Cardiac Review and Evaluation Committee criteria for the diagnosis of cardiac dysfunction. Adapted from Seidman, et al. (2002). Cardiac dysfunction in the trastuzumab clinical trials experience. Journal of Clinical Oncology, Vol. 20, pp. 1215 – 1221
\r\n\t
",isbn:"978-1-83968-298-8",printIsbn:"978-1-83968-297-1",pdfIsbn:"978-1-83968-299-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"362b356f3ae4c3b5ab5a5fe69d92d270",bookSignature:"Dr. Luigi Cocco",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10385.jpg",keywords:"Virtual Analysis, Target Definition, Assembly Solution, Robotics, Software Architecture, Data Fusion, Autonomous Driving, Functional Safety, Vehicle Battery, Charging Infrastructures, Hybrid Vehicles, Cybersecurity",numberOfDownloads:490,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 6th 2020",dateEndSecondStepPublish:"July 27th 2020",dateEndThirdStepPublish:"September 25th 2020",dateEndFourthStepPublish:"December 14th 2020",dateEndFifthStepPublish:"February 12th 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Cocco received his master's degree in Telecommunication Engineering and his Ph.D. in Information Engineering before joining the automotive industry. From the Ferrari F1 Team to Automobili Lamborghini, he has worked on Electrical/Electronics systems, he has expertise in Research & Design, Supply Quality and Product Development. Currently, he is System Responsible for Passive Safety & ADAS of Maserati vehicles at Maserati S.p.A.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"112023",title:"Dr.",name:"Luigi",middleName:null,surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco",profilePictureURL:"https://mts.intechopen.com/storage/users/112023/images/system/112023.jpg",biography:'Dr. Luigi Cocco has received his master\'s degree in Telecommunication Engineering and his Ph.D. in Information Engineering before to join the automotive industry. Since 2005, From the Ferrari F1 Team to Automobili Lamborghini, he has worked on Electrical/Electronics systems; he has expertise in Research & Design, Supply Quality and Product Development. Currently, he is System Responsible for Passive Safety & ADAS of Maserati vehicles. His research interests include electronic measurements and digital signal processing, he has published several papers and three books with InTech: "Modern Metrology Concerns” (2012), "New Trends and Developments in Metrology” (2016) and "Standards, methods, and solutions of Metrology” (2018).',institutionString:"Maserati S.p.A.",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"3",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:[{id:"74236",title:"New Robust Control Design of Brake-by-Wire Actuators",slug:"new-robust-control-design-of-brake-by-wire-actuators",totalDownloads:46,totalCrossrefCites:0,authors:[null]},{id:"74309",title:"Role of Bearings in New Generation Automotive Vehicles: Powertrain",slug:"role-of-bearings-in-new-generation-automotive-vehicles-powertrain",totalDownloads:72,totalCrossrefCites:0,authors:[null]},{id:"74420",title:"Hydrogen Fuel Cell Implementation for the Transportation Sector",slug:"hydrogen-fuel-cell-implementation-for-the-transportation-sector",totalDownloads:120,totalCrossrefCites:0,authors:[null]},{id:"73891",title:"Quantum Calculations to Estimate the Heat of Hydrogenation Theoretically",slug:"quantum-calculations-to-estimate-the-heat-of-hydrogenation-theoretically",totalDownloads:60,totalCrossrefCites:0,authors:[null]},{id:"73339",title:"Generation and Relaxation of Residual Stresses in Automotive Cylinder Blocks",slug:"generation-and-relaxation-of-residual-stresses-in-automotive-cylinder-blocks",totalDownloads:69,totalCrossrefCites:0,authors:[null]},{id:"74124",title:"Quality and Trends of Automotive Fuels",slug:"quality-and-trends-of-automotive-fuels",totalDownloads:25,totalCrossrefCites:0,authors:[null]},{id:"74097",title:"Hydrogen Storage: Materials, Kinetics and Thermodynamics",slug:"hydrogen-storage-materials-kinetics-and-thermodynamics",totalDownloads:49,totalCrossrefCites:0,authors:[null]},{id:"73923",title:"Hybrid Steering Systems for Automotive Applications",slug:"hybrid-steering-systems-for-automotive-applications",totalDownloads:53,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@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, copy-editing 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:"1547",title:"Modern Metrology Concerns",subtitle:null,isOpenForSubmission:!1,hash:"27edf8c2b79a9c6ae0c3d87ca8cae49c",slug:"modern-metrology-concerns",bookSignature:"Luigi Cocco",coverURL:"https://cdn.intechopen.com/books/images_new/1547.jpg",editedByType:"Edited by",editors:[{id:"112023",title:"Dr.",name:"Luigi",surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4622",title:"New Trends and Developments in Metrology",subtitle:null,isOpenForSubmission:!1,hash:"27aa3947c35b65d08f9c1f4a56b7f468",slug:"new-trends-and-developments-in-metrology",bookSignature:"Luigi Cocco",coverURL:"https://cdn.intechopen.com/books/images_new/4622.jpg",editedByType:"Edited by",editors:[{id:"112023",title:"Dr.",name:"Luigi",surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7669",title:"Standards, Methods and Solutions of Metrology",subtitle:null,isOpenForSubmission:!1,hash:"29d82c2091fb9ca1c49620000d170f2c",slug:"standards-methods-and-solutions-of-metrology",bookSignature:"Luigi Cocco",coverURL:"https://cdn.intechopen.com/books/images_new/7669.jpg",editedByType:"Edited by",editors:[{id:"112023",title:"Dr.",name:"Luigi",surname:"Cocco",slug:"luigi-cocco",fullName:"Luigi Cocco"}],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:"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:"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:"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:"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"}},{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:"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"}}]},chapter:{item:{type:"chapter",id:"32613",title:"Trastuzumab and Cardiotoxicity",doi:"10.5772/34093",slug:"trastuzumab-and-cardiotoxicity",body:'\n\t\tIn the last two decades relevant improvements have been achieved in cancer therapy with a significant increase in overall survival. However these achievements have also been accompanied by a rise in the occurrence of side effects involving several organs, in particular the cardiovascular system. Indeed, the incidence of cardiotoxicity is continuously growing which can vanish the effectiveness of cancer therapy.
\n\t\t\tBreast cancer is the second most common form of cancer in women and the leading cause of death caused by malignancy. Over the past 25 years, breast cancer incidence has risen globally, with the highest rates in industrialized countries. However, the survival rate of cancer patients has greatly increased because of early detection through screening, as well as improvement in pharmacologic treatment. Women are, therefore, now living sufficiently long for delayed consequences of treatment to become increasingly evident.
