5 Gy/3fx ; 26 Gy/1fx | 14 | 80% | 2YOS 33% |
Hara et al, 2002 | retrospective | 14/18 | 20-30Gy/1fx | 12 | 78 | |
Lee et al, 2003 | retrospective | 19/25 | 30-40 Gy/3-4fx | 18 | 88 | Med.LPFS 18mo |
Hof et al, 2007 | retrospective | 61/71 | 12-30 Gy/1fx | 14 | 88.6 (1YR) | 3YOS 47.8% |
Okunieff et al, 2006 | retrospective | 42/125 | 50 Gy/10fx | 18.7 | 94 | Med.S 23.4mo |
Norihisa et al, 2008 | retrospective | 34/43 | 48-60 Gy/4-5fx | 27 | 90 | 2YOS 84.3% |
Kim et al, 2009 | retrospective | 31/134 | 50 Gy/10fx | 16 | 87.1 | Med.S 16mo |
Ernst-Stecken et al, 2006 | prospective | 21/39 | 35-40 Gy/5fx | NA | CR:51 PR:33 SD:3 | Med.LPFS 6.4mo |
Rusthoven et al, 2009 | prospective | 38/63 | 48-60 Gy/3fx | 15.4 | 96 | Med.S 19mo |
Results of SBRT in lung metastases
There are numerous retrospective studies on the use of SBRT for the treatment of lung oligometastases from North America, Europe and East Asia (Table 3). Early results from Blomgren’s and Uematsu’s studies showed excellent local control rates of 92% and 98%, respectively although the follow up periods were short (Blomgren et al, 1995; Uematsu et al, 1995). Subsequently, Nakagawa treated 14 patients with 21 tumors with SBRT to a single dose of 16 to 24 Gy. The local control rate and 2 year overall survival rate were 95% and 35%, respectively (Nakagawa et al, 2000). In a report of Wulf et al, the 41 patients with 51 metastatic lung tumors were treated with SBRT of 30 to 37.5 Gy in 3 fractions or 26 Gy of a single dose. The crude local control rate was 80% at a median follow up 14 months and 2 years overall survival rate was 33% (Wulf et al, 2001). And Hof et al also treated 61 patients with 71 lung metastases with SBRT to a single dose of 12 Gy to 30 Gy. The actuarial local progression free rate was 79% at 1 year and overall survival rate was 47.8% on 3 years (Hof et al, 2007). In a report of Okunieff et al, they treated 50 patients with five or fewer lung metastases with SBRT. At a median follow up of 18.7 months, 94% local control rate and 50% of 2 years overall survival rate were yielded (Okunieff et al, 2006). Kim et al also treated the patients with multiple lung metastases with SBRT to a dose of 50 Gy in 10 fractions during 2 weeks. The local control rate was 87.1% and median survival time was 16.0 months (Kim et al, 2009). Two prospective studies’ outcomes were also shown in table 3. In a report from Germany, Ernst-Stecken et al reported the results of dose escalating phase I/II trial of SBRT for lung tumors, Overall, 21 patients (three with primary lung tumors) with 39 tumors were treated with SBRT starting at dose level of 35 Gy (7 Gy x 5) and the dose was then escalated to 40 Gy (8 Gy x 5). In total, 21 and 18 tumors were treated to 35 Gy and 40 Gy, respectively. Rates of complete response, partial response, stable disease and progressive disease were 51%, 33%, 3% and 13%, respectively (Ernst-Stecken et al, 2006). In 2009, in a multi-institutional phase I/II trial of SBRT for patients with 1 to 3 lung metastatic tumors less than 7 cm diameter, the total radiation dose was safely escalated from 48 Gy to 60 Gy in 3 fractions. The 2 year actuarial local control rate was 96% and median survival time was 19 months (Rusthoven et al, 2009).
type | No of pts /targets | Dose(Gy/fx) | FU (mo) | LC(%) | Survival | |
Blomgren et al, 1998 | retrospective | 17/21 | 20-40 Gy/1-2fx | 9.6 | 95 | |
Katz et al, 2007 | retrospective | 69/174 | 30-55Gy/2-6fx | 14.5 | 76-57 | Med.S 14.5mo |
Wulf et al, 2001 | retrospective | 23/23 | 28-30Gy/2-4fx | 9 | 76-61 | |
Herfarth et al, 2001 | prospective | 33/56 | 14-26Gy/1fx | 18 | 67 | 1YSR 72% |
Kanavagh et al, 2006 | prospective | 21/28 | 36-60Gy/3fx | 18 | 93 | |
Mendez-Romero et al, 2006 | prospective | 17/34 | 37.5Gy/3fx | 12.9 | 100-86 |
Results of SBRT in liver metastases
Blomgren’s early data on SBRT for liver metastases showed promising results of 95% local control rate on 9.6 months follow up (Blomgren et al, 1998). In the study of University of Rochester, which represents the largest study in SBRT for liver metastases, Katz et al treated 69 patients with 174 liver metastases with SBRT to a median dose of 48 Gy(range, 30-55Gy) in 2 to 6 fractions. The mean number of lesions was 2.5 (range, 1-6). The most common primary sites were colorectal (n=20) and breast (n=16). The median follow up was 14.5 months. The local control rates were 76% and 57% at 10 and 20 months, respectively. The median overall survival time was 14.5 months (Katz et al, 2007). Wulf et al reported their experience on 23 patients treated with SBRT for liver metastases. The prescribed dose was 30 Gy in three fractions. The actuarial local control rates on one and two year after treatment were 76 and 61%, respectively (Wulf et al, 2001). Herfarth et al performed a dose escalation study utilizing single dose SBRT from 14 Gy to 26 Gy. Fifty six liver metastases of 33 patients were treated and their local control rate was 67% on 18 months after treatment. Local failures were observed mainly in patients treated to a lower dose. For patients treated to higher dose (>20 Gy), the actuarial local control rate was 81% (Herfarth et al, 2001). In a study of Colorado University, Kavanagh et al reported 93% of actuarial local control rate on 18 months and indicated that a very high rate of durable in-filed tumor control can be safely achieved with SBRT to one to three liver lesions to a prescription dose of 60 Gy in 3 fractions (Kanavagh et al, 2006). Mendez-Romero et al reported the results of 17 patients with 34 metastatic liver tumors treated in phase I/II study of SBRT. The prescribed dose was 37.5 Gy in 3 fractions. The actuarial one and two year local control rates were 100% and 86%, respectively and the actuarial overall survival rate at one and two years were 85% and 62%, respectively (Mendez-Romero et al, 2006).
SBRT has emerged as a novel treatment modality in the multidisciplinary management of spinal metastasis. Compared with conventional radiotherapy, SBRT can deliver a much higher biologic equivalent dose to the spinal tumor while respecting the dose constraints of the spinal cord or cauda equine, which are usually the dose limiting structures. The inclusion criteria for spinal SBRT are solitary or oligometastatic disease or bone only disease in otherwise high performance status patients, maximum of two consecutive or non contiguous spinal segments involved by tumor, failure of prior XRT (upto one course and 45 Gy maximum) or surgery, non myeloma tumor type, gross residual disease or deemed to high risk for recurrence postsurgery, patients refusal or medical comorbidities precluding surgery, gross tumor optimally more than 5 mm from the spinal cord, Karnofsky performance status > 40-50, MRI- or CT documented spinal tumor, histologic confirmation of neoplastic disease and Age > 18. These are yielded from reports by various authors for spine SBRT. And these criteria are based on relevant studies, which include those reporting both the dose/fractionation used and duration of follow up for patients treated for metastatic spinal tumors. However, the final treatment recommendation should involve ideally a multidisciplinary tumor board composed of surgeons, radiation oncologists, medical oncologists, and medical physicists.
Number of Tumor/pts | Target volume/image | Dose/fx | Re-RTx | FU (mo) | LC/criteria | |
Ryu et al, 2004 | 61/49 | Involved spinal segment/CT or MR | 10-16 Gy/1fx | ERT 25 Gy/10 plus SBRS boost 6-8 Gy/1 | 6-24 | 93%/imaging and clinical |
Milker-Zabel et al, 2003 | 19/18 | PTV=GTV plus entire VB/CT-MRI fusion | 24-45 Gy, Median 2 Gy fraction | 19/18 Median 39.6 Gy, 2 Gy fraction | 12 | 95%/clinical |
Gerszten et al, 2005 | 26/26 | Postkypoplasty VB+extension/CT | 16-20 Gy/1fx | 4-36 | 92%/imaging or clinical | |
Gerszten et al, 2007 | 500/393 | GTV=PTV/CT | 12.5-25 Gy/1 | 7 patients combined EBRT plus SBRT boost | 3-53 | 88%/imaging |
Sahgal et al, 2007 | 60/38 | GTV=PTV/CT | 8-30 Gy/1-5 | 37/26 tumors had previous irradiated | 1-48 | 87%/imaging and clinical |
Chang et al, 2007 | 74/63 | GTV + potential extension of structure /CT | 30 Gy/5fx or 27 Gy/ 3fx | 35/63 (55.6%) patients of previous spinal RT (median 33 Gy; range 30-54 Gy)was allowed | 1-50 | 77%/imaging |
Clinical Results of SBRT in spinal metastasis
In a report from Henry Ford Hospital, Ryu et al treated 61 spinal tumors in 49 patients with single dose of SBRT alone to a dose of 10 to 16 Gy. With follow up time ranging from 6 to 24 months, the local control rate was 93% on imaging and clinical response including complete or partial pain control was achieved in 52 of 61 tumors (85%) (Ryu et al, 2004). In a report of SBRT as reirradiation, Milker-Zable treated 19 tumors from 18 patients with a dose range from 24 to 45 Gy in 2 Gy fractions. Their previous median dose was 39.6 Gy in 2 Gy fractions. With a median follow up time 12 months, the clinical response rate was 95%. They defined PTV as a gross tumor volume plus entire vertebral body through CT with MRI fusion and defined spinal cord as spinal cord from MRI plus safety margin of 2 to 3 mm. Dose constraints of spinal cord on SBRT as reirradiation was maximal dose to spinal cord less than 20 Gy in 10 fractions to a median percent of spinal cord (Milker-Zabel et al, 2003). In a postoperative SBRT series from Pittsburg Medical center, Gerszten et al reported the results of SBRT using Cyberkinife from 26 tumors in 26 patients. The prescribed dose was 16 to 20 Gy at the 80% isodose line with a median follow up of 16 months, the local control rate was 92%. Pain control was evaluated using a ten point verbal visual analog scale and was improved in 24 out of 26 patients (Gerszten et al, 2005). And in the largest report from same group, Gerszten et al treated a total of 393 patients with 500 spinal metastases with Cyberknife based single dose SBRT to doses ranging from 12.5 to 25 Gy. Seven patients also received external radiation therapy. With a median follow up of 21 months, the local control rate was 88%. Among the 336 evaluable patients, 290 (86%) achieved improvement in pain based on a ten point visual analog scale (Gerszten et al, 2007). Sahgal et al reported the treatment results of Cyberknife based SBRT for spinal metastases from University of California SanFrancisco in abstract form. They treated 60 spinal metaststases in 38 patients with a dose ranging from 8 to 30 Gy in one to five fractions (median 24 Gy in three fractions). With a median follow up of 8.5 months, the local control rate was 87% and the pain improvement was achieved in 31 out of 46 tumor sites (67%) (Sahgal et al, 2007). In a phase I/II trial from MD Anderson Cancer Center, Chang et al reported the results of 63 patients with 74 tumors treated with SBRT to a dose of 30 Gy in five fractions or 27 Gy in three fractions. Thirty five patients had prior external radiotherapy. With a median follow up of 21.3 months, the local control rate was 77% and the one year progression free rate was 84% (Chang et al, 2007).
Authors | No of pts/tumors | Sum of GTV | Dose/fx | FU (mo) | Outcome |
Milano et al, 2008 | 121 /293 | 0.3-422 ml Med. 28 ml | 50Gy/10 (SRS 10-20Gy/1) | 2 year OS/PFS/LC/DC, 50%/26%/67%/34%; 4 year OS/PFS/LC/DC, 28%/20%/60%/25% | |
Salama et al, 2008 | 29/56 | Max. dimension of volume ≤ 10cm or < 500cm3 | 24-36 Gy/3 | 5.3-27 (med. 14.9) | Response rate 59%; PFSR 21%; LC 57% |
Salama et al, 2011 | 61/113 | Max. dimension of volume ≤ 10cm or < 500cm3 | 24-48 Gy/3 | Med. 20.9 | 1 year OS/PFS 81.5%/33.3%; 2 year OS/PFS 56.7%/22.0% |
Clinical results of 5 or fewer oligometastases
There are fewer reports about SBRT in multisite oliogometastases (Table 6). Among them the largest trial was performed in Rochester University hospital. Milano et al reported that the 4 year overall survival, progression free survival, local control and distant control were 28%, 20%, 60% and 25%, respectively after SBRT for multiple sites oligometastases from 121 patients. And they showed that number of metastases (range, 1~5) was not correlated with treatment outcomes. Salama et al firstly performed dose escalation study of SBRT in patients with oligometastases involving multiple organs (Milano et al, 2008). In phase I/II trial, they treated 56 tumors in 29 patients with a dose to 24 to 36 Gy in 3 fractions. With a median follow up 14.9 months, local control and progression free survival rate were, 57% and 21%, respectively (Salama et al, 2008). In a final report from same group, Salama et al could escalate the dose from 24 Gy to 48 Gy in 3 fractions. Fifty six tumors in 29 patients were treated and their 1 and 2 year overall survival rate was 81.5% and 56.7%, respectively. And they showed superior outcome in the patient with one to three metastases to the others with four or five metastases (2 year overall survival; 60.3% vs 21.9%) but there was not statistical significance (p=0.22) (Salama et al, 2011).