\n\t\t\tApproximately 20-25% of breast cancer overexpresses the human epidermal growth factor receptor II (HER-2). Amplification of HER-2 gene confers aggressive behavioral traits on breast cancer cells, including incresead growth and proliferation, enhanced invasiveness and metastatic capability. (Slamon, 1987)
\n\t\t\tHER-2 is a transmembrane tyrosine kinase receptor and a member of the epidermal growth factor receptor (EGFR) family,and regulate many important cell-type specific functions, particularly cell growth, proliferation and survival. (Slamon, 1987, Chien, 2006)
\n\t\t\tThe use of trastuzumab (a humanized monoclonal antibody against HER-2 receptor) has changed the natural history of patients with HER-2 positive breast cancer. In the metastatic setting, the combination of trastuzumab plus chemotherapy has significantly improved survival, response rate, time to progression, and quality of life when compared with standard chemotherapy (Slamon 1987, 2001, Vogel, 2002). In the adjuvant setting, the use of trastuzumab decreased the risk of recurrence and death (Buzdar, 2005). Given these impressive results, trastuzumab has become the standard of care for treatment of patients with HER-2 positive breast cancer.
\n\t\t\tAlthough trastuzumab is devoid of the classical toxicities related with cancer treatment, one of major concerns noted is the occurrence of symptomatic and asymptomatic cardiac dysfunction. In fact, this treatment showed to be associated with an increased incidence of heart failure that ranged from 4.1% in the adjuvant setting to 27% in patients with metastatic disease who received concurrent anthracycline therapy (Perez E., 2004). Early identification of patients at risk for cardiotoxicity is a major challenge for both cardiologists and oncologists, for the definition of more tailored antineoplastic therapeutic interventions. The use of cardiac biomarkers such as BNP, N-terminal pro-BNP, and troponin I, has been suggested as a method for early detection of cardiotoxicity. Also, newer measurements of LV function such as strain, strain rate and speckle tracking may be sensitive tools to detect myocardial dysfunction before changes in EF are evident, possibly identifying at-risk patients at an earlier stage.
\n\t\tBased in substantial improvement achieved with trastuzumab in the trials performed, US Food and Drug Administration approved in 1998 this agent for the treatment of metastatic breast cancer. Indeed, in phase 2 trial was found an objective response in 12% of patients. (Baselga et al., 1996) These benefits were further confirmed in larger phase 2 and phase 3 trials (Cobleigh et al., 1999, Slamon et al., 2001). The phase 3 trial was design to compare a conventional chemotherapy regime with and without additional trastuzumab treatment. The data demonstrated that trastuzumab association to chemotherapy produced substantial response rate, improvement in time to disease progression, as well as reduction in 1-year mortality. (Slamon et al., 2001)
\n\t\t\t\tSince 2006 the use of trastuzumab has been extended to treat HER-2 positive early breast cancer patients. Five major randomized trials (Herceptin Adjuvant trial - HERA, National Surgical Adjuvant Breast and Bowel Project - NSABP B-31, North Central Cancer Treatment Group - NCCTG N9831, Breast Cancer International Research Group – BCIRG 006 and Finland Herceptin trial - FinHer) have proven the benefit of adjuvant trastuzumab in early breast cancer patients. More than 11 000 patients were enrolled and treatment with trastuzumab led to about 50% improvement in disease-free survival and 33% improvement in overall survival. (Romond et al., 2005, Piccart-Gebhart et al., 2005, Tan-Chiu et al., 2005, Slamon et al., 2005, Joensuu et al., 2006).
\n\t\t\t\tThus, concurrent treatment with trastuzumab is actually the standard of care for patients with early HER-2 positive breast cancer.
\n\t\t\tA precise definition of cardiotoxicity is still lacking. The Cardiac Review and Evaluation Committee supervising trastuzumab trials created a practical and easily applicable definition, which considered chemotherapy-induced cardiotoxicity as one or more of the following: 1) cardiomyopathy characterized by a decrease in LVEF, either global or more severe in the septum, 2) heart failure (HF) symptoms, 3) signs associated with HF, such as S3 gallop, tachycardia, edema, 4) decline in initial LVEF of at least 5% to less than 55% with accompanying signs or symptoms of HF, or asymptomatic decrease in LVEF in the range of equal to or greater than 10% to less than 55% (Seidman, 2002). (Table 1)
\n\t\t\t\t1.Cardiomyopathy characterized by a decrease in LVEF or changes of contraction most apparent in the interventricular septum 2.Heart failure symptoms 3.Signs associated with heart failure 4.Decline in initial LVEF of at least 5% to less than 55% with signs and symptoms of heart failure or asymptomatic decrease in LVEF of at least 10% to less than 55% | \n\t\t\t\t\t\t
Cardiac Review and Evaluation Committee criteria for the diagnosis of cardiac dysfunction. Adapted from Seidman, et al. (2002). Cardiac dysfunction in the trastuzumab clinical trials experience. Journal of Clinical Oncology, Vol. 20, pp. 1215 – 1221
Cardiotoxicity can develop in a subacute, acute, or chronic manner:
\n\t\t\t\tAcute or subacute cardiotoxicity develop during the treatment period up to 2 weeks after therapy. It is characterized by electrocardiographic abnormalities such as QT-intervals changes, ventricular repolarization abnormalities, supraventricular and ventricular arrhythmias or by acute heart failure, pericarditis, myocarditis or acute coronary syndromes.
Chronic cardiotoxicity is the most frequent and feared form. It can be divided in 2 groups according to the timing of symptoms onset: early, when occur in the first year after treatment and late when manifests more than 1 year after chemotherapy. The most common feature of chronic cardiotoxicity is asymptomatic systolic left ventricular dysfunction that can further lead to congestive HF. The incidence of this type of cardiotoxicity depends on several factors such as, total administered dose of chemotherapy, time of follow-up, age, history of previous cardiac disease, previous mediastinal radiation, as well as on the criteria used for cardiotoxicity assessment, ranging in different studies from 5% to 65% of patients. (Dolci, 2008, Pai, 2000).
The classic example of cardiotoxicity from anticancer treatment is anthracycline-related cardiomyopathy that remains the most common cardiotoxic chemotherapy agent. However many other agents can cause cardiotoxicity, namely the monoclonal antibody trastuzumab.
\n\t\t\t\tThe development of chemotherapy-induced cardiomyopathy has significant implications. It has not only a negative impact on the cardiac outcome of cancer patients, but also limits their therapeutic options.