SBRT has been defined as hypofractionated (1-5 fractions) extracranial stereotactic radiation delivery, thus when selecting the fractional and total dose, several clinical considerations are important, including; (1) predicted risks of late normal tissue complications; (2) predicted tumor control; (3) financial costs and time expenditure for treatment planning and delivery. Among these, the long term effect of hypofractionated dose delivery to small volumes of normal tissues is not well understood, and certainly more clinical studies with longer follow up are needed to better define the variable associated with risks of late toxicity. Table 7 shows the normal tissue dose volume constraints to prevent late radiation complication in NCCN guidleline version 2.2012.
OAR | 1 fraction | 3 fractions | 4 fractions | 5 fractions |
Spinal cord | 14 Gy | 18 Gy (6 Gy/fx) | 26 Gy (6.5 Gy/fx) | 30 Gy (6 Gy/fx) |
Esophagus | 15.4 Gy | 30 Gy (10 Gy/fx) | 30 Gy (7.5 Gy/fx) | 32.5 Gy (6.5 Gy/fx) |
Brachial plexus | 17.5 Gy | 21 Gy (7 Gy/fx) | 27.2 Gy (6.8 Gy/fx) | 30 Gy (6 Gy/fx) |
Heart/pericardium | 22 Gy | 30 Gy (10 Gy/fx) | 34 Gy (8.5 Gy/fx) | 35 Gy (7 Gy/fx) |
Great vessels | 37 Gy | 39 Gy (13 Gy/fx) | 49 Gy (12.25 Gy/fx) | 55 Gy (11 Gy/fx) |
Trachea & proximal bronchi | 20.2 Gy | 30 Gy (10 Gy/fx) | 34.8 Gy (8.7 Gy.fx) | 32.5 Gy (6.5 Gy/fx) |
Rib | 30 Gy | 30 Gy (10 Gy/fx) | 34.8 Gy (8.7 Gy.fx) | 32.5 Gy (6.5 Gy/fx) |
Skin | 26 Gy | 30 Gy (10 Gy/fx) | 36 Gy (9 Gy/fx) | 40 Gy (8 Gy/fx) |
Stomach | 12.4 Gy | 27 Gy (9 Gy/fx) | 30 Gy (7.5 Gy) | 35 Gy (7 Gy/fx) |
Normal tissue dose volume constraints for SBRT from NCCN guidelines
The recommendation from Table 7 is frequently referenced in SBRT for non small cell lung cancer (Ettinger et al, 2012) and so, there is no information about intra abdominal organ including small intestine, liver and kidney. Radiobiologically, normal tissues can be categorized into two groups of serially arranged tissues and parallel arranged tissues. In a review article from Rochester University in New York, Milano et al recommended the fractional dose limitations to small volume of normal tissue which were expected to be safe with respect to risk of radiation necrosis in serially arranged tissues and they also noted the dose constraints of parallel arranged normal tissues such as lung, liver and kidney for safe SBRT in same article (table 8 and 9) (Milano, 2008).
Number of fractions | |||||
Normal tissue | 1 | 3 | 5 | 8 | 10 |
Spinal cord | 8-10 Gy | 5-6 Gy | 4-5 Gy | 3-4 Gy | 3 Gy |
Trachea & bronchi | - | - | 7-9 Gy | 6-7 Gy | 4-5 Gy |
Brachial plexus | - | - | 8-10 Gy | 6-7 Gy | 5-6 Gy |
esophagus | - | - | 6-8 Gy | 4-5 Gy | 3-4 Gy |
Chest wall/ribs | - | 10-15 Gy | 6-8 Gy | 6-7 Gy | 5-6 Gy |
Small bowel | 10-12 Gy | 10-12 Gy | 6-8 Gy | 5-6 Gy | 4-5 Gy |
Lung | 20 Gy | 20 Gy | 8-10 Gy | 7-8 Gy | 5-7 Gy |
Liver | 25 Gy | 20 Gy | 8-10 Gy | 7-8 Gy | 5-6 Gy |
Recommendation for safe hypofractionated SBRT fractional dose to small volume of serially arranged tissues.
Lung | 700-1000 ml of lung not involved with gross disease or planning target volume V20 of 25-30% |
Liver | 700-1000 ml of liver not involved with gross disease or planning target volume Two thirds of normal liver < 30 Gy |
Kidney | Minimize dose receiving "/> 20 Gy Two thirds of one kidney < 15 Gy (with another functional kidney) |
Recommendation for safe hypofractionated SBRT dose volume metrics for parallel arranged normal tissues
Deriving standard acceptable maximally effective and minimally toxic dose fractionation schemes presents a challenge, even with available outcome data. In fact, this complexity arises from not only the different dose-fractionation schemes used, but also in differences in how the dose is prescribed. Further study and longer follow up are needed to ascertain the dose fractionation schedule that optimizes tumor control while minimizing toxicity and to better understand the optimal normal tissue dose volume constraints.
A subset of patients with oligometastases have been alive a prolonged disease free state, some > 7 years, most eventually succumbed to further metastatic progression. There are several studies which have examined the pattern of recurrence after resection, radiofrequency ablation, or cryosurgery and SBRT of oligometastases. Table 10 shows the literature summary of the pattern of recurrence after treatment of limited liver metastases.
First author | Sugihara et al, 1993 | Aloia et al, 2006 | Kosari et al, 2002 | Ravikumar et al, 1991 | Milano et al, 2010 |
Primary cancer | colorectal | colorectal | various | colorectal | various |
Treatment modality | resection | resection | radio-frequency | cryosurgery | SBRT |
Number of recur/total | 64/107 (60%) | 71/150 (57%) | 23/45 (51%) | 17/24 (71%) | 37/42 (88%) |
Follow up(mo) | 6-164 Median 35 | 4-138 Median 31 | 6-34 Median 19.5 | 5-60 Median 24 | 6-67 Median 21 |
Recurrence in | |||||
Liver only | - | 18% | 52% | 35% | 22% |
Extrahepatic only | - | 62% | 4% | 6% | 5% |
Liver+extrahepatic | - | 20% | 43% | 59% | 73% |
Liver | 53% | 38% | 96% | 94% | 95% |
Lung | 31% | 58% | - | - | 32% |
CNS | - | 1% | - | - | 8% |
Bone | - | 6% | - | - | 19% |
other | 28% | 17% | - | - | 32% |
The pattern of recurrence after local treatment of limited liver metastases
All authors reported that the first new recurrence or metastases occurred quite commonly in the same organ, although metastases to other organs are common as well. New metastases occurring shortly after completion of treatment including SBRT presumably represents the growth of initially occult metastatic disease versus rapid metastatic progression, whereas new metastases that occurs after a longer time interval represents more indolent growth of initially occult metastatic disease versus a more remote occurrence of distant spread. However, a few present studies can determine a mechanism to account for new metastases. Some variables are thought important in predicting where subsequent metastases are likely to occur. The initial organ involvement, use of chemotherapy, type of local therapy, primary cancer type, histology and grade are expected to be important which can impact the pattern of subsequent recurrence. In addition, genotypic and phenotypic changes which lead to metastatic potential must exist and should be explained in the future.
In its current form, stereotactic hypofractionated radiotherapy is still in its infancy as an experimental treatment for oligometastases. At this point, a recommendation cannot be made for a fractionation scheme, which suggests the need for prospective investigation. There are multiple ongoing clinical trials on the use of SBRT for oligometastases in various body sites and the results of those trials are eagerly awaited. Given the high propensity for distant progression, the combination of novel systemic therapy and SBRT is to be explored. Interested readers can visit the web site (www.clinicaltrials.gov) to a full list of clinical trials of SBRT for various metastatic sites.
Pain occurs in all demographics, with a higher prevalence in some clusters (such as the elderly) and can be either acute or chronic [1, 2]. Chronic pain is a complex interplay between biology and psychology, where the intensity/magnitude differs depending on personal, sensory, emotional experience and persists more than 3 months beyond “normal” healing time [3, 4]. This type of pain affects more than 1.5 billion people worldwide [5] and has an estimated prevalence ranging between 17-27% [6, 7, 8, 9]. Chronic pain represents a significant financial burden that exceeds €300 trillion (approximately 1.5%-3% of the gross domestic product across the European Union) and up to $635 billion in the United States [10, 11]. According to the International Association for the Study of Pain (IASP), the main overarching categories of chronic pain are primary (such as fibromyalgia) and secondary pain (the focus of this chapter). Secondary chronic pain is further divided into six distinct categories: cancer-related pain, postsurgical or posttraumatic pain, secondary headache/orofacial pain, secondary visceral pain, and secondary musculoskeletal pain [12, 13].
\nMost chronic pain begins with the occurrence of an acute injury event resulting in pain that if left untreated can develop chronically into a pathological condition and can increase the risk of future deleterious health issues such as sleep deficiency, delayed wound healing, immune dysfunction, cardiovascular problems (related to the stress response) and respiratory problems (such as pneumonia; [14, 15]). Persistent, unrelieved pain can negatively impact quality of life, daily functioning, sleep quality, work productivity and is associated with a substantial personal economic burden [16].
\nPathologic pain is associated with multiple maladaptations in the nervous, endocrine, and immune systems [17, 18, 19] that often presents at multiple sites [20] and can be classified into nociceptive (somatic and visceral), neuropathic, nociplastic, or mixed [21]. Nociplastic describes pain of unknown origin that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors, evidence of disease or lesion of the somatosensory system causing the pain, such as early (pre structural damage) osteoarthritis [21]. Similarly, recent suggestions propose that generalised chronic pain is an expression of maladaptive plasticity within the nociceptive system [22, 23] and is relevant to the present chapter as osteoarthritic pain is generally accepted to be mainly of nociceptive origin [24].
\nMost painful conditions initially involve the activation of dorsal root ganglion (DRG) neurons, which give rise to high threshold Aδ- and C-fibres (nociceptors) that innervate peripheral tissues (skin, bone, joints, viscera; [25]). Primary afferent neurons transduce painful stimuli action potentials through to the spinal cord (to ascending spinal neurons). Transmission of input from nociceptors, through the spinal column and to the central nerves system is mediated by monosynaptic contacts and/or through interneurons [19, 26]. In the spinal cord, neurotransmitter inhibition is mediated by the release of endogenous opioids (such as met-enkephalins and endorphins; [27]) or gamma-aminobutyric acid (GABA) which activate presynaptic opioid and/or GABA receptors on central nociceptor terminals to reduce excitatory transmitter release (Figure 1). The central integration of signals from excitatory and inhibitory neurotransmitters from cognitive, emotional, and environmental factors results in the perception of “pain”. When the intricate balance between biological (neuronal), psychological (i.e. memory, distraction etc.) and social (i.e. attention, reward etc.) factors becomes disturbed, chronic pain develops [18].
\nPeripheral and central nociceptor pain signalling pathways following exposure to different pharmaceutical drugs. Without pharmaceutical intervention (naive state), activation of peripheral nociceptors in response to noxious stimuli, such as mechanical stress (OA) initiates the release of chemical mediators such as prostaglandins, bradykinin and cytokines at the peripheral terminal of the afferent neuron (peripheral sensitisation) which is modulated by the GPCRs, NA+ and K+ channels. This results in the activation of PKA, PLC releasing intracellular Ca2+ and the generation of action potential which transfers information to the (pre synapse) C-terminal afferent neuron (central sensitization). This triggers the release of neurotransmitters i.e. glutamate and substance P into the spinal synapse of the dorsal horn and activates AMPA or NMDA receptors on the post synaptic dorsal horn. As a result, there is an increased influx of Ca2+ and Na+, inhibition of K+ influx and depolarization of the cell membrane. These signals travel to the brain where they are transcribed into the perception of pain. Pharmaceutical invention acts by modulating various aspects of the pain signalling pathway such as opioids (opioids such as morphine bind to GPCRs preventing the presynaptic release of a number of neurotransmitters), NSAIDs (inhibit the activity of COX) and acetaminophen (inhibits the activity of COX in the central nervous system but appears to lacks peripheral anti-inflammatory properties). Figure created using
Pain that is induced by an acute injury, initially localised, relatively proportional to the degree of tissue damage and typically increases with movement is referred to as “nociceptive pain.” Specifically, as immune surveillance cells recognise the danger signals unmasked by tissue injury, the innate immune system initiates an inflammatory response to remove cellular debris and begins the healing process. Activated endothelial cells, stromal cells, and infiltrating immune cells release vasoactive and inflammatory mediators, including histamine, bradykinin, substance P, serotonin, nitric oxide, cytokines, chemokines, and prostaglandins, which amplify signal transduction in the peripheral terminals of nociceptors [26, 28]. These inflammatory mediators augment the responsiveness of nociceptors by increasing expression of pain-sensing ion channels and promoting release of pronociceptive mediators (autosensitization; [29]). This peripheral inflammation caused by local injury and continuous inputs from sensitised nociceptors promote ‘central sensitization’, a process that alters pain processing in the spinal dorsal horn, and in subcortical and cortical regions of the brain [30, 31]. Noxious signals associated with the injury are detected by peripheral nociceptor terminals of primary afferent neurons, transmitted via the spinal cord to the brain, processed and interpreted as highly unpleasant pain experiences [32]. Nociceptor terminals express molecules, such as transient receptor potential ion channels (TRP), voltage-gated sodium channels (Nav), voltage-gated calcium channels (VGCC), or acid-sensing ion channels (ASICs), which respond to heat, cold, acids, or mechanical stress and transduce them into action potentials [26]. The signal is then transmitted through peripheral axons to the cell bodies of the primary neurons, located in the dorsal root ganglia. Unmyelinated C-fibres and myelinated Aδ-fibres transmit noxious stimuli, whereas thinly myelinated Aδ-fibres transmit innocuous mechanical stimuli, such as touch. The central axons of the primary neurons enter the spinal cord through the dorsal horn and synapse with secondary somatosensory neurons and, to some extent, with motor neurons to form withdrawal reflex circuits. Signal propagation to the secondary neurons is subject to modulation by descending tracts from the brainstem and by interneurons in the dorsal horn. The signal is then transmitted to the thalamus, from where tertiary afferent neurons are projected to multiple areas of the cortex involved in pain processing [33].
\nNeuropathic pain (NP) is defined as “pain caused by a lesion or disease of the somatosensory nervous system” [34]. Chronic neuropathic pain is caused by damage to nerve fibres that respond by misappropriating sensory inputs leading to spontaneous painful sensation, through multiple mechanisms in the nervous system and its associated modulators. Peripheral nerve damage can result in chronic neuropathic pain through multiple routes [35] via peripheral pain-processing unmyelinated C-fibres and thinly-myelinated fibres because of metabolic damage, toxins, medications, cytokines, and inflammation [36]. This can result in morphological and chemical changes such as fibre density and neuronal hyperexcitability [30, 37, 38, 39, 40]. Throughout the axon, trauma, compression, hypoxia, inflammation and chemical damage lead to fibre degeneration and alterations in gene expression [41], resulting in ectopic firing, faulty signal transmission [42], detrimental physiological alterations [43, 44, 45] and peripheral second-order targets [46, 47, 48]. This results in negative impacts on nociceptive pathways causing them to become sensitised [49], leading to maladaptive central sensitization [50] and increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input [51]. At the molecular level, these damaged processes disrupt second-order neuronal transduction, through alterations in receptor expression, calcium permeability, synapse location and the release of pain-promoting mediators [52, 53, 54, 55]. The precise molecular targets of neuropathic pain stem from multiple mechanisms of peripheral nerve fibre excitation and sensitization leading to sustained electrochemical signalling and to neuropathic pain stimulus [56, 57].
\nBoth acute and chronic pain are, in general, treated with a wide group of pharmaceutical medications known as “analgesics.” The most frequently used are opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, also referred to as acetaminophen or N-acetyl-p-aminophenol [58].
\nOpioid drugs (e.g. morphine, codeine, methadone, fentanyl and their derivatives) are the most widely used analgesic medications globally, so much so that an estimated 26.8 million people were living with ‘opioid use disorder’ globally in 2016, resulting in >100,000 opioid overdose deaths annually [59]. Opioids are a group of pharmaceutical formulations that interact with endogenous opioid receptors to distort neurotransmitter singling pathways through localised peripheral sensory neurons [60, 61] with the goal to reducing pain sensation. Opioid receptors are a large superfamily of seven-transmembrane G protein-coupled receptors and are classified as μ (μ1, μ2, μ3), δ (δ1, δ2), k (k1, k2, k3) and ORL1 [62, 63], of which almost all opioid drugs in use today interact with μ receptors. These receptors are inhibitory and prevent the presynaptic release of a number of neurotransmitters to inhibit the release of glutamate, calcitonin gene related protein (CGRP), and substance P. This is an important action considering the established roles of these molecules in pain signalling and nociceptive transmission (Figure 1; [64]). For example, morphine, extracted from opium, is by far the most commonly known opioid [59], which is thought to have been in use since the third century B.C. [22], but identified at the molecular level with high binding affinity to sites in the intestine and brain [65]. These receptors mediate an inhibitory signal of neural transmission induced by opioid drugs to produce an analgesic action (Figure 1). Pain stimuli are detected by nociceptors at the spinal cord dorsal horn [66] where they act on the substantia gelatinosa (inhibitory interneurons rich with opioid receptors) and are activated by the antinociceptive descending system, to control the transmission of painful stimuli from primary nerve fibres to spino-thalamic neurons [22]. Opioid receptors have an intricate relationship with inflammatory status. Early studies showed that the systemic or local application of receptor agonists elicited greater analgesic effects in inflamed compared to non-inflamed tissue (reviewed in; [67]). Furthermore, opioid receptor trafficking (movement within the neuron) is augmented, expression on DRG membranes is enhanced [68, 69] and axonal transport stimulated by cytokines and nerve growth factor that are produced within inflamed tissues [70, 71]. This enhanced/altered state resulted in increased antinociceptive function of opioid receptors on peripheral nerves [60, 72].
\nThe major limiting factors of opioid therapy are the variety of side effects such as constipation, vomiting, myosis, cough reflex suppression, modulation of the immune system and one of the most dangerous, respiratory rhythm and respiratory depression [73, 74]. Interestingly, studies have shown that long-term use in chronic non-malignant (e.g. musculoskeletal) pain has not been proven effective [75], rather, abuse of prescription opioids have reached epidemic proportions leading to addiction, overdoses and increased death rates [76, 77, 78]. Importantly, these side effects may be drug specific and affect immune function differently [79, 80]. Nonetheless, chronic use of opioid medication can cause cellular adaptions that lead to modulation of cellular growth, inflammation, wound healing [81, 82]. For a more detailed overview of the potential side effects and opioid tolerance refer to the following references [83, 84, 85, 86].
\nRegardless of the potential impact that opioid agonists could have on pain relief, meta-analyses show no improvement in clinically significant pain reduction scores, and epidemiological data suggest that quality of life and functional capacity are only minimally changed [75, 78]. Nonetheless, more data is required from larger studies (specifically in OA), however the aforementioned adverse effects and lack of analgesic efficacy has led to significant dropout rates in long-term studies [75, 78, 87, 88, 89].
\nNSAIDs (particular enzyme inhibiters) are among the most widely used medications globally [90, 91] because of the lower potential for addiction (as shown by the US opioid epidemic; [92]), robust efficacy, and long history of clinical use [93].
\nThe prevalence of ‘non-aspirin’ NSAID use has been well studied and is dynamic across age, body mass index and geographical ancestry, ranging between ~15-45%, women being the highest users and ibuprofen generally being the most reported [94, 95, 96]. Short-term use of NSAIDs is particularly prevalent (~50–80% per year) in athletes and soldiers (individuals that may be at risk for acute and chronic musculoskeletal injuries; [97, 98, 99]). Extended periods of NSAID treatment (e.g., more than 3 times per week for more than 3 months per year) have been reported in 10% of adults in the United States [100], a rate that can be expected to increase with age [101].
\nNSAIDs act primarily by mediating peripheral pain sensitization driven by inflammatory stimuli, such as acute or sport injuries, (osteo)arthritis etc. and are less effective in treating pain due to nerve damage (neuropathic pain). At the point of inflammatory pain, initiated by nociceptive stimuli, NSAIDs augment the experienced nociceptive excitability (peripheral and central sensitization; [102]). NSAIDs work differently to opioids in that they do not block central pathways of nociception, but inhibit the formation of prostanoids via competitive inhibition of arachidonic acid binding to cyclooxygenase enzyme (COX) isoform active sites [103], which sensitise nociceptive pain. There are two cyclooxygenase isoforms that are the targets of NSAIDs; COX-1 that are expressed in most tissues (including the endothelium, monocytes, gastrointestinal epithelial cells, and platelets) and controls the basal production of prostanoids (Figure 1) and COX-2 that are not regularly expressed in most tissues but are upregulated in response to and during the inflammatory process (in tissues such as vascular endothelium, rheumatoid synovial, endothelial cells, monocytes, and macrophages) through the actions of various inflammatory mediators such as bacterial endotoxins, tumour necrosis factor-alpha and interleukins [104]. The increase in COX-2 protein levels are the primary driving force for enhanced production of prostanoids at inflammatory sites [105, 106]. The resulting COX-2 products, particularly prostaglandin (PG) E2, potentiate this response, where PGE2 and prostacyclin (PGI2), produced during local inflammation, augment pain signalling by peripheral and central neurons [15]. PGE2 and PGI2 increase the sensitivity of pain receptors (or nociceptors) in the periphery and enhance the activity of various pain mediators [104, 107]. This mechanism propagates via brain derived PGE2 travelling through the blood–brain barrier, via venules, during systemic inflammation and lessens the inhibition of neurons in the hypothalamus [108]. Drugs that inhibit both COX isoforms with comparable potency (i.e. nonselective NSAIDs such as ibuprofen and ketoprofen) tend to preferentially activate the COX-1 pathway, while drugs with intermediate or selective target COX-2 inhibition (such as nimesulide, meloxicam, diclofenac, celecoxib, rofecoxib, etoricoxib, lumiracoxib etc.) have lesser potential for COX-1 activation [109]. This pathway selectivity is of significant importance as both COX isoform elicit different potentially harmful adverse effects.
\nIn a recent meta-analysis (n = 220,000 patients) of placebo-controlled trials, NSAIDs (coxibs, diclofenac, ibuprofen, and naproxen, predominantly COX-1 inhibiters) significantly increased the risk of upper gastrointestinal complications [eg, ulcer perforations, bleeding, obstructions; 110]. The authors also showed an increased risk of major vascular and coronary events with high doses of coxibs and diclofenac while ibuprofen was associated with an increase in major coronary (but not vascular) events comparable with that of coxibs and oral diclofenac (predominantly COX-2 inhibiters; [110]). These data are corroborated with findings from meta-analysis of observational studies showing low risk of upper gastrointestinal complications (aceclofenac, celecoxib, and ibuprofen predominantly COX-2 inhibiters), intermediate risk (diclofenac, meloxicam, and ketoprofen etc.) and high risk (tenoxicam, naproxen, indomethacin, diflunisal, piroxicam, ketorolac, and azapropazone predominantly COX - inhibiters) depending on the NSAID, likely in a dose dependent fashion [111]. Similarly, total daily oral diclofenac had a linear dose dependent relationship cardiovascular event risk [112]. These dose dependencies are likely a product of the relative effectiveness on either COX-1 or COX-2 inhibition [113, 114, 115, 116]. As both (non-inhabited) COX-1 and COX-2 produce cytoprotective prostanoids, inhibition of both COX isozymes (induced by NSAIDs) suppress these prostanoids and promotes damage to the gastrointestinal tract and cardiovascular tissues [109, 117]. Based on these and other safety findings, the American Heart Association recommends patients take the lowest effective dose of NSAIDs for the shortest duration of time [118].
\nAPAP are likely to be the most commonly used pharmaceutical worldwide [119, 120], are expected to reach a global market value of USD 999.4 million in 2020 [121] and is included in the 21st World Health Organisation Model List of Essential Medicines as updated in March 2017 [122]. However, recently there have been debates from the National Institute for Health and Care Excellence, about the relevance of APAP for some conditions [123]. The efficacy of paracetamol to treat chronic pain has been questioned with systematic reviews showing limited (sometimes null) effects on chronic pain in some conditions [120, 124, 125]. Nonetheless, APAP can be beneficial for acute pain, [126, 127, 128], similar to NSAIDs and opioids [129, 130, 131]. The precise mechanism of action remains unknown, however this is most likely due to the interwoven interactions that APAP have in multiple pain pathways. Our current knowledge suggests that APAPs are metabolised by the liver into p-aminophenol, then bound with arachidonic acid, primarily in the brain, to form AM404 (N- (4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide) through fatty acid amide hydrolase (FAAH) activity [132, 133, 134]. Like NSAIDs, APAP are analgesic and antipyretic, however APAP lacks peripheral anti-inflammatory properties, therefore act through the central nervous system and not peripheral tissues [135]. Current evidence suggests that there are four metabolic systems that interact to elicit the analgesic and antipyretic properties of APAP, the Eicosanoid, Opioidergic, Seretogentic and Endocannabinoid systems [136].