\n\t\t\tCardiotoxicity was an unexpected finding in the phase 3 trials, as early clinical trials provided little or no indication of trastuzumab-induced cardiomyopathy. Although heart failure was seen in some patients enrolled in phase 2 trials, the rate of occurrence was low and patients were at increased risk due to previous anthracycline treatment. Subsequent reports of trastuzumab-related cardiotoxicity in the phase 3 combination chemotherapy trials prompted a retrospective analysis of seven phase 2 and 3 trastuzumab trials by an independent Cardiac Review and Evaluation Committee (CREC). (Seidman, Hudis, & Pierri, 2002) An accurate assessment of cardiotoxicity in these trials has proved difficult because their design was different in what concerns the number of patients, definition of cardiotoxicity, analysis of end points and duration of follow-up. CREC used a new set of criteria to define cardiotoxicity (Table 1) and events were also classified by the New York Heart Association (NYHA) functional classification system. Data from 1219 patients enrolled in those 7 trials were retrospectively analyzed and cardiotoxicity was detected in 112 patients (9.2%). The incidence of trastuzumab-induced cardiomyopathy ranged from 1% to 27% in different arms of trials and was higher when trastuzumab and anthracyclines were used concurrently (Seidman, Hudis, & Pierri, 2002)(Table 2)
\n\t\t\t\tRetrospective analysis conducted by the Cardiac Review and Evaluation Committee of seven studies to detect trastuzumab-related cardiotoxicity. Adapted from Keefe DL (2002). Trastuzumab-associated cardiotoxicity. Cancer, Vol. 95, pp. 1592-1600AC=anthracycline plus cyclophosphamide, CD=cardiac dysfunction, NYHA=New York Heart
Concerns about cardiotoxicity, together with the remarkable tumor response to this therapy, served as an impetus for several large trials collectively known as the trastuzumab adjuvant trials, which incorporate appropriate cardiac monitoring (Buzdar,2005, Perez, 2004, Cobleigh, 1999, Slamon 2001, Romond, 2005). The study protocol in these trials determined baseline assessment of LVEF using echocardiogram or myocardial scintigraphy and the exclusion of patients with impaired cardiac function, high doses of cumulative anthracycline exposure, and previous history of heart disease. Data from these trials are summarized in Table 3.
\n\t\t\t\tSummary of trastuzumab-induced cardiotoxicity from adjuvant trials. Adapted form Popat & Smith. (2008). Therapy insight: anthracyclines and trastuzumab – the optimal management of cardiotoxic side effects. Nature Clinical Practice, Vol. 5, pp. 324-335
In the combined analysis of NCCTG N9831 and NSABP B-31 trials (administration of trastuzumab concurrent with adjuvant taxanes after anthracycline chemotherapy), was found that trastuzumab was withdrawal before 52 weeks in 31.4% of patients treated. In 14.2% of them was due to asymptomatic LVEF decline and in 4.7% due to HF symptoms (Romond et al., 2005). The 3-year cumulative incidence of NYHA class III or IV HF or death from cardiac causes reported in N9831 trial was 2.9% in the trastuzumab group, compared to 0% in the control group. In B-31 trial this endpoint was detected in 4.1% in those treated with trastuzumab and 0.8% in the control group. Twenty-seven patients from the total of 31 women who developed trastuzumab-induced cardiomyopathy, were followed for at least 6 months and only 1 patient had persistent symptoms of heart failure. (Slamon, 2001) These results were subsequently analysed by an independent group of reviewers that constituted the Adjuvant Cardiac Review and Evaluation Committee (ACREC) (Seidman, 2002). This independent review confirmed earlier risk estimates by showing that the concurrent use of trastuzumab and anthracycline based chemotherapy, increased the rate of congestive heart failure (CHF) nearly four-fold, from 0.45% to 2.0%, at a median follow-up of 1.9 and 2.0 years, respectively.
\n\t\t\t\tIn HERA trial (Perez, 2004) was reported a smaller number of cardiac events compared with B-31 and N9831 studies. This trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with HER-2 positive early breast cancer. The overall rate of trastuzumab withdrawal due to safety issues was 6.8%, with 4% stopping the treatment due to cardiac issues. The rate of symptomatic CHF was 2% in the trastuzumab group and 0.2% in the control group, with NYHA class III or IV CHF occurring in 0.6% of patients receiving trastuzumab and 0% of the control group. An asymptomatic or mildly symptomatic decline in LVEF was seen in 7.4% of women on trastuzumab and 2.3% of controls (Perez, 2004, Seidman, 2002). The overall risk of severe CHF reported in HERA was lower than that in B-31 (0.6% versus 4%) as was the proportion of patients who discontinued trastuzumab due to cardiac issues. The explanation for these differences is not clearly established, but we can speculate that it may be due to the longer interval between stopping anthracyclines and initiating trastuzumab or to the inclusion criteria that determined a LVEF≥55% in HERA trial compared to 50% for N9831/B-31 trials.
\n\t\t\t\tAn aspect of interest in the BCIRG trial is that one arm of this study did not include concomitant or sequential therapy with anthracyclines. This fact permitted the assessment of the true effect of trastuzumab on the heart without having to adjust for previous anthracycline lesion, that otherwise interfere with interpretation of cardiotoxicity. The incidence of NYHA class III or class IV CHF was 5.1-fold greater in the anthracycline group than in the nonanthracycline arm (1.96% versus 0.38%) and the number of patients with LVEF decline of more than 10% from baseline was 19% and 9%, respectively.
\n\t\t\tCardiotoxicity came to the forefront of concerns over chemotherapy in the early 1970s, when was detected a cumulative dose-related cardiac dysfunction was detected related with anthracycline treatment.
\n\t\t\t\tThis agent produces a cardiac dysfunction identified as type I, characterized by ultrastructural abnormalities, morphological cellular (vacuoles, myofibrillar disarray and dropout, necrosis) and heart (dilated cardiomyopathy) changes and subsequent clinical evident dysfunction. (Billingham, 1978, Lefrak, 1973, Billingham, 1978) It is dose-related and virtually irreversible. Described methods to minimize type I cardiotoxicity include prolonged infusional administration schedules (Legha, 1982) and use of the free-radical scavenger dexrazoxane (Swain, 2004). Additionally, liposomal delivery, are being studied liposomal delivery systems (Ewer, 2002 ) and less-toxic analogs and less toxic analogs are being study.
\n\t\t\t\tIn contrast, type II cardiac dysfunction associated with trastuzumab therapy does not seem to cause any ultrastructural change, while a myocardial dysfunction under cardiac stress is present. (Ewer, 2005) Other specific features are: it seems not to be dose-related, it increases when trastuzumab is given concurrently with anthracyclines, it seems to be reversible, and normal cardiac function may be restored with medical management of heart failure (Seidman, 2002, Valero, 2004, Perez, 2004, Ewer, 2008). Table 4 compares type I and type II chemotherapy-related cardiac dysfunction.
\n\t\t\t\tChemotherapy-related cardiac dysfunction. Reprinted from Ewer & Lippman (2005).Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. Journal of Clinical Oncology, Vol. 23, pp. 2900-2902
The mechanisms of type I and type II cardiac dysfunction are complex and distinct. Type I cardiotoxicity is due, predominantly to iron-based oxygen free-radical that induce oxidative stress on cardiac cells. These free radicals produce peroxidation of myocyte membranes and subsequent influx of intracellular calcium, accelerated degradation of key sarcomeric protein and disruption of new sarcomere protein synthesis. (Valero, 2004, Ewer, 2002)
\n\t\t\t\tThe molecular basis of type II chemotherapy related cardiac dysfunction is beginning to be elucidated (Speyer, 2002, Crone, 2002, Ozcelik, 2002, Sawyer, 2002, Negro, 2004). The mechanism of trastuzumab induced cardiotoxicity involves, at least in part, the ErbB2 pathway. This agent binds to the extracellular domain of the HER-2 protein and thus blocks ErbB2 signalling required for the growth, repair, and survival of cardiac cells. (Negro, 2004) ErbB2 signalling is highly complex, involving multiple ligand classes, cell systems, and pathway interactions. Of those actions, activation of the transcription factor nuclear-B (NF-B) seems to play an important rule. Indeed the NF-B pathway is also involved in cardiac cells under stress, such as in myocardial infarction and hypertension and it seems to be essential in restoring the reperfusion after ischemia and also in reducing apoptosis. (Feldman, 2007).
\n\t\t\t\tEvidence supports a critical role for neuregulin 1 (NRG1) signalling through HER-2/HER-4 heterodimerization in cardiomyocyte survival pathways and maintenance of function. (Sawyer, 2002) NRG1 is produced by cardiac endothelial cells, binds HER-4 on cardiomyocytes and leads to heterodimerization with HER-2, with consequent activation of diverse intracellular signalling pathways, such as the PI3-kinase/AKT and MAP kinase pathways. Mouse models have given important contributes to these discovers. Mice with HER428 and NRG131 knockouts are both embryonically lethal.
\n\t\t\t\tMoreover, the essential role of HER-2 in maintenance of cardiac contractile function and structure and the possible protective effect provided by HER-2 was shown in a mouse model with a cardiac-restricted conditional HER-2 deletion mutant. Indeed, these mice stayed alive, but developed a dilated cardiomyopathy. (Negro, 2004, Crone, 2002, Ozcelik, 2002) This model provided support to the hypothesis that cardiac lesion related to trastuzumab is the result of direct targeting and inhibition of the HER-2 receptor, rather than immune-mediated or non-cardiac effects. Additionally, these mice were also sensitized to develop an anthracycline-induced cardiac dysfunction reflecting that seen clinically.
\n\t\t\t\tInhibition of the previous described pathways after an insult such as anthracycline treatment could thus interfere with the heart’s repair mechanisms. Indeed, de Kort et al. (2007) showed that myocardial HER-2 is upregulated in humans shortly after anthracycline exposure, providing support for the vulnerable-window hypothesis. (Fig 1.)
\n\t\t\t\tA) Simplified flow diagram of myocyte injury after anthracycline administration. Cell death is preceded by a period of vulnerability during which cell repair may take place. (B) The addition of trastuzumab inhibits cell repair compounding the loss of cardiac myocytes. HER2= human epidermal growth factor receptor 2. Reprinted from Ewer, M. (2010). Troponin I Provides Insight Into Cardiotoxicity and the Anthracycline-Trastuzumab Interaction. Journal of Clinical Oncology, Vol. 28, No. 25, pp 3901-3909
Although inhibition of HER-2 signalling seems to be a central mechanism of trastuzumab-related cardiomyopathy, the pathophysiologic mechanism is likely more complex. Indeed early clinical results with lapatinib, an oral tyrosine kinase inhibitor, show minimal cardiotoxicity. (Geyer, 2006) Actually the explanation for this paradox is not sufficiently clear and remains an area of intense investigation. It is suggested that the difference between the two drugs may be explained by trastuzumab effect on adenosine triphosphate (ATP) depletion. Cardiac cells need an important quantity of ATP molecules and thus an agent that interferes with mitochondrial activity has the potential of alter normal myocyte function by decreasing the energy source. (Menendez, 2007) The binding between erbB2 and a specific antibody can unbalance BCL-XL/BCL-XS, leading to depolarization of the mitochondrial membrane potential, with reduction of ATP and subsequent alteration of contractility (Force, 2007).
\n\t\t\tThe most established risk factors for the development of trastuzumab-induced cardiotoxicity are age > 50 years and concurrent or prior exposure to anthracycline chemotherapy (Perez, 2004, Pinder, 2007). Based on data of the NSABP B-31 trial (Tan-Chiu, et al., 2005), baseline LVEF < 55% and post-chemotherapy LVEF < 55% were also considered as significant risk factors. Current or previous treatment with antihypertensive medication and a body mass index (BMI) >25 have been shown to increase the risk of cardiotoxicity in some trials, but the results are not uniform or consistent. Prior radiotherapy to a left-sided breast cancer, race or history of smoking were not associated to a increased risk of cardiac toxicity during trastuzumab treatment.
\n\t\t\t\tOne important aspect is that clinical trials are limited to women under 65 years old and with a good performance status (Hutchins, 1999). Thus, trastuzumab safety data only apply to a relatively young and healthy group of patients. As the incidence of cancer increases greatly with age and more than 70% of all newly diagnosed cancers are in patients >65 years, information about efficacy and safety of chemotherapy is needed in this population. This was the impetus of a recent study by C. Serrano et al (Serrano, 2011) that intended to assess the cardiac safety profile and potential cardiac risk factors associated with trastuzumab in breast cancer patients >70 years. The records of forty-five women between the ages of 70 and 92 were evaluated and was found a significantly increased incidence of cardiac events among patients with a history of cardiac disease (heart failure, arrhythmias, myocardial ischemia, or valvular heart disease) and diabetes. The overall incidence of cardiac events was 26.7%, and in 8.9% of them it was clinically evident. Thirty-three percent of women with known history of heart disease developed either asymptomatic or symptomatic cardiotoxicity compared to 9.1% with no previous cardiac disease (p=0.01). Additionally, 33.3% of diabetic women developed cardiac dysfunction compared to only 6.1% without diabetes. However, it is important to be cautious when interpreting these data given the small sample size and the very limited power to detect small differences in multivariate analysis.
\n\t\t\t\tIn patients being simultaneous treated with anthracyclines and trastuzumab the probability of develop cardiotoxicity increases after a cumulative dose of doxorubicin superior to 300 mg/m2 (Perez, 2004). The sequence in which chemotherapy agents are administered seem to influence the development of cardiac dysfunction. When anthracyclines and trastuzumab were administered simultaneously, the incidence of NYHA class III or IV HF was 16%. (Slamon, 2001). The interval between administration of anthracycline and trastuzumab was about 3 weeks in the NSABP B-31 and BCIRG 006 trials, and it was showed an incidence of class III or IV CHF of 4.1% and 1.9%, respectively (Romond 2005). This interval was larger in HERA trial, being approximately 3 months, and was found an incidence of cardiac dysfunction of 0.6%, similar to that obtained in the nonanthracycline arm of the BCIRG 006 trial (0.4%). (Piccart-Gebhart, 2005, Tan-Chiu, 2005, Joensuu, 2006) Thus, it seems that the greater the interval between treatment with these two drugs, the less cardiotoxicity is found. (Ewer, 2009) (Fig. 2)
\n\t\t\tIncidence of heart failure in the different trials in what concern timing post anthracycline treatment. Reprinted from Nat. Rev Cardiovasc Med ©2010 Nature Publishing
Current data on trastuzumab-induced cardiomyopathy suggest that either symptomatic or asymptomatic LVEF decline has potential to recover by stopping the agent and introducing medical therapy for HF.