\nBriefly, like NSIADs, APAP can inhibit central cyclo-oxygenases (COX-1, COX-2) including a proposed third isoform COX-3 [137, 138, 139, 140, 141, 142]. Although the results are controversial [143] it is thought that they are involved in prostaglandin (PGs) production thus the analgesic mechanism of action. Furthermore, APAP are more effective in environments with low peroxide tone and low arachidonic acid levels, such as in the central nerves system, mainly through local depletion of glutathione leading to decreased production of PGE2 [139]. Considering the antinociceptive effects of APAP, one of the main brain derived metabolites AM404 (N-arachidonoyl-phenolamine) is decrease in the presence of opioid receptor antagonist. AM404 inhibits the nociceptive activity of particular APAPs in part by modulating many neurotransmitters, including 5-HT, glutamate, and γ-aminobutyric acid [143, 144, 145]. Although the precise receptors have not been identified [146, 147, 148, 149], serotonin antagonists block the analgesic effect of APAP through mainly indirect non-binding mechanisms [146, 150]. One possible interaction with the serotonergic pathway maybe though altering CNS monoamine neuron types in the brain that contain a major receptor for PGE2 (EP3 receptor [139]). Further to the above, AM404 can inhibit anandamide [151], with stimulation of (canobinoide 1) CB1 receptor activity (without binding) via FAAH [133], suggesting a reliance of APAP antinociceptive activity on interaction with the endocannabinoid system [134, 152]. Interestingly, AM404 is not identifiable in the blood after APAP administration [133] which might explain, to some degree, the absence of peripheral anti-inflammatory action [134]. This could help to explain why APAP may not have significant clinical effect on conditions such as osteoarthritis (further details below; [153, 154]). A recent study confirmed that APAPs act mainly on central analgesic pathways, showing that APAP modifies the activity and connectivity of analgesia via FAAH, activating a signalling cascade involving TRPV1 channels, mGlu5 receptors, PLC, DAGL and CB1 receptors, associated with the release of glutamate and GABA – through the endocannabinoid systems [155]. Though the molecular mechanisms that provide analgesia are beginning to come to light, there is also potential substantial detrimental side effects of APAPs.
\nAPAPs are generally considered safe if administered at appropriate doses for short periods [156]. However, they remain one of the leading causes of liver disease in high-income countries [157, 158] which has led to legislative restrictions in many countries [159]. It is well accepted that APAPs cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] and that this toxicity can be effected by interindividual variation [162]. Nonetheless, consuming APAP can increase the risks of hospitalisation for perforation, peptic ulceration and bleeding [163], relative rates of adverse cardiovascular events such as myocardial infarction, stroke, coronary heart disease and upper gastrointestinal disease such as gastroduodenal ulcers and haemorrhages [164], often in a dose response manor. However, observational studies show a favourable side effect profile for APAPs compared with NSAIDs when used in older people with chronic pain conditions [165]. Data from the most recent meta-analysis shows that APAPs are nearly four times more likely to have abnormal results on liver function tests than placebo [166].
\nOsteoarthritis (OA) is a complex musculoskeletal condition that effects people of all ages but particularly those over 55 years [167, 168, 169, 170, 171]. According to the Osteoarthritis Research Society International (OARSI) OA can be defined as;
\nOA is a pro-inflammatory branch of rheumatic disease that effects synovial joints progressively and is caused by the failure of joint tissues to repair following damage. This damage may have been caused by stresses due to an abnormality in the articular cartilage, subchondral bone, ligaments, menisci, periarticular muscles, peripheral nerves or synovium [173, 174]. While cartilage degradation is the traditionally structural trademark of OA, it is generally considered a whole joint disease with many other morphological features [175, 176, 177, 178]. For example, an osteoarthritic joint may exhibit sclerosis in the subchondral bone, osteophytes [179], local inflammation such as synovitis [177, 178, 180, 181] and bone marrow lesions [182]. Failure of normal biological repair processes that leads to breakdown of cartilage and bone [183] is characterised by symptoms of pain, stiffness, functional disability [184] that can lead to negative impacts on fatigue, mood, sleep, overall quality of life [185, 186].
\nOA confers a number of modifiable and non-modifiable risk factors [174, 187]. Non-modifiable risk factors include previous joint injury [188, 189], malalignment and other mechanical factors [175, 176, 190, 191, 192, 193], age [189], sex [194], ethnicity [195] and genetic predisposition [196, 197, 198]. Modifiable risk factors include obesity [181, 189, 199, 200, 201, 202], metabolic syndrome [181, 203, 204, 205, 206], in particular diabetes mellitus [207, 208, 209] and habitual diet [187, 210].
\nThe condition is one of the most common causes of chronic pain and the most common cause of joint pain [211] with conservative estimates suggesting that there are approximately 500 million suffers worldwide [167, 212]. OA affects ~13% of all over 50’s (~7% in all ages; [213]) and has no cure [214, 215, 216, 217, 218] while being the 11th highest contributor to years lived with disability [159].
\nChronic inflammatory-associated pain can have multiple mechanisms [219, 220, 221, 222, 223] and can stem from mechanical stress or central sensitization either concurrently and/or vary in their influences over time [224]. Pain derived from OA can generally be characterised into two common clinical forms of pain, intermittent but severe/intense and persistent pain or aching [225]. These pain experiences can come from neuropathic and nociceptive process, as discussed above. The prevalence of neuropathic pain features at the knee in OA patients ranges from 19% to 29% [221, 226, 227]. However, recent studies of peripheral and central nerve sensitization [228], as well as nerve ending damage and regrowth [229, 230] have shown that neuropathic pain contributes substantially to the condition. This central sensitization is prominent in those that experience a high level of pain that is not proportional to radiographic evidence of structural damage [219] and contributes more to the pain experienced in women with symptomatic OA, compared to men [231]. Generally, a higher degree of central sensitization or neuropathic pain is associated with high pain intensity and a greater chance of developing chronic pain following joint replacement [232, 233]. The remaining 70-80% of knee OA pain appears to be nociceptive in nature, thus OA can be described as a chronic mild to moderate nociceptive dominant pain condition [24, 234] and should be considered as such with regards to initial treatment [24].
\nThe diversity of pathophysiological maladaptation in OA effected joints and the low associations of these changes with pain, suggests doubt over the link between joint structural condition and the experience of pain. This is evident from the poor relationship between radiographic images and reported pain. A recent systematic review showed that the prevalence of knee pain in patients with radiographic knee OA ranged from 15% to 81% [235]. However, some studies reported associations between the structural damage of the joint (cartilage and bone) and pain [236] but at higher levels of X-ray derived pathology (Kellgren/Lawrence grade; [237]). Nonetheless, pain may still indicate a level of disease activity. In a number of studies looking more specifically at joint morphological characterises, OA pain has been associated with the rate of medial cartilage loss (also after adjustment for radiographic OA stage; [238]), osteophytes [239], more erosive OA compared to non-erosive OA [240] and changes of bone marrow lesions and synovitis [182]. These data show the complexity of the disease-pain nexus and suggests that the disease should, in the first instance (i.e. mild OA), be treated generally with lifestyle and nutritional intervention rather that pharmaceuticals that target specific pathological pathways (Figure 1) [241]. Regardless, pharmaceutical therapies remain the main treatment for such conditions [242].
\nOA is a progressive condition with no cure where opioids, acetaminophen and non-steroidal anti-inflammatory drugs (NSAID) are the traditional, non-lifestyle, approach for early management. However, as eluded to earlier, these pharmaceutical treatments are often accompanied with significant side effects. For example, NSAIDs are the traditional approach for early clinical management of mild-to-moderate OA [241] and in the US 65% of all OA patients are prescribed NSAID for pain management - this is the current recommended strategy for OA clinical management by the leading authorities [243]. While some NSAIDs are effective at improving pain and physical function, they come with significant and potentially harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events [244]. Although some of these risks may be reduced using topical administration such as Diclofenac gel/cream [245, 246]. Two recent large-scale studies have shown that, depending on the particular medication, the risk of hospital admissions (due to heart failure) can be nearly two times greater (Ketorolac; [247]) in OA/rheumatoid arthritis (n = 24,081), with ibuprofen (generally speaking, the most used NSAID) presenting with the highest rates of NSAID toxicity [248].
\nApproximately 34% of OA patients use Paracetamol [249], in isolation or in combination with NSAIDs. In fact, the effectiveness of Paracetamol to improve pain management has recently been called into question [124], as it has been shown to be ineffective for treating OA pain [125, 250] and may have similar side effects as ibuprofen [251], particularly when consumed at higher doses [164]. Specifically, in knee or hip OA, a recent Cochrane review concluded that Paracetamol provides no clinically important improvements in pain in the immediate and short term (up to 12 weeks; [16]). In addition, a recent network meta-analysis (56 randomised controlled trials, 22 128 participants) suggests that paracetamol was least effective for the treatment of knee and/or hip OA compared with celecoxib (NSAID) or the combination of glucosamine and chondroitin [117] – confirming other reports [252]. In contrast, some authors have concluded that paracetamol had similar efficacy to NSAIDs for the treatment of OA [253]. It is also important to remember that overuse of APAPs can cause liver injury, hepatotoxicity, mitochondrial toxicity [160, 161] which is relevant to a chronic condition with no known cure. These data led to confusion in earlier guidelines that consistently recommended the prescription of paracetamol (acetaminophen) as the first line analgesic for these conditions [90, 91, 241, 254, 255]. However, the data are now relatively clear that there is little clinically meaningful effect of Paracetamol for OA pain [153, 154].
\nThe potential negative effects such as addiction and the physiological side effects of opioid use are well documented, as discussed above, however they remain highly prescribed for OA and are expected to triple in the coming years [256, 257]. More than half of those prescribed opioids in the first year of OA have been shown to be inappropriately dispensed [257]. The prevalence of opioid use for OA ranges from 8-26% and in Australia, with the use for knee/hip OA has being described as “alarmingly high” [257]. A number of systematic reviews and meta-analysis have been performed in recent years and have unanimously shown that the tolerability is low, efficacy for pain relief in OA is not clinically relevant and the potential harms are high [258, 259, 260]. Despite calls for guidelines to be changed on the use of opioids and the above-mentioned pharmaceuticals, their use is increasing (likely with the prevalence of the disease) and by proxy the negative consequences rising in tandem. Therefore, non-pharmaceutical food-based alternatives (termed bioactive nutraceuticals) have been developed and are beginning to be recommended as early treatment [261, 262, 263] to improve OA symptoms including pain [241, 264, 265, 266].
\nGiven the possible side-effects of pharmaceutical treatments, any reduction in their use is of particular importance to OA public health. As such, a number of non-pharmaceutical alternatives have been developed that may reduce the use/required dose of pharmaceuticals while maintaining or improving the impacts on OA pain and physical function. The majority of these alternatives are termed “nutraceuticals” (a portmanteau of the words “nutrition” and “pharmaceutical”), coined in 1989 by Dr. Stephen DeFelice [267], founder and chairman of the Foundation for Innovation in Medicine.
\nWhile it is unlikely that Hippocrates (traditionally regarded as the father of modern medicine; died 375 BCE) actually said: “Let food be your medicine and medicine your food” [268], this is often cited in the context of nutraceuticals. A more apt and legitimate quote defines the position of nutraceuticals in health and disease as “beyond diet, before drug”, coined by Ettore Novellino in 2012 [269].
\nThere is currently no universally accepted definition of a nutraceutical [270], with the main confusion being the differences between nutraceuticals and functional foods, and the lack of regulatory definition between them (Table 1) [270, 271, 272, 273]. In fact, current European regulations do not distinguish between nutraceuticals and food supplements (see the EC Regulation n. 1924/2006 of the European Parliament and Council, recently updated by the UE regulation 2015/2283), therefore neither does the European Food Safety Authority [274, 275]. However, a number of proposed definitions exist (Table 1) and from these definitions, for the purposes of this chapter, a nutraceutical will be defined as;
\nAuthor(s) | \nDefinition | \n
---|---|
DeFelice, [267]; coined in 1989 | \n“A nutraceutical is any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” | \n
Zeisel, [271] | \n“……as those diet supplements that deliver a concentrated form of a presumed bioactive agent from a food, presented in a non-food matric, and used to enhance health in dosages that exceed those that could be obtained from normal food” | \n
U.S. Nutraceutical Research and Education [276] | \n“a dietary supplement, food or medical food that has a benefit, which prevents or reduces the risk of a disease or health condition, including the management of a disease or health condition or the improvement of health; and is safe for human consumption in the quantity, and with the frequency required to realise such properties” | \n
The European Nutraceutical Association [277] | \n“are nutritional products that provide health and medical benefits, including the prevention and treatment of disease. In contrast to pharmaceuticals however, these are not synthetic substances or chemical compounds formulated for specific indications. These are products that contain nutrients (partly in concentrated form) and mostly are assigned to the category of food. Dietary supplements are a typical example for nutraceuticals, but also dietetic and functional foods may be counted among these products.” | \n
Health Canada [278] | \n“A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against chronic disease” | \n
Corzo et al. [279] | \n“Nutraceuticals are biological substances extracted from natural sources by non-denaturing processes to preserve their original properties without any chemical manipulation.” | \n
Currently used definitions to describe nutraceuticals.
As such, the following sections will discuss those nutraceuticals that are currently not in mainstream use but may have the potential to aid in treatment of OA (i.e. the well discussed Glucosamine and Chondroitin will not feature in this chapter) but are in regular use worldwide [280]. The identified nutraceuticals that have been compared to/with NSAID/analgesics for OA can be divided into three categories, defined by their origin, and are presented in Table 2;
Terrestrial Botanicals, compounds derived from ‘land’ plant sources (avocado/soybean, pine bark extract and turmeric/curcumin).
Marine Botanicals, compounds derived from ‘marine’ plant sources (Lithothamnion species).
Marine Fauna, derived from marine animals (fish oil and green lipped mussel).