\n\t\t\t\tIn the CREC review (Seidman, 2002) of the 112 patients who developed cardiotoxicity, 79% responded to HF therapies. Further evidence of this phenomenon comes from MD Anderson series (Guarneri, 2006). In patients who developed symptomatic CHF, 79% recover after discontinuation of trastuzumab and with appropriate treatment. Of note, one patient recovered quickly with cardiac therapy during treatment with trastuzumab and one died of progressive CHF.
\n\t\t\t\tIn those patients with asymptomatic decline of LVEF, trastuzumab was stopped in 41%. Recovery of LVEF was observed in 89% of women, independently of HF treatment. For the remainder who continued trastuzumab, LVEF recovered in 75% of patients.
\n\t\t\t\t\n\t\t\t\t\tEwer et al (2005) published an observational study of 38 patients with trastuzumab-related cardiotoxicity. Thirty-one patients discontinued the agent and were treated with HF therapies. In all of them LVEF returned to baseline over a period of months (mean time: 1.5 months). In six women who stopped trastuzumab, but were not receiving HF treatment, 2 had persistent LV dysfunction during the 6 months follow-up. Trastuzumab was not withdrawal in one patient, despite evidence of cardiotoxicity, and after initiation of HF therapy was demonstrated a slight increase of LVEF. In a subgroup of patients (Ewer, 2002) treated with the maximum-tolerated doses of angiotensin converting enzyme inhibitors and beta-blockers, which had a full recovery of LVEF and had stable CHF, trastuzumab was reintroduced. The median duration of trastuzumab therapy was 8.4 months. In 88% of women (Ewer, 2005) LVEF remained stable and without recurrences of CHF, in the remainder, LVEF deteriorated and CHF reoccurred, necessitating permanent trastuzumab withdrawal. (Fig. 3) None of the patients died due to cardiac disease, and only one patient needed to be hospitalized because of CHF with volume overload.
\n\t\t\t\tChanges in left ventricular ejection fraction from baseline to re-treatment with trastuzumab (*) P<0.05 versus before trastuzumab therapy. (+) P<0.05 versus after trastuzumab therapy. Reprinted from Ewer et al. (2005) Reversibility of trastuzumab related cardiotoxicity: new insights based on clinical course and response to medical treatment. Journal of Clinical Oncology, Vol. 23, pp. 7820–7826
Similar results were obtained in trastuzumab adjuvant trials. In B-31 (Tan-Chiu et al. 2005) the majority of patients who developed cardiac dysfunction recovered completely (55.5%) or partially (30.6%), as in HERA trial (Piccart-Gebhart, 2005) were there was 81% of recovery.
\n\t\t\t\tAlthough current data is limited regarding the potential long-term effects of trastuzumab on cardiac function, actual evidence of trastuzumab-induced cardiotoxicity should be evaluated in the context of the improvements in disease-free survival, response rate and quality of life attributable to trastuzumab therapy. (Table 5) Thus efforts should be placed on close cardiac function monitoring and development of strategies to early diagnosis.
\n\t\t\tOutside the trials, the best cardiac monitoring strategy remains undefined. The British Society of Echocardiography (Fox, 2006) and more recently the European Society for Medical Oncology (Bovelli et al., 2010), issued a statement regarding the cardiac monitoring of patients proposed to receive trastuzumab. Clinical evaluation and assessment of cardiovascular risk factors and comorbidities should be performed to all women prior the initiation of this agent.
\n\t\t\t\tLong-term cardiac risk.benefit analysis of trastuzumab-based adjuvant chemotherapy. Reprinted from Patrick G. et al (2010). Trastuzumab-Related Cardiotoxicity Following Anthracycline-Based Adjuvant chemotherapy: How Worried Should We Be? Journal of Clinical Oncology, Vol 28, No. 21, pp 3407-3410
The statements specified that LV function must be assessed before treatment and at 3-month intervals during the administration of trastuzumab.
\n\t\t\t\tEchocardiography is the recommended method for evaluating LV function. (Bovelli et al., 2010) Among the imaging techniques, echocardiography has multiple advantages as it is easily accessible, with no radiation exposure and can assess LV systolic and diastolic dysfunction, heart valve disease, pericarditis and pericardial effusion.
\n\t\t\t\tLVEF is the most frequent parameter used for evaluation of cardiac function before initiating chemotherapy and a value less than 54% is considered a risk factor for subsequent development of HF. Extreme caution during consecutive assessment of LVEF is fundamental, in order to diminish the intra and interobserver variability. The use of 3-dimensional echocardiography or administration of contrast for left ventricle opacification can be useful strategies to achieve this proposal. However, LVEF is not a sensitive index to detect early systolic cardiac dysfunction. (Bovelli et al., 2010) Other echocardiographic techniques such as Doppler-derived parameters seem to show early changes in myocardial function in this setting. (Hare, 2009, Fallah-Rad, 2008).
\n\t\t\t\tMyocardial scintigraphy provides a very reliable measurement of LVEF, however does not allow evaluation of regional myocardial kinetic or diastolic function, which can be important aspects of cardiotoxicity. Additionally, it has the disadvantage of radiation exposure.
\n\t\t\t\tCardiac magnetic resonance imaging (MRI) is the gold standard for accurate assessment of LV volumes and LVEF, and also allows evaluation of myocardial perfusion and tissue characterization. The common feature of trastuzumab-induced cardiotoxicity is increase of LV volumes, decrease in LVEF and delayed enhancement within the mid-myocardium portion of LV (Fallah-Rad et al., 2008). MRI has already been validated for LV function monitoring in patients treated with trastuzumab, however, due to its high cost and limited availability, it can not be used as screening test.
\n\t\t\t\tIn this field, for an accurate monitoring oncologists and cardiologists should work as a team and prompt multidisciplinary approach to patient care, in order to detect damage caused by chemotherapy and achieve a positive resolution.
\n\t\t\tIdentification of patients who will develop heart failure as a result of trastuzumab treatment remains an ongoing challenge. Currently, clinical examination and consecutive LVEF measurements have been used to determine the cardiac toxicity of chemotherapy. However, it has important limitations, namely the fact that a decline of LVEF represents a relatively late stage of cardiac dysfunction. Earlier detection of subclinical cardiac damage could lead to identifying, intervening, and possibly preventing late adverse cardiac outcomes. In the setting of trastuzumab-induced cardiotoxicity, it could allow to identify patients at higher risk that could benefit from prophylactic therapy, and also identify those who may recover from cardiac dysfunction and thus, not discontinued indiscriminately trastuzumab therapy depriving most patients from drug’s effectiveness.
\n\t\t\t\tThere is an intense research in this area, especially in what concern the role of cardiac biomarkers and new echocardiographic techniques.