Proposed main active compound | \nTreatment regime | \nEffect on OA Analgesia and NSAID | \nReference | \n
---|---|---|---|
Avocado/soybean unsaponifiables | \nAvocado/soybean unsaponifiables 300 mg or 600 mg ASU for 3 months | \n↓ NSAIDs and analgesics use by 50% vs. placebo ↓ pain (~50%) in both 300 mg and 600 mg vs. placebo | \n[281] | \n
Avocado/soybean unsaponifiables | \nPiascledine/ASU (300 mg daily) for 6 months | \n↓ Participants using analgesics and NSAIDs (from 58.8% to 24.9%) ↓ Median pain (by ~50%) and pain intensity, pain at rest (by 100%) and pain during walking (by ~60%) ↓ Mobility score (by ~50%) | \n[282] | \n
Avocado/soybean unsaponifiables | \nAvocado/soybean mixture, 300 mg daily orally versus celecoxib,200 mg/day orally for 8 weeks | \n↓ Cartilage oligomeric matrix protein (COMP) in both groups (by ~37%, Avocado/soybean and ~ 27%, celecoxib), with no differences between groups | \n[283] | \n
Fish oil/ | \nPhytalgic (fish-oil, vitamin E, Urtica dioica) 3 capsules daily for 12 weeks | \n↓ NSAIDs use vs. the placebo (by ~60%) ↓ Analgesic use vs. the placebo (BY ~40%) ↓ Pain (by ~37%), stiffness (by ~43%) and function (by ~40$) vs. placebo | \n[284] | \n
Green lipped mussel | \n600 mg of BioLex(R)-GLM extract daily or placebo for 12 weeks | \n↓ Paracetamol use (by ~30% post-trial) vs. placebo ↓ Stiffness (by ~19%) vs. placebo, no difference pain | \n[285] | \n
Pine bark extract | \nPycnogenol (pine bark extract) 100 mg for 3 months | \n↓ Use of drugs (by ~57%) vs. placebo ↓ Gastrointestinal complications (by ~60%) vs. placebo ↓ WOMAC score (by ~40%) vs. placebo ↑ Walking distance (by ~34%), compared to no improvement in placebo | \n[286] | \n
Turmeric | \nTurmeric extracts (2 g extracts/day) or ibuprofen (800 mg) for 0, 2, 4 and 6 weeks | \n↓ Pain on walking stairs vs. ibuprofen (however, ibuprofen was greater at baseline thus throughout) No difference in pain on level walking, 100 m walking time or stair climb | \n[287] | \n
Turmeric | \nTurmeric extracts (1500 mg extracts/day) or ibuprofen (1200 mg/day) for 4 weeks | \n↓ WOMAC score, pain and function compared to baseline scores at all time points, and was non-inferior to ibuprofen. ↓ Rate of abdominal pain/distention vs. ibuprofen (by ~60%) | \n[288] | \n
Curcumin | \nBCM-95® Curcumin: 500 mg/capsule twice daily, Curcumin 500 mg + diclofenac sodium 50 mg/capsule twice daily, diclofenac 50 mg/ capsule twice daily, all for 8 weeks | \n↓ Disease Activity Score (by ~45%), CRP (by ~52%), American College of Rheumatology score, improved pain (by ~60%), erythrocyte sedimentation rate (by ~11%), greater in Curcumin and Curcumin+ diclofenac vs. diclofenac alone | \n[289] | \n
Curcumin | \nBCM-95® (curcumin, demethoxycurcumin, bisdemethoxycurcumin, and volatile oils from turmeric rhizome), 500-mg three times daily versus diclofenac 50-mg tablet two times daily for 28 days | \n↓ Pain similar in both groups (by ~78% for both), no difference between groups ↑ KOOS variables (n = 5) similar in both groups, no difference between groups ↑ Flatulence in diclofenac vs. curcumin (by ~79%) ↓ Requirement for H2 blockers in curcumin vs. diclofenac (by 100%, i.e. zero in curcumin) ↓ Incidence of adverse effects in curcumin vs. diclofenac (by ~76%) | \n[290] | \n
Curcumin | \nLongvida®, 800 mg patented lipophilic matrix delivering 160 mg curcumin versus Ibuprofen (400 mg) orally and daily for 12 weeks | \n↓ Pain in both (by ~60%), no difference between groups | \n[291] | \n
Curcumin | \nHerbal formulation of curcumin (300 mg), gingerols (7.5 mg), and piperine (3.75 mg; Mixodin) versus Naproxen 250 mg capsules, both twice a day for 4 weeks | \n↓ prostaglandin E2 (PGE2) in booth groups with no difference between the two (~27 pg./mL) | \n[292] | \n
Curcumin | \nMeriva tablets, a curcumin-phosphatidylcholine phytosome complex, 200 mg equivalent curcumin daily with best available care (BCA) compared to BCA only as control for 8 months | \n↓ NSAIDs use (by ~80%) vs. control ↓ Gastrointestinal complaints (by ~40%) vs. control ↓ Pain (by ~44%), stiffness (by ~28%), physical function (by ~40%), WOMAC score (by ~41%), compared to no improvements in controls ↑ Karnofsky Performance Scale (by ~22%), compared to no improvement in controls ↑ Treadmill walking distance (345% increase from baseline) compared to 89% in controls ↓ inflammatory markers sCD40L (by ~56%), IL-1β (by ~35%), IL-6(by ~27%), sVCAM-1 (by ~30%), ESR (by ~25%), compared to no change in controls | \n[293] | \n
Curcumin | \nTheracurmin® (10% of curcumin, 2% other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% of water; 180 mg of curcumin) for 8 weeks | \n↓ NSAID (celecoxib) dependence (p = 0.0252) ↓ Pain (by ~55%) vs. placebo | \n[294] | \n
Curcumin | \nC3 complex, 500 mg curcuminoid capsules including 5 mg Bioperine, 3 times daily for 6 weeks | \n↓ Naproxen use (by ~73%) vs. controls ↓ Pain (by >38%), function (by ~41%) and WOMAC score (by ~41%) vs. placebo | \n[295] | \n
Ginger | \nTopical ginger extract gel (4% gel Plygersic) versus sodium diclofenac gel applied 1 mL of solution 4 times a day for 6 weeks | \n↓ Pain (by ~27%), symptoms (by ~27%) No difference in the above between groups | \n[296] | \n
Ginger | \nDiclofenac 50 mg orally or Ginger 750 or Ginger 750 mg and Diclofenac 50 mg orally for 12 weeks | \n↓ Pain and WOMAC score in all three groups, greatest improvement with Ginger (60%; 75%) the addition of ginger to Diclofenac (67%; 79%), compared to Diclofenac alone (59%; 64%) ↓ Use of rescue medication (paracetamol) in Ginger (50%) and Ginger with Diclofenac (87%) compared to Diclofenac alone (not statistically significant) | \n[297] | \n
Lithothamnion species (Red Algae) | \nAquaminF, 267 mg Lithothamnion, 3 capsules per day, 3 times a day for 12 weeks | \n↑ ROM (by 5.2°) and 6MWD (By 136 ft) following 50% forced reduction from all NSAID in AquaminF vs. placebo No difference in rescue medication (acetaminophen) consumption between groups ↑ Six meter walking distance (by~92%) following 50% forced reduction from all NSAID in AquaminF vs. placebo | \n[298] | \n
Lithothamnion species combination | \nAquamin+, 2668 mg Lithothamnion, 268 mg seawater-derived Mg(OH)2 and pine bark extract 120 mg versus 2000 mg Glucosamine Sulphate Daily dose for 12 weeks | \n↓ Pain (by ~11%), symptoms (by ~7%), no change in Glucosamine ↑ Sport and recreation (by ~9%), no change in Glucosamine ↑ Timed up and go performance (by 7%), no change in Glucosamine ↓ Rescue analgesic use (by 72%) vs. Glucosamine | \n[299] | \n
Nutraceuticals shown to reduce analgesic and NSAID use.
Turmeric/curcumin extracts (spices used mainly in South Asian cooking) or nutraceuticals combinations where turmeric/curcumin extracts are the main active ingredient, have the greatest amount of evidence for improving OA symptoms, with some recent data on NSAID and analgesics use (Table 2) [300]. Two studies have directly compared raw turmeric/curcumin extracts to NSAIDs and their effectiveness for OA symptoms [287, 288]. These data show that turmeric extracts either improved or were shown to be non-inferior for knee osteoarthritis (KOA) pain, pain during stair walking and resulted in less side effects (particularly the rate of abdominal pain/distention) compared to oral ibuprofen [287, 288, 289]. Furthermore, patented/propriety formulations of turmeric/curcumin extracts have been developed around the world and show some promising effects on OA (Table 2). Interestingly, Chandran et al. demonstrated that curcumin formulated as BCM-95® or ‘BCM-95® + diclofenac sodium’ showed superior ‘Disease Activity Scores’, American College of Rheumatology score, pain, CRP levels and erythrocyte sedimentation rate, compared to diclofenac alone (Indian population; [289]). The same formulation showed similar improvements of KOOS variables, but BCM-95® resulted in less adverse events (including flatulence) and a lower requirements for H2 blockers (0% vs. 28%; a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach), compared to diclofenac [290]. In the longest of these studies (8 months in a European cohort), the addition of Meriva® (curcuminoids 20%, phosphatidylcholine 40%, and microcrystalline cellulose 40%) to the “best available treatment”, reduced NSAID and analgesia use by 63% compared to the control group (“best available treatment” only). This reduction resulted in less side-effects between 45-67%, depending on the specific adverse advent, compared to side-effects in the control group (2-12%; [293]). Similarly, an alternative preparation (C3 complex®; Curcuminoids 500-mg capsules with 5-mg Bioperine®) reduced the use of naproxen by 84% (compared to 19% in placebo) in Iranian KOA patients and a further alternative (Theracurmin®; 10% of curcumin, 2% other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 46% glycerin, 4% gum ghatti, and 38% of water; 180 mg of curcumin) reduced dependence on celecoxib in Japanese KOA patients (from ~70% to ~30% versus ~80 to ~60% in placebo; [294]). Recently, Heidari-Beni et al. [301] presented findings from a herbal formulation containing curcumin (300 mg), gingerols (7.5 mg) and piperine (3.75 mg), taken twice a day for 4 weeks. This formulation reduced PGE2 (see above text and Figure 1) of KOA patients to the same extent as Naproxen (250 mg capsules daily). There is significant mechanistic evidence to support these
Alternative terrestrial botanicals have shown some advantages for OA. Three studies have investigated avocado/soybean extracts and their potential in reducing NSAID and analgesics use. One large randomised control trial (n = 260) showed that after 30 days (and continued to day 90) of supplementation, the extracts (300 or 600 mg) reduced the daily intake of NSAID and analgesics compared to placebo. Furthermore, 71% (compared to 36% in placebo) of avocado/soybean extract participants reduced their daily intake by greater than 50%, [281]. Although it must be noted that the treatment was stopped in nine participants due to adverse events from the extract, however the authors did not statistically analyse incidence of adverse events of the remaining participants, but they were generally similar to placebo. These results were somewhat supported by a smaller (n = 31; part of a large cohort receiving a number of nutraceutical compounds) observational study showing that the proportion of OA patients using analgesics and NSAIDs dropped by 34% over 6 months consuming avocado/soybean extracts [282]. Although, in this large scale “real-world” (PEGASus) study cohort where analgesic and NSAID use was assessed by phone interview bi-monthly over 2 years, avocado/soybean extracts showed no effect on reducing medication use [313]. Recently, a 2-month supplementation of avocado/soybean unsaponifiables (n = 30; 300 mg daily) was compared to celecoxib (n = 30; 200 mg/day) for changes in a biomarker of cartilage breakdown (Cartilage oligomeric matrix protein; COMP). The results showed that both interventions reduced serum COMP levels with a tendency for greater improvements with avocado/soybean unsaponifiables (33.8% vs. 30.3%; p = 0.06; [283]). These data in addition to other mechanistic work show that avocado/soybean unsaponifiables can impact both inflammatory and structural protein biomarkers of OA pathology. Specifically they can inhibit IL-1, reduce production of stromelysin, IL-6, IL-8 and PGE-2, increase the expression of TGF-β and activate collagen synthesis [283, 314, 315, 316]. There is some debate over the efficacy of avocado/soybean extracts to alleviate analgesics and NSAID use but there is developing molecular evidence that they may elicit similar reductions on
Two studies investigated Ginger root extract formulations in OA NSAID use. Compared to 1% diclofenac gel, topical ginger extract (Plygersic gel) reduce KOOS variables (pain, symptoms etc.) equally after a six week intervention in mild radiographic KOA [296]. Further, oral consumption of a Ginger root extract formulation, compared (1) 50 mg of oral Diclofenac with Ginger 750, (2) Ginger 750 mg and (3) Diclofenac 50 mg for 12 weeks [297]. All interventions decreased pain and WOMAC variables but there was a reduction in rescue medication in the ginger groups, although this was not statically significant [297]. While these results are interesting, significantly more research is needed with larger more well controlled studies but there is molecular evidence to support these reported effects. Ginger root species can block the formation of inflammatory mediators such as thromboxane, leukotrienes and prostaglandins and inhibit COX and lipoxygenase in arachidonic acid metabolism [317, 318, 319, 320, 321, 322, 323, 324, 325] i.e. similar mechanisms to those presented in Figure 1.
\nFinally, the trade marked Pycnogenol® (pine bark extract; 100 mg) has been shown to reduces NSAID use by 58%, compared to only 1% in the placebo group in early-KOA patients over 12 weeks [286]. This resulted in reduced hospital admissions and days spent in hospital by 50% compared to placebo (n = 156; [286]). As with the above, Pycnogenol inhibits activation of NFκB pathway mediators, particularly, COX and pain-producing prostaglandins and also activates metabolomic compounds with anti-inflammatory bio-efficacy [326, 327, 328]. Again, these data are interesting and demonstrate good potential but require further
New Zealand Green Lipped Mussel (Perna canaliculus) lipid extracts have recently been investigated for their potentially benefits for OA symptoms. Moderate-to-severe hip and knee OA patients received 600 mg of Biolex®-GLM for 12 weeks or a placebo and were allowed to consume paracetamol for additional pain relief [285]. Participants consuming the placebo took more paracetamol each week of the 12 weeks resulting in a statically significant change at the final week (p = 0.001), however did not differ in NSAID equivalence score. This suggests that there may be some potential for Green Lipped Mussel to reduce analgesic medication, although less so than others mentioned herein. Again, Green Lipped Mussel appears to inhibit COX enzymes, competitive inhibition of arachidonic acid metabolism and reduce chronic inflammation [329].
\nA fish oil and Urtica dioica preparation has also been shown to reduce medication use in OA. A proprietary combination of omega-3 and omega-6 fatty acids, Urtica dioica (the common nettle), zinc and vitamin E (Phytalgic®) progressively reduced NSAID and analgesia use over a tree month period (n = 81; 6.5 Paracetamol 500 mg-Equivalent per week, compared to 16.5 in the placebo group; [284]). The authors ascribed this adaptation to the anti-inflammatory potential of the mineral composition, mainly from Urtica dioica within the formulation rather than the fish oil component [284]. This was most likely the case as a previous study showed no effect of cod liver oil an OA [330] and the articles referenced to show a mechanistic potential for fish oil components (n-3 and n-6 polyunsaturated fatty acids) have recently been retracted [331, 332].
\nThe marine red Algae species Lithothamnion corallioide, rich in sea water derived minerals including Calcium and Magnesium (AquaminF®), have recently been investigated for a potential impact on NSAID usage. In a randomised control trial of moderate-to-severe KOA patients that were regularly consuming NSAIDs, AquaminF (534 mg daily) was an effective agent for improving physical performance (six minuet walking distance), when NSAID use was intentionally reduced to 50% of previous consumption, but not when NSAID consumption was reduced to zero [298]. Furthermore, Lithothamnion (2668 mg) combined with seawater-derived Mg(OH)2 (268 mg) and pine bark extract (120 mg) reduced analgesic and NSAID use by 72% compared to Glucosamine Sulphate (2000 mg Daily dose) [299]. Mechanistically, Lithothamnion corallioide species appear to have the ability to inhibit the NFκB pathway, reduce inflammatory cytokines such as tumour necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and COX2, along with reduced serum TNF-α [333, 334, 335, 336]. This suggested there is potential for Lithothamnion species to reduce the KOA-related drug dependency
These data are of considerable interest to those suffering from OA and medical practitioners concerned with the broader health impacts of pharmaceuticals use in OA patients. There appears to be a growing body of evidence suggesting that a variety of nutraceutical compounds, many in preparatory formulations, could provide some relief from the burden of NSAID and analgesic dependence, thus their associated side-effects. Currently the data are limited with respect to replication, sample size and duration, making conclusions about long term effectiveness difficult. The one potential exception is turmeric/curcumin extracts that in a recent meta-analysis it was shown that typically 1000 mg/day of curcumin was effective for improve OA symptoms (potentially better that NSAID) over 8-12 weeks - but the authors still call for significantly more research, specifically with increased sample size and better design quality [300].
\nWhile the precise molecular mechanisms of OA progression remain unclear, it appears to be exacerbated by the activation of NFκB signalling pathway, initiated by a host of mechanical and chemical stress stimuli, including excessive mechanical stress brought about by surplus body mass, proinflammatory cytokines and extracellular matrix degradation products [337, 338]. These actions reduce the amount of articular cartilage in the joints and degrade subchondral bone, thus induce pain and difficulty in movement. As a result, OA treatments focus on relieving pain and swelling, improving joint mobility, increasing musculoskeletal strength and minimising the disabling effects of the disease [339]. The NFκB signalling pathway and inflammatory mechanisms appear to be the molecular actions of the majority of the above nutraceuticals in combination with the inhibition of COX enzymes. These imply that their mechanism of action for pain relief (and therefore potential reduction in analgesic use) are via peripheral nociceptive action with little interaction through neuropathic mechanisms (unless through local inflammatory assault of nerve fibres).
\nAs discussed throughout, there appears to be even further benefit through combinations of nutraceuticals that may have an additive effects to reduce NSAID/analgesic use and are recommended [263]. However, additional work needs to be carried out to understand the individual effects of these combinations in addition to the synergistic impact. This requirement is evident through the work by Jacquet et al. [284] where it appears that the proposed benefit of the combination was not attributable to the ingredient that is mentioned and discussed firstly (fish oil), rather the benefit lies with Urtica dioica and mineral composition. These combinations are often proprietary formulations where the precise combinations are not publicly available. However, where this is not the case better understanding can be achieved through
In conclusion, this chapter has described and discussed chronic pain, specifically osteoarthritis, and presented evidence that specific nutraceuticals and combinations may have potential to either elicit the same pain reliving effect of NSAIDs and analgesics or reduce the dependency on these drugs. Specifically, the greatest evidence exists for the inclusion of turmeric/curcumin extracts as an mild-OA treatment adjunct to reduce NSAID consumption. Any reduction in the use of harmful pharmaceutical drugs should be a welcome inclusion to any treatment plan particularly when some nutraceuticals, that appear to interact with similar molecular pathways as the discussed analgesics, may be capable of offering such benefit. However, it must be noted that significantly more experimental evidence is required for a number of these bioactives and their propitiatory formulations before specific recommendations can be made.
\nThe authors have no acknowledgements to make.
\nThe authors declare no conflict of interest.
General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed.
',metaTitle:"Horizon 2020 Compliance",metaDescription:"General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed. ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\\n\\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\\n\\nIn other words, publishing with IntechOpen guarantees compliance.
\\n\\nRead more about Open Access in Horizon 2020 here.
\\n\\nWhich scientific publication to choose?
\\n\\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\\n\\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\\n\\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
\n\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\n\nIn other words, publishing with IntechOpen guarantees compliance.
\n\nRead more about Open Access in Horizon 2020 here.
\n\nWhich scientific publication to choose?
\n\nWhen choosing a publication, Horizon 2020 grant recipients are encouraged to provide open access to various types of scientific publications including monographs, edited books and conference proceedings.
\n\nIntechOpen publishes all of the aforementioned formats in compliance with the requirements and criteria established by the European Commission for the Horizon 2020 Program.
\n\nAuthors requiring additional information are welcome to send their inquiries to funders@intechopen.com
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5820},{group:"region",caption:"Middle and South America",value:2,count:5289},{group:"region",caption:"Africa",value:3,count:1761},{group:"region",caption:"Asia",value:4,count:10546},{group:"region",caption:"Australia and Oceania",value:5,count:909},{group:"region",caption:"Europe",value:6,count:15932}],offset:12,limit:12,total:119318},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{sort:"dateEndThirdStepPublish",topicId:"6"},books:[{type:"book",id:"10801",title:"Uric Acid",subtitle:null,isOpenForSubmission:!0,hash:"d947ab87019e69ab11aa597edbacc018",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10800",title:"Ligase",subtitle:null,isOpenForSubmission:!0,hash:"1f10ff112edb1fec24379dac85ef3b5b",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10800.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10837",title:"Peroxisomes",subtitle:null,isOpenForSubmission:!0,hash:"0014b09d4b35bb4d7f52ca0b3641cda1",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10841",title:"Hydrolases",subtitle:null,isOpenForSubmission:!0,hash:"64617cf21bf1e47170bb2bcf31b1fc37",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10841.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8977",title:"Protein Kinase - New Opportunities, Challenges and Future Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"6d200cc031706a565b554fdb1c478901",slug:null,bookSignature:"Dr. Rajesh Kumar Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",editedByType:null,editors:[{id:"329385",title:"Dr.",name:"Rajesh",surname:"Singh",slug:"rajesh-singh",fullName:"Rajesh Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10797",title:"Cell Culture",subtitle:null,isOpenForSubmission:!0,hash:"2c628f4757f9639a4450728d839a7842",slug:null,bookSignature:"Prof. Xianquan Zhan",coverURL:"https://cdn.intechopen.com/books/images_new/10797.jpg",editedByType:null,editors:[{id:"223233",title:"Prof.",name:"Xianquan",surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10799",title:"Phenolic Compounds",subtitle:null,isOpenForSubmission:!0,hash:"339199f254d2987ef3167eef74fb8a38",slug:null,bookSignature:"Prof. Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/10799.jpg",editedByType:null,editors:[{id:"41865",title:"Prof.",name:"Farid A.",surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10741",title:"Synthetic Genomics - From Natural to Synthetic Genomes",subtitle:null,isOpenForSubmission:!0,hash:"eb1cebd0b9c4e7e87427003ff7196f57",slug:null,bookSignature:"Dr. Miguel Fernández-Niño and Dr. Luis H. Reyes",coverURL:"https://cdn.intechopen.com/books/images_new/10741.jpg",editedByType:null,editors:[{id:"158295",title:"Dr.",name:"Miguel",surname:"Fernández-Niño",slug:"miguel-fernandez-nino",fullName:"Miguel Fernández-Niño"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10886",title:"Genetic Polymorphisms - New Insights",subtitle:null,isOpenForSubmission:!0,hash:"a71558dd7dfd16ad140168409f887f7e",slug:null,bookSignature:"Prof. Mahmut Çalışkan",coverURL:"https://cdn.intechopen.com/books/images_new/10886.jpg",editedByType:null,editors:[{id:"51528",title:"Prof.",name:"Mahmut",surname:"Çalışkan",slug:"mahmut-caliskan",fullName:"Mahmut Çalışkan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10794",title:"Potassium in Human Health",subtitle:null,isOpenForSubmission:!0,hash:"0fbab5c7b5baa903a6426e7bbd9f99ab",slug:null,bookSignature:"Dr. Jie Tang",coverURL:"https://cdn.intechopen.com/books/images_new/10794.jpg",editedByType:null,editors:[{id:"181267",title:"Dr.",name:"Jie",surname:"Tang",slug:"jie-tang",fullName:"Jie Tang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10803",title:"Reactive Oxygen Species",subtitle:null,isOpenForSubmission:!0,hash:"176adcf090fdd1f93cb8ce3146e79ca1",slug:null,bookSignature:"Prof. Rizwan Ahmad",coverURL:"https://cdn.intechopen.com/books/images_new/10803.jpg",editedByType:null,editors:[{id:"40482",title:"Prof.",name:"Rizwan",surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10839",title:"Protein Detection",subtitle:null,isOpenForSubmission:!0,hash:"2f1c0e4e0207fc45c936e7d22a5369c4",slug:null,bookSignature:"Prof. Yusuf Tutar and Dr. Lütfi Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/10839.jpg",editedByType:null,editors:[{id:"158492",title:"Prof.",name:"Yusuf",surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:28},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:9},{group:"topic",caption:"Business, Management and Economics",value:7,count:3},{group:"topic",caption:"Chemistry",value:8,count:11},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:10},{group:"topic",caption:"Engineering",value:11,count:25},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:7},{group:"topic",caption:"Mathematics",value:15,count:3},{group:"topic",caption:"Medicine",value:16,count:48},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:4},{group:"topic",caption:"Psychology",value:21,count:5},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:13},popularBooks:{featuredBooks:[],offset:0,limit:12,total:null},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8148",title:"Investment Strategies in Emerging New Trends in Finance",subtitle:null,isOpenForSubmission:!1,hash:"3b714d96a68d2acdfbd7b50aba6504ca",slug:"investment-strategies-in-emerging-new-trends-in-finance",bookSignature:"Reza Gharoie Ahangar and Asma Salman",coverURL:"https://cdn.intechopen.com/books/images_new/8148.jpg",editors:[{id:"91081",title:"Dr.",name:"Reza",middleName:null,surname:"Gharoie Ahangar",slug:"reza-gharoie-ahangar",fullName:"Reza Gharoie Ahangar"}],equalEditorOne:{id:"206443",title:"Prof.",name:"Asma",middleName:null,surname:"Salman",slug:"asma-salman",fullName:"Asma Salman",profilePictureURL:"https://mts.intechopen.com/storage/users/206443/images/system/206443.png",biography:"Professor Asma Salman is a blockchain developer and Professor of Finance at the American University in the Emirates, UAE. An Honorary Global Advisor at the Global Academy of Finance and Management, USA, she completed her MBA in Finance and Accounting and earned a Ph.D. in Finance from an AACSB member, AMBA accredited, School of Management at Harbin Institute of Technology, China. Her research credentials include a one-year residency at the Brunel Business School, Brunel University, UK. Prof. Salman also served as the Dubai Cohort supervisor for DBA students under the Nottingham Business School, UK, for seven years and is currently a Ph.D. supervisor at the University of Northampton, UK, where she is a visiting fellow. She also served on the Board of Etihad Airlines during 2019–2020. One of her recent articles on “Bitcoin and Blockchain” gained wide visibility and she is an active speaker on Fintech, blockchain, and crypto events around the GCC. She holds various professional certifications including Chartered Fintech Professional (USA), Certified Financial Manager (USA), Women in Leadership and Management in Higher Education, (UK), and Taxation GCC VAT Compliance, (UK). She recently won an award for “Blockchain Trainer of the Year” from Berkeley Middle East. Other recognitions include the Women Leadership Impact Award by H.E First Lady of Armenia, Research Excellence Award, and the Global Inspirational Women Leadership Award by H.H Sheikh Juma Bin Maktoum Juma Al Maktoum.",institutionString:"American University in the Emirates",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"American University in the Emirates",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9959",title:"Biomedical Signal and Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"22b87a09bd6df065d78c175235d367c8",slug:"biomedical-signal-and-image-processing",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9959.jpg",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9515",title:"Update in Geriatrics",subtitle:null,isOpenForSubmission:!1,hash:"913e16c0ae977474b283bbd4269564c8",slug:"update-in-geriatrics",bookSignature:"Somchai Amornyotin",coverURL:"https://cdn.intechopen.com/books/images_new/9515.jpg",editedByType:"Edited by",editors:[{id:"185484",title:"Prof.",name:"Somchai",middleName:null,surname:"Amornyotin",slug:"somchai-amornyotin",fullName:"Somchai Amornyotin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9021",title:"Novel Perspectives of Stem Cell Manufacturing and Therapies",subtitle:null,isOpenForSubmission:!1,hash:"522c6db871783d2a11c17b83f1fd4e18",slug:"novel-perspectives-of-stem-cell-manufacturing-and-therapies",bookSignature:"Diana Kitala and Ana Colette Maurício",coverURL:"https://cdn.intechopen.com/books/images_new/9021.jpg",editedByType:"Edited by",editors:[{id:"203598",title:"Ph.D.",name:"Diana",middleName:null,surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7030",title:"Satellite Systems",subtitle:"Design, Modeling, Simulation and Analysis",isOpenForSubmission:!1,hash:"b9db6d2645ef248ceb1b33ea75f38e88",slug:"satellite-systems-design-modeling-simulation-and-analysis",bookSignature:"Tien Nguyen",coverURL:"https://cdn.intechopen.com/books/images_new/7030.jpg",editedByType:"Edited by",editors:[{id:"210657",title:"Dr.",name:"Tien M.",middleName:"Manh",surname:"Nguyen",slug:"tien-m.-nguyen",fullName:"Tien M. Nguyen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10413",title:"A Collection of Papers on Chaos Theory and Its Applications",subtitle:null,isOpenForSubmission:!1,hash:"900b71b164948830fec3d6254b7881f7",slug:"a-collection-of-papers-on-chaos-theory-and-its-applications",bookSignature:"Paul Bracken and Dimo I. Uzunov",coverURL:"https://cdn.intechopen.com/books/images_new/10413.jpg",editedByType:"Edited by",editors:[{id:"92883",title:"Prof.",name:"Paul",middleName:null,surname:"Bracken",slug:"paul-bracken",fullName:"Paul Bracken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9154",title:"Spinal Deformities in Adolescents, Adults and Older Adults",subtitle:null,isOpenForSubmission:!1,hash:"313f1dffa803b60a14ff1e6966e93d91",slug:"spinal-deformities-in-adolescents-adults-and-older-adults",bookSignature:"Josette Bettany-Saltikov and Gokulakannan Kandasamy",coverURL:"https://cdn.intechopen.com/books/images_new/9154.jpg",editedByType:"Edited by",editors:[{id:"94802",title:"Dr.",name:"Josette",middleName:null,surname:"Bettany-Saltikov",slug:"josette-bettany-saltikov",fullName:"Josette Bettany-Saltikov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8148",title:"Investment Strategies in Emerging New Trends in Finance",subtitle:null,isOpenForSubmission:!1,hash:"3b714d96a68d2acdfbd7b50aba6504ca",slug:"investment-strategies-in-emerging-new-trends-in-finance",bookSignature:"Reza Gharoie Ahangar and Asma Salman",coverURL:"https://cdn.intechopen.com/books/images_new/8148.jpg",editedByType:"Edited by",editors:[{id:"91081",title:"Dr.",name:"Reza",middleName:null,surname:"Gharoie Ahangar",slug:"reza-gharoie-ahangar",fullName:"Reza Gharoie Ahangar"}],equalEditorOne:{id:"206443",title:"Prof.",name:"Asma",middleName:null,surname:"Salman",slug:"asma-salman",fullName:"Asma Salman",profilePictureURL:"https://mts.intechopen.com/storage/users/206443/images/system/206443.png",biography:"Professor Asma Salman is a blockchain developer and Professor of Finance at the American University in the Emirates, UAE. An Honorary Global Advisor at the Global Academy of Finance and Management, USA, she completed her MBA in Finance and Accounting and earned a Ph.D. in Finance from an AACSB member, AMBA accredited, School of Management at Harbin Institute of Technology, China. Her research credentials include a one-year residency at the Brunel Business School, Brunel University, UK. Prof. Salman also served as the Dubai Cohort supervisor for DBA students under the Nottingham Business School, UK, for seven years and is currently a Ph.D. supervisor at the University of Northampton, UK, where she is a visiting fellow. She also served on the Board of Etihad Airlines during 2019–2020. One of her recent articles on “Bitcoin and Blockchain” gained wide visibility and she is an active speaker on Fintech, blockchain, and crypto events around the GCC. She holds various professional certifications including Chartered Fintech Professional (USA), Certified Financial Manager (USA), Women in Leadership and Management in Higher Education, (UK), and Taxation GCC VAT Compliance, (UK). She recently won an award for “Blockchain Trainer of the Year” from Berkeley Middle East. Other recognitions include the Women Leadership Impact Award by H.E First Lady of Armenia, Research Excellence Award, and the Global Inspirational Women Leadership Award by H.H Sheikh Juma Bin Maktoum Juma Al Maktoum.",institutionString:"American University in the Emirates",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"American University in the Emirates",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10201",title:"Post-Transition Metals",subtitle:null,isOpenForSubmission:!1,hash:"cc7f53ff5269916e3ce29f65a51a87ae",slug:"post-transition-metals",bookSignature:"Mohammed Muzibur Rahman, Abdullah Mohammed Asiri, Anish Khan, Inamuddin and Thamer Tabbakh",coverURL:"https://cdn.intechopen.com/books/images_new/10201.jpg",editedByType:"Edited by",editors:[{id:"24438",title:"Prof.",name:"Mohammed Muzibur",middleName:null,surname:"Rahman",slug:"mohammed-muzibur-rahman",fullName:"Mohammed Muzibur Rahman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9959",title:"Biomedical Signal and Image Processing",subtitle:null,isOpenForSubmission:!1,hash:"22b87a09bd6df065d78c175235d367c8",slug:"biomedical-signal-and-image-processing",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/9959.jpg",editedByType:"Edited by",editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editedByType:"Edited by",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editedByType:"Edited by",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"654",title:"Seismology",slug:"seismology",parent:{title:"Geology and Geophysics",slug:"geology-and-geophysics"},numberOfBooks:13,numberOfAuthorsAndEditors:311,numberOfWosCitations:364,numberOfCrossrefCitations:199,numberOfDimensionsCitations:451,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"seismology",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"8257",title:"Seismic Waves",subtitle:"Probing Earth System",isOpenForSubmission:!1,hash:"6a7acf0b6350ff87cc629283bfe248f8",slug:"seismic-waves-probing-earth-system",bookSignature:"Masaki Kanao and Genti Toyokuni",coverURL:"https://cdn.intechopen.com/books/images_new/8257.jpg",editedByType:"Edited by",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8361",title:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics",subtitle:null,isOpenForSubmission:!1,hash:"788c034eec48a4e2f1f6a2f1788d3346",slug:"applied-geophysics-with-case-studies-on-environmental-exploration-and-engineering-geophysics",bookSignature:"Ali Ismet Kanlı",coverURL:"https://cdn.intechopen.com/books/images_new/8361.jpg",editedByType:"Edited by",editors:[{id:"243975",title:"Dr.",name:"Ali Ismet",middleName:null,surname:"Kanlı",slug:"ali-ismet-kanli",fullName:"Ali Ismet Kanlı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8282",title:"Polar Seismology",subtitle:"Advances and Impact",isOpenForSubmission:!1,hash:"69e0f0e64b988f29d30532c2618705b2",slug:"polar-seismology-advances-and-impact",bookSignature:"Masaki Kanao",coverURL:"https://cdn.intechopen.com/books/images_new/8282.jpg",editedByType:"Authored by",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"4",chapterContentType:"compact",authoredCaption:"Authored by"}},{type:"book",id:"6213",title:"Risk Assessment",subtitle:null,isOpenForSubmission:!1,hash:"ee3d73b48171426d2edb88e55e20f615",slug:"risk-assessment",bookSignature:"Valentina Svalova",coverURL:"https://cdn.intechopen.com/books/images_new/6213.jpg",editedByType:"Edited by",editors:[{id:"62677",title:"Dr.",name:"Valentina",middleName:null,surname:"Svalova",slug:"valentina-svalova",fullName:"Valentina Svalova"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5958",title:"Seismic and Sequence Stratigraphy and Integrated Stratigraphy",subtitle:"New Insights and Contributions",isOpenForSubmission:!1,hash:"c7007d85d2a3d26fe08d934f72b0278d",slug:"seismic-and-sequence-stratigraphy-and-integrated-stratigraphy-new-insights-and-contributions",bookSignature:"Gemma Aiello",coverURL:"https://cdn.intechopen.com/books/images_new/5958.jpg",editedByType:"Edited by",editors:[{id:"100661",title:"Dr.",name:"Gemma",middleName:null,surname:"Aiello",slug:"gemma-aiello",fullName:"Gemma Aiello"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3059",title:"Engineering Seismology, Geotechnical and Structural Earthquake Engineering",subtitle:null,isOpenForSubmission:!1,hash:"2edf2eec98179a50d827dd4fd9dbe011",slug:"engineering-seismology-geotechnical-and-structural-earthquake-engineering",bookSignature:"Sebastiano D'Amico",coverURL:"https://cdn.intechopen.com/books/images_new/3059.jpg",editedByType:"Edited by",editors:[{id:"52181",title:"Dr.",name:"Sebastiano",middleName:null,surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3551",title:"Earthquake Research and Analysis",subtitle:"New Advances in Seismology",isOpenForSubmission:!1,hash:"b1e244d7ea470738d42bc37e38470f22",slug:"earthquake-research-and-analysis-new-advances-in-seismology",bookSignature:"Sebastiano D'Amico",coverURL:"https://cdn.intechopen.com/books/images_new/3551.jpg",editedByType:"Edited by",editors:[{id:"52181",title:"Dr.",name:"Sebastiano",middleName:null,surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2227",title:"Tectonics",subtitle:"Recent Advances",isOpenForSubmission:!1,hash:"3b4c2f80af61284334fb3655852de9f7",slug:"tectonics-recent-advances",bookSignature:"Evgenii Sharkov",coverURL:"https://cdn.intechopen.com/books/images_new/2227.jpg",editedByType:"Edited