\n\t\t\t\tTwo dimensional evaluation of LVEF constitutes the most common way to assess cardiac function in chemotherapy-induced cardiomyopathy, but it has some limitations, namely low reproducibility and dependence of hemodynamic conditions.
\n\t\t\t\t\tMyocardial strain and strain rate (SR) are newer echocardiographic techniques for evaluation of LV function, offering sensitive measurement of myocardial deformation, and seem to be able to identify subclinical dysfunction in various settings, before impairment of LVEF becomes evident. (Geyer et al., 2010). These parameters can be assessed by tissue Doppler imaging (TDI) or more recently, by speckle tracking (ST).
\n\t\t\t\t\tTDI uses Doppler principles to quantify tissue-derived signals, enabling a quantitative analysis of systo-diastolic function in terms of global, regional, segmental and parietal function. Strain and SR assessed by TDI are pulsed Doppler measurements with spatial integration, obtained by determination of myocardial parietal displacement, taking into account the linear distance between the two points. (Ho & Solomon, 2006).
\n\t\t\t\t\tSpeckle tracking is a distinct method to evaluate global and regional LV function. It’s not Doppler based and thus, allow assessment of strain and SR independently of angle, a limitation of TDI. An important feature of this technique is the possibility of assessing longitudinal, radial and circumferential LV deformation in a single acquisition. Additionally, it is simple to perform, the processing can be done subsequently offline and has a reduced intra and interobserver variability (Geyer et al., 2010).
\n\t\t\t\t\tThese echocardiographic techniques have been evaluated in murine models of chemotherapy-related cardiotoxicity and more recently, in patients with anthracycline-induced cardiomyopathy. (Neilan et al, 2006, Jassal et al, 2009)
\n\t\t\t\t\tRecently some research has been done to elucidate the role of these imaging techniques in subclinical detection of trastuzumab-induced cardiotoxicity.
\n\t\t\t\t\t\n\t\t\t\t\t\tHare et al. (2009) studied 35 women treated with trastuzumab in the adjuvant and metastatic setting. LVEF measured either by 2D and 3D echocardiography, as well as myocardial E-velocity, did not demonstrate significant change in the patients evaluated. However, a reduction in longitudinal SR at 3 months after trastuzumab administration was detected in 18 patients. (Fig. 4) Three of them had a subsequent decrease in LVEF and another 2 patients showed a decline in LVEF within 20 months of follow-up. Data from this study suggest SR to be a parameter able to identify early impairment of cardiac function in trastuzumab-induced cardiomyopathy setting.
\n\t\t\t\t\tExample of preclinical reduction in myocardial deformation. Reductions in TDI SR and 2D speckle-tracking strain from initial echocardiogram (A) over 2 months during therapy with trastuzumab (B), with no concomitant reduction in 3D LVEF in a patient who ceased trastuzumab for symptoms consistent with myocardial dysfunction. GS, Global strain. Reprinted from Hare, J. et al (2009). Natasha Woodward, Thomas H. Marwick Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab. American Heart Journal, Vol. 158, No. 2, pp. 294-301
The study published by Fallah et al. (2011) showed similar results. Indeed it was found that an early reduction in TDI and strain values was subsequently followed by a significant decline of LVEF. Forty two patients were studied and 10 of them developed cardiac dysfunction, necessitating withdrawal of trastuzumab. There weren’t significant differences in baseline TDI and strain parameters between patients who developed cardiotoxicity and those who maintain normal LVEF measurements. However, at 3 months after initiation of therapy was found a significant decrease in lateral S’ value in patients who developed cardiac dysfunction, as well as a reduction in peak global longitudinal and radial strain. Although LVEF was normal at 3 months, TDI and strain measurements were reduced in all 10 patients who demonstrated an impairment of LVEF at 6 months follow up.
\n\t\t\t\t\tA possible explanation for the increased sensitivity of strain in early detection of chemotherapy-induce cardiotoxicity can be a preferential regional pattern of damage, such that normal myocardial segments compensate the impaired function of the other, leading to a preserved LVEF.
\n\t\t\t\t\tTDI and speckle tracking imaging are thus, very promissory tools for early detection of LV systolic dysfunction in trastuzumab treated patients.
\n\t\t\t\tTroponin I (TNI) has high sensibility and specificity to detect myocardial ischemia. Raised levels have been found after anthracycline administration and seem to predict subsequent cardiac morbidity and mortality. Indeed, Cardinale et al. 2004) showed that detectable TNI after high-dose chemotherapy is a predictor of LVEF impairment and higher rate of major cardiac events, especially in women who maintain elevation of TNI for more than a month (Fig.5).
\n\t\t\t\t\tIn addition, they reported a high negative predictive value for TNI (99%), which is important to identify low-risk patients who probably don’t need close monitoring after treatment.
\n\t\t\t\t\tCumulative cardiac events rate in 3 study groups. P<0.001 for TnI +/+ vs TnI-/- and TnI+/-, and for TnI +/- vs TnI-/-. Reprinted from Cardinale, D. et al. (2004). Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy. Circulation, Vol. 109, pp. 2749-2754
The role of TNI in the clinical setting of trastuzumab-induced cardiotoxicity was recently assessed by Cardinale et al. (2010). A substantial finding of the study was that TNI assessment permits to detect patients more likely to developed LVEF impairment and to identify those who are less prone to recover. Indeed, trastuzumab-induced cardiotoxicity was detected in 72% of those who had elevation of TNI and in 7% of patients with normal TNI. From those who developed cardiac dysfunction, 60% recovered. The patients, whom LVEF did not return to baseline values had previous elevation of TNI, and additionally was found that this subgroup had a higher rate of cardiac events along the follow up (Fig.6). Interestingly, in those women with normal TNI who developed trastuzumab-related cardiotoxicity, was observed a subsequent normalization of LVEF and a lower rate of major cardiac events. These data are consistent with the hypothesis that a normal TNI value can predict LVEF recovery.
\n\t\t\t\t\tAdditionally, the rate of major cardiac events, and thus increased morbidity, was higher in the patients who showed elevation of TNI.
\n\t\t\t\t\tCan be inferred that TNI permit to divide patients in two subgroups: those with good outcome, from those more prone to adverse events in whom close surveillance and prevention of further cardiotoxicity is needed.
\n\t\t\t\t\tA) Kaplan-Meier curve of time to first cardiac event in patients developing trastuzumab-induced cardiotoxicity (TIC) and in patients who did not (No TIC). (B) Cumulative major adverse cardiac events in patients who recovered from cardiac dysfunction (Recovery) and in those who did not (No-recovery). Time zero refers to detection of cardiotoxicity and start of heart failure (HF) therapy. Reprinted from: Cardinale et al. (2010). Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation. Journal of Clinical Oncology, Vol. 28, No. 25, pp. 3910-3916
Other studies such as the one published by Sawaya et al. (2011) showed similar results. Indeed an elevated TNI at three months predicted cardiac dysfunction at six months, as these patients were nine times more prone to developed cardiotoxicity than those with normal TNI values.
\n\t\t\t\t\tB-type natriuretic peptide (BNP) is a marker of increased filling pressure of LV, as it is a hormone released by myocardial cells in volume overload setting. An important feature is that it can be detectable in a subclinical stage of HF and its value reflects HF severity. (Emdin et al., 2005)
\n\t\t\t\t\tThus it seemed reasonable to assume that BNP would be increased in patients with chemotherapy-induced cardiomyopathy. However, data currently available are heterogeneous. Some studies reported an elevation of BNP after treatment (Sandri et al., 2005, Pinchon et al., 2005), others obtained negative results (Sawaya et al., 2011). Therefore, the utility of BNP as a biomarker of cardiac damage induced by chemotherapy was not confirmed.
\n\t\t\t\t\tLarger, prospective trials are needed to elucidate BNP role in this setting.
\n\t\t\t\tGuidelines suggest HF standard therapy in patients with symptomatic or asymptomatic evidence of trastuzumab-induced cardiac dysfunction. However, as these patients have been excluded from almost all large randomized trials assessing the efficacy of HF treatment, there isn’t definite evidence whether the long-term benefits of HF therapy can be directly transferred to this setting (Bovelli, 2010, Eschenhagen, 2011).
\n\t\t\tNevertheless, data from adjuvant trials of trastuzumab and observational studies, such as the one conducted by Ewer et al (2005), support the use of HF therapy specially angiotensin converting enzyme inhibitors (ACEI) and beta-blockers.
\n\t\t\tSome other questions in this setting need to be addressed. Should we withdraw trastuzumab in patients who developed cardiotoxicity independently of the grade of LVEF impairment? Some authors proposed an evaluation scheme showed in Table 6, in which trastuzumab should be stopped in asymptomatic patients if LVEF declines more than 20 points from baseline or LVEF<30%, and in symptomatic patients if LVEF reduces more than 30 points from baseline. And should we discontinue the drug in all patients who developed cardiotoxicity or just in high-risk patients? Based on results of the study by Cardinale et al. (2010) we can speculate that patients with normal value of TNI and reduction in LVEF could be maintained in trastuzumab therapy while receiving HF therapy and close monitoring. However we don’t have yet a definite answer. Another important issue is, should we treat prophylactically high-risk patients? The data from Cardinale et al. (2006) suggest that early treatment with enalapril in patients with TNI positive after high-dose chemotherapy, prevent the development of cardiac dysfunction. (Fig. 7) Indeed, in those patients treated with ACEI, LVEF remained normal and compared with the untreated patients, a lower rate of adverse cardiac events was seen. (Table 6)
\n\t\t\tCardiac events in the study groups. Reprinted from Cardinale, D. et al. (2006). Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation, Vol. 114, pp. 2474-2481
Patients showing increased TNI value during follow-up in the ACEI group (open bars) and control subjects (solid bars). P<0.001 (log-rank test). Mean ± SD TNI values at each considered step are given at the bottom. *P<0.05 vs ACEI group. Reprinted from Cardinale, D. et al. (2006). Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation, Vol. 114, pp. 2474-2481
\n\t\t\t\tKalay et al. (2006) studied the impact of prophylactic carvedilol use in patients receiving anthracycline chemotherapy and showed that LVEF maintained stable in those treated with beta-blocker, contrary to what occurred in the untreated group.
\n\t\t\tProbably the MANTICORE - Multidisciplinary Approach to Novel Therapies In Cardiology Oncology Research - trial, will add some light to this issue. This is a randomized, placebo-controlled trial that aims to determine if standard HF therapies can prevent trastuzumab-induced cardiotoxicity. (Pituskin, 2011)
\n\t\t\tProposal for the evaluation and treatment of heart failure in patients undergoin treatment with trastuzuma. Adapted from Keefe DL. (2002). Trastuzumab-associated cardiotoxicity. Cancer, Vol. 95, pp. 1592-1600 ↓=decrease, B=beta-blockers, CF=cardiac failure, LVEF=left ventricular ejection fraction, NC=noncardiac pathology. trastuzumab
Some authors suggest other strategies to minimize cardiotoxicity (Sengupta, 2008), such as the adoption of non-anthracyclines regimes, to prefer larger intervals between the administration of anthracyclines and trastuzumab or to diminish the duration of trastuzumab adjuvant therapy. However, our conviction is that we should prompt effort in early diagnosis of cardiac dysfunction and appropriate treatment, in order to not deprive patients to a treatment with such substantial therapeutic benefits and propose the algorithm presented in Figure 8, for the management of patients receiving trastuzumab.
\n\t\tProposed algorithm for the management of patients receiving treatment with trastuzumab. Abbreviations: ACEI, angiotensin-converting enzyme inhibitor, ARB, angiotensin II receptor blocker, ECG, electrocardiography, HF, heart failure, LVEF, left ventricular ejection fraction (adapted from Martin M et al (2009),
Trastuzumab is the standard of care for treatment of patients with ERB2-positive breast cancer. When used in combination with chemotherapy, trastuzumab can improve overall survival in patients with ERB2-positive metastatic breast cancer and disease free survival and overall survival in patients with early ERB2-positive breast cancer. Because of the risk of cardiac dysfunction associated with trastuzumab therapy, cardiac function should be monitored closely (Carver, 2010).
\n\t\t\tCardiotoxicity has a strong impact on patients with cancer. This paradigm suggests that a multidisciplinar team of cardiologists and oncologists may provide a more comprehensive care to this complex patient population.
\n\t\t\tThe main strategy is early detection of high risk patients and prompt prophylatic treatment. New echocardiographic methods to detect subclinical myocardial changes, measurement of cardiospecific biomarkers may become useful routine methods for identifying patients more prone to developing cardiotoxicity and in whom a preventive pharmacologic approach together with a closer cardiac monitoring could reduce a major cause of mortality in women with breast cancer.
\n\t\tStability constant of the formation of metal complexes is used to measure interaction strength of reagents. From this process, metal ion and ligand interaction formed the two types of metal complexes; one is supramolecular complexes known as host-guest complexes [1] and the other is anion-containing complexes. In the solution it provides and calculates the required information about the concentration of metal complexes.
Solubility, light, absorption conductance, partitioning behavior, conductance, and chemical reactivity are the complex characteristics which are different from their components. It is determined by various numerical and graphical methods which calculate the equilibrium constants. This is based on or related to a quantity, and this is called the complex formation function.
During the displacement process at the time of metal complex formation, some ions disappear and form a bonding between metal ions and ligands. It may be considered due to displacement of a proton from a ligand species or ions or molecules causing a drop in the pH values of the solution [2]. Irving and Rossotti developed a technique for the calculation of stability constant, and it is called potentiometric technique.