by",editors:[{id:"32743",title:"Prof.",name:"Evgenii",middleName:null,surname:"Sharkov",slug:"evgenii-sharkov",fullName:"Evgenii Sharkov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1602",title:"New Achievements in Geoscience",subtitle:null,isOpenForSubmission:!1,hash:"f2742feb8ad590c91677e0dd148fc36d",slug:"new-achievements-in-geoscience",bookSignature:"Hwee-San Lim",coverURL:"https://cdn.intechopen.com/books/images_new/1602.jpg",editedByType:"Edited by",editors:[{id:"3910",title:"Dr.",name:"Hwee-San",middleName:null,surname:"Lim",slug:"hwee-san-lim",fullName:"Hwee-San Lim"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2051",title:"Earthquake Research and Analysis",subtitle:"Statistical Studies, Observations and Planning",isOpenForSubmission:!1,hash:"492268d0be01c6d76f0e2e4ac5c35730",slug:"earthquake-research-and-analysis-statistical-studies-observations-and-planning",bookSignature:"Sebastiano D'Amico",coverURL:"https://cdn.intechopen.com/books/images_new/2051.jpg",editedByType:"Edited by",editors:[{id:"52181",title:"Dr.",name:"Sebastiano",middleName:null,surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"605",title:"Earthquake Research and Analysis",subtitle:"Seismology, Seismotectonic and Earthquake Geology",isOpenForSubmission:!1,hash:"7f97c97f3cf8d09622afa27f3fd2d1e4",slug:"earthquake-research-and-analysis-seismology-seismotectonic-and-earthquake-geology",bookSignature:"Sebastiano D'Amico",coverURL:"https://cdn.intechopen.com/books/images_new/605.jpg",editedByType:"Edited by",editors:[{id:"52181",title:"Dr.",name:"Sebastiano",middleName:null,surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2048",title:"Earthquake Research and Analysis",subtitle:"New Frontiers in Seismology",isOpenForSubmission:!1,hash:"28d7da86de8c245c5391e4a78f6c2d53",slug:"earthquake-research-and-analysis-new-frontiers-in-seismology",bookSignature:"Sebastiano D'Amico",coverURL:"https://cdn.intechopen.com/books/images_new/2048.jpg",editedByType:"Edited by",editors:[{id:"52181",title:"Dr.",name:"Sebastiano",middleName:null,surname:"D'Amico",slug:"sebastiano-d'amico",fullName:"Sebastiano D'Amico"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:13,mostCitedChapters:[{id:"37859",doi:"10.5772/50009",title:"Plate Tectonic Evolution of the Southern Margin of Laurussia in the Paleozoic",slug:"plate-tectonic-evolution-of-the-southern-margin-of-laurussia-in-the-paleozoic",totalDownloads:4863,totalCrossrefCites:12,totalDimensionsCites:41,book:{slug:"tectonics-recent-advances",title:"Tectonics",fullTitle:"Tectonics - Recent Advances"},signatures:"Jan Golonka and Aleksandra Gawęda",authors:[{id:"16567",title:"Dr.",name:"Jan",middleName:null,surname:"Golonka",slug:"jan-golonka",fullName:"Jan Golonka"}]},{id:"37864",doi:"10.5772/50145",title:"Role of the NE-SW Hercynian Master Fault Systems and Associated Lineaments on the Structuring and Evolution of the Mesozoic and Cenozoic Basins of the Alpine Margin, Northern Tunisia",slug:"role-of-the-ne-sw-hercynian-master-fault-systems-and-associated-lineaments-on-the-structuring-and-ev",totalDownloads:6637,totalCrossrefCites:14,totalDimensionsCites:23,book:{slug:"tectonics-recent-advances",title:"Tectonics",fullTitle:"Tectonics - Recent Advances"},signatures:"Fetheddine Melki, Taher Zouaghi, Mohamed Ben Chelbi, Mourad Bédir and Fouad Zargouni",authors:[{id:"39860",title:"Dr.",name:"Taher",middleName:null,surname:"Zouaghi",slug:"taher-zouaghi",fullName:"Taher Zouaghi"},{id:"147368",title:"Dr.",name:"Fetheddine",middleName:null,surname:"Melki",slug:"fetheddine-melki",fullName:"Fetheddine Melki"}]},{id:"26255",doi:"10.5772/30219",title:"Modelling Seismic Wave Propagation for Geophysical Imaging",slug:"modelling-seismic-wave-propagation-for-geophysical-imaging-",totalDownloads:6059,totalCrossrefCites:11,totalDimensionsCites:22,book:{slug:"seismic-waves-research-and-analysis",title:"Seismic Waves",fullTitle:"Seismic Waves - Research and Analysis"},signatures:"Jean Virieux, Vincent Etienne, Victor Cruz-Atienza, Romain Brossier, Emmanuel Chaljub, Olivier Coutant, Stéphane Garambois, Diego Mercerat, Vincent Prieux, Stéphane Operto, Alessandra Ribodetti and Josué Tago",authors:[{id:"12036",title:"Dr.",name:"Stephane",middleName:null,surname:"Operto",slug:"stephane-operto",fullName:"Stephane Operto"},{id:"12331",title:"Dr.",name:"Romain",middleName:null,surname:"Brossier",slug:"romain-brossier",fullName:"Romain Brossier"},{id:"12332",title:"Pr.",name:"Jean",middleName:null,surname:"Virieux",slug:"jean-virieux",fullName:"Jean Virieux"},{id:"121171",title:"Dr.",name:"Stéphane",middleName:null,surname:"Garambois",slug:"stephane-garambois",fullName:"Stéphane Garambois"},{id:"122541",title:"Dr.",name:"Emmanuel",middleName:null,surname:"Chaljub",slug:"emmanuel-chaljub",fullName:"Emmanuel Chaljub"},{id:"122542",title:"Dr.",name:"Olivier",middleName:null,surname:"Coutant",slug:"olivier-coutant",fullName:"Olivier Coutant"},{id:"122544",title:"Dr.",name:"Vincent",middleName:null,surname:"Etienne",slug:"vincent-etienne",fullName:"Vincent Etienne"},{id:"122545",title:"Dr.",name:"Diego",middleName:null,surname:"Mercerat",slug:"diego-mercerat",fullName:"Diego Mercerat"},{id:"122546",title:"Mr.",name:"Vincent",middleName:null,surname:"Prieux",slug:"vincent-prieux",fullName:"Vincent Prieux"},{id:"122548",title:"Dr.",name:"Alessandra",middleName:null,surname:"Ribodetti",slug:"alessandra-ribodetti",fullName:"Alessandra Ribodetti"},{id:"122550",title:"Dr.",name:"Victor",middleName:"M.",surname:"Cruz-Atienza",slug:"victor-cruz-atienza",fullName:"Victor Cruz-Atienza"},{id:"122551",title:"Mr.",name:"Josué",middleName:null,surname:"Tago",slug:"josue-tago",fullName:"Josué Tago"}]}],mostDownloadedChaptersLast30Days:[{id:"37864",title:"Role of the NE-SW Hercynian Master Fault Systems and Associated Lineaments on the Structuring and Evolution of the Mesozoic and Cenozoic Basins of the Alpine Margin, Northern Tunisia",slug:"role-of-the-ne-sw-hercynian-master-fault-systems-and-associated-lineaments-on-the-structuring-and-ev",totalDownloads:6636,totalCrossrefCites:14,totalDimensionsCites:23,book:{slug:"tectonics-recent-advances",title:"Tectonics",fullTitle:"Tectonics - Recent Advances"},signatures:"Fetheddine Melki, Taher Zouaghi, Mohamed Ben Chelbi, Mourad Bédir and Fouad Zargouni",authors:[{id:"39860",title:"Dr.",name:"Taher",middleName:null,surname:"Zouaghi",slug:"taher-zouaghi",fullName:"Taher Zouaghi"},{id:"147368",title:"Dr.",name:"Fetheddine",middleName:null,surname:"Melki",slug:"fetheddine-melki",fullName:"Fetheddine Melki"}]},{id:"64562",title:"Electrical Resistivity Tomography: A Subsurface-Imaging Technique",slug:"electrical-resistivity-tomography-a-subsurface-imaging-technique",totalDownloads:1926,totalCrossrefCites:3,totalDimensionsCites:4,book:{slug:"applied-geophysics-with-case-studies-on-environmental-exploration-and-engineering-geophysics",title:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics",fullTitle:"Applied Geophysics with Case Studies on Environmental, Exploration and Engineering Geophysics"},signatures:"Bing Zhou",authors:null},{id:"67965",title:"Seismic Velocity Structure in and around the Japanese Island Arc Derived from Seismic Tomography Including NIED MOWLAS Hi-net and S-net Data",slug:"seismic-velocity-structure-in-and-around-the-japanese-island-arc-derived-from-seismic-tomography-inc",totalDownloads:953,totalCrossrefCites:4,totalDimensionsCites:6,book:{slug:"seismic-waves-probing-earth-system",title:"Seismic Waves",fullTitle:"Seismic Waves - Probing Earth System"},signatures:"Makoto Matsubara, Hiroshi Sato, Kenji Uehira, Masashi Mochizuki, Toshihiko Kanazawa, Narumi Takahashi, Kensuke Suzuki and Shin’ichiro Kamiya",authors:null},{id:"37860",title:"Structural Geological Analysis of the High Atlas (Morocco): Evidences of a Transpressional Fold-Thrust Belt",slug:"structural-geological-analysis-of-the-high-atlas-morocco-evidences-of-a-transpressional-fold-thrust-",totalDownloads:14020,totalCrossrefCites:7,totalDimensionsCites:12,book:{slug:"tectonics-recent-advances",title:"Tectonics",fullTitle:"Tectonics - Recent Advances"},signatures:"Alessandro Ellero, Giuseppe Ottria, Marco G. Malusà and Hassan Ouanaimi",authors:[{id:"144013",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Ottria",slug:"giuseppe-ottria",fullName:"Giuseppe Ottria"},{id:"144580",title:"Dr.",name:"Alessandro",middleName:null,surname:"Ellero",slug:"alessandro-ellero",fullName:"Alessandro Ellero"},{id:"158054",title:"Dr.",name:"Marco G.",middleName:null,surname:"Malusà",slug:"marco-g.-malusa",fullName:"Marco G. Malusà"},{id:"158056",title:"Prof.",name:"Hassan",middleName:null,surname:"Ouanaimi",slug:"hassan-ouanaimi",fullName:"Hassan Ouanaimi"}]},{id:"57107",title:"Pharmaceuticals and Personal Care Products: Risks, Challenges, and Solutions",slug:"pharmaceuticals-and-personal-care-products-risks-challenges-and-solutions",totalDownloads:1084,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"risk-assessment",title:"Risk Assessment",fullTitle:"Risk Assessment"},signatures:"Zakiya Hoyett",authors:[{id:"209465",title:"Dr.",name:"Zakiya",middleName:null,surname:"Hoyett",slug:"zakiya-hoyett",fullName:"Zakiya Hoyett"}]},{id:"43814",title:"Damage Estimation Improvement of Electric Power Distribution Equipment Using Multiple Disaster Information",slug:"damage-estimation-improvement-of-electric-power-distribution-equipment-using-multiple-disaster-infor",totalDownloads:1244,totalCrossrefCites:2,totalDimensionsCites:2,book:{slug:"earthquake-research-and-analysis-new-advances-in-seismology",title:"Earthquake Research and Analysis",fullTitle:"Earthquake Research and Analysis - New Advances in Seismology"},signatures:"Yoshiharu Shumuta",authors:[{id:"73485",title:"Dr.",name:"Yoshiharu",middleName:null,surname:"Shumuta",slug:"yoshiharu-shumuta",fullName:"Yoshiharu Shumuta"}]},{id:"57751",title:"Sequence Stratigraphy of Fluvial Facies: A New Type Representative from Wenliu Area, Bohai Bay Basin, China",slug:"sequence-stratigraphy-of-fluvial-facies-a-new-type-representative-from-wenliu-area-bohai-bay-basin-c",totalDownloads:1297,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"seismic-and-sequence-stratigraphy-and-integrated-stratigraphy-new-insights-and-contributions",title:"Seismic and Sequence Stratigraphy and Integrated Stratigraphy",fullTitle:"Seismic and Sequence Stratigraphy and Integrated Stratigraphy - New Insights and Contributions"},signatures:"Jingzhe Li and Jinliang Zhang",authors:[{id:"202289",title:"Prof.",name:"Jinliang",middleName:null,surname:"Zhang",slug:"jinliang-zhang",fullName:"Jinliang Zhang"},{id:"204039",title:"Dr.",name:"Jingzhe",middleName:null,surname:"Li",slug:"jingzhe-li",fullName:"Jingzhe Li"}]},{id:"61767",title:"A New Trend in Cryoseismology: A Proxy for Detecting the Polar Surface Environment",slug:"a-new-trend-in-cryoseismology-a-proxy-for-detecting-the-polar-surface-environment",totalDownloads:655,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"polar-seismology-advances-and-impact",title:"Polar Seismology",fullTitle:"Polar Seismology - Advances and Impact"},signatures:"Masaki Kanao",authors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}]},{id:"42784",title:"Advanced Applications in the Field of Structural Control and Health Monitoring After the 2009 L’Aquila Earthquake",slug:"advanced-applications-in-the-field-of-structural-control-and-health-monitoring-after-the-2009-l-aqui",totalDownloads:2086,totalCrossrefCites:3,totalDimensionsCites:4,book:{slug:"engineering-seismology-geotechnical-and-structural-earthquake-engineering",title:"Engineering Seismology, Geotechnical and Structural Earthquake Engineering",fullTitle:"Engineering Seismology, Geotechnical and Structural Earthquake Engineering"},signatures:"Vincenzo Gattulli",authors:[{id:"159477",title:"Prof.",name:"Vincenzo",middleName:null,surname:"Gattulli",slug:"vincenzo-gattulli",fullName:"Vincenzo Gattulli"}]},{id:"43262",title:"Pushover Analysis of Long Span Bridge Bents",slug:"pushover-analysis-of-long-span-bridge-bents",totalDownloads:3383,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"engineering-seismology-geotechnical-and-structural-earthquake-engineering",title:"Engineering Seismology, Geotechnical and Structural Earthquake Engineering",fullTitle:"Engineering Seismology, Geotechnical and Structural Earthquake Engineering"},signatures:"Vitaly Yurtaev and Reza Shafiei",authors:[{id:"161878",title:"Ph.D.",name:"Vitaly",middleName:null,surname:"Yurtaev",slug:"vitaly-yurtaev",fullName:"Vitaly Yurtaev"}]}],onlineFirstChaptersFilter:{topicSlug:"seismology",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"chapter.detail",path:"/books/frontiers-in-radiation-oncology/curative-radiotherapy-in-metastatic-disease-how-to-develop-the-role-of-radiotherapy-from-local-to-me",hash:"",query:{},params:{book:"frontiers-in-radiation-oncology",chapter:"curative-radiotherapy-in-metastatic-disease-how-to-develop-the-role-of-radiotherapy-from-local-to-me"},fullPath:"/books/frontiers-in-radiation-oncology/curative-radiotherapy-in-metastatic-disease-how-to-develop-the-role-of-radiotherapy-from-local-to-me",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()