To determine the stability constant, Bjerrum has used a very simple method, and that is metal salt solubility method. For the studies of a larger different variety of polycarboxylic acid-, oxime-, phenol-containing metal complexes, Martel and Calvin used the potentiometric technique for calculating the stability constant. Those ligands [3, 4] which are uncharged are also examined, and their stability constant calculations are determined by the limitations inherent in the ligand solubility method. The limitations of the metal salt solubility method and the result of solubility methods are compared with this. M-L, MLM, and (M3) L are some types of examples of metal-ligand bonding. One thing is common, and that is these entire types metal complexes all have one ligand.
The solubility method can only usefully be applied to studies of such complexes, and it is best applied for ML; in such types of system, only ML is formed. Jacqueline Gonzalez and his co-worker propose to explore the coordination chemistry of calcium complexes. Jacqueline and et al. followed this technique for evaluate the as partial model of the manganese-calcium cluster and spectrophotometric studies of metal complexes, i.e., they were carried calcium(II)-1,4-butanediamine in acetonitrile and calcium(II)-1,2-ethylendiamine, calcium(II)-1,3-propanediamine by them.
Spectrophotometric programming of HypSpec and received data allows the determination of the formation of solubility constants. The logarithmic values, log β110 = 5.25 for calcium(II)-1,3-propanediamine, log β110 = 4.072 for calcium(II)-1,4-butanediamine, and log β110 = 4.69 for calcium(II)-1,2-ethylendiamine, are obtained for the formation constants [5]. The structure of Cimetidine and histamine H2-receptor is a chelating agent. Syed Ahmad Tirmizi has examined Ni(II) cimetidine complex spectrophotometrically and found an absorption peak maximum of 622 nm with respect to different temperatures.
Syed Ahmad Tirmizi have been used to taken 1:2 ratio of metal and cimetidine compound for the formation of metal complex and this satisfied by molar ratio data. The data, 1.40–2.4 × 108, was calculated using the continuous variation method and stability constant at room temperature, and by using the mole ratio method, this value at 40°C was 1.24–2.4 × 108. In the formation of lead(II) metal complexes with 1-(aminomethyl) cyclohexene, Thanavelan et al. found the formation of their binary and ternary complexes. Glycine,
Using the stability constant method, these ternary complexes were found out, and using the parameters such as Δ log K and log X, these ternary complex data were compared with binary complex. The potentiometric technique at room temperature (25°C) was used in the investigation of some binary complex formations by Abdelatty Mohamed Radalla. These binary complexes are formed with 3D transition metal ions like Cu2+, Ni2+, Co2+, and Zn2+ and gallic acid’s importance as a ligand and 0.10 mol dm−3 of NaNO3. Such types of aliphatic dicarboxylic acids are very important biologically. Many acid-base characters and the nature of using metal complexes have been investigated and discussed time to time by researchers [7].
The above acids (gallic and aliphatic dicarboxylic acid) were taken to determine the acidity constants. For the purpose of determining the stability constant, binary and ternary complexes were carried in the aqueous medium using the experimental conditions as stated above. The potentiometric pH-metric titration curves are inferred for the binary complexes and ternary complexes at different ratios, and formation of ternary metal complex formation was in a stepwise manner that provided an easy way to calculate stability constants for the formation of metal complexes.
The values of Δ log K, percentage of relative stabilization (% R. S.), and log X were evaluated and discussed. Now it provides the outline about the various complex species for the formation of different solvents, and using the concentration distribution, these complexes were evaluated and discussed. The conductivity measurements have ascertained for the mode of ternary chelating complexes.
A study by Kathrina and Pekar suggests that pH plays an important role in the formation of metal complexes. When epigallocatechin gallate and gallic acid combine with copper(II) to form metal complexes, the pH changes its speculation. We have been able to determine its pH in frozen and fluid state with the help of multifrequency EPR spectroscopy [8]. With the help of this spectroscopy, it is able to detect that each polyphenol exhibits the formation of three different mononuclear species. If the pH ranges 4–8 for di- or polymeric complex of Cu(II), then it conjectures such metal complexes. It is only at alkaline pH values.
The line width in fluid solutions by molecular motion exhibits an incomplete average of the parameters of anisotropy spin Hamilton. If the complexes are different, then their rotational correlation times for this also vary. The analysis of the LyCEP anisotropy of the fluid solution spectra is performed using the parameters determined by the simulation of the rigid boundary spectra. Its result suggests that pH increases its value by affecting its molecular mass. It is a polyphenol ligand complex with copper, showing the coordination of an increasing number of its molecules or increasing participation of polyphenol dimers used as ligands in the copper coordination region.
The study by Vishenkova and his co-worker [8] provides the investigation of electrochemical properties of triphenylmethane dyes using a voltammetric method with constant-current potential sweep. Malachite green (MG) and basic fuchsin (BF) have been chosen as representatives of the triphenylmethane dyes [9]. The electrochemical behavior of MG and BF on the surface of a mercury film electrode depending on pH, the nature of background electrolyte, and scan rate of potential sweep has been investigated.
Using a voltammetric method with a constant-current potential sweep examines the electrical properties of triphenylmethane dye. In order to find out the solution of MG and BF, certain registration conditions have been prescribed for it, which have proved to be quite useful. The reduction peak for the currents of MG and BF has demonstrated that it increases linearly with respect to their concentration as 9.0 × 10−5–7.0 × 10−3 mol/dm3 for MG and 6.0 × 10−5–8.0 × 10−3 mol/dm3 for BF and correlation coefficients of these values are 0.9987 for MG and 0.9961 for BF [10].
5.0 × 10−5 and 2.0 × 10−5 mol/dm3 are the values used as the detection limit of MG and BF, respectively. Stability constants are a very useful technique whose size is huge. Due to its usefulness, it has acquired an umbrella right in the fields of chemistry, biology, and medicine. No science subject is untouched by this. Stability constants of metal complexes are widely used in the various areas like pharmaceuticals as well as biological processes, separation techniques, analytical processes, etc. In the presented chapter, we have tried to explain this in detail by focusing our attention on the applications and solutions of stability of metal complexes in solution.
Stability or formation or binding constant is the type of equilibrium constant used for the formation of metal complexes in the solution. Acutely, stability constant is applicable to measure the strength of interactions between the ligands and metal ions that are involved in complex formation in the solution [11]. A generally these 1-4 equations are expressed as the following ways:
Thus
K1, K2, K3, … Kn are the equilibrium constants and these are also called stepwise stability constants. The formation of the metal-ligand-n complex may also be expressed as equilibrium constants by the following steps:
The parameters K and β are related together, and these are expressed in the following example:
Now the numerator and denominator are multiplied together with the use of [metal-ligand] [metal-ligand2], and after the rearranging we get the following equation:
Now we expressed it as the following:
From the above relation, it is clear that the overall stability constant βn is equal to the product of the successive (i.e., stepwise) stability constants, K1, K2, K3,…Kn. This in other words means that the value of stability constants for a given complex is actually made up of a number of stepwise stability constants. The term stability is used without qualification to mean that the complex exists under a suitable condition and that it is possible to store the complex for an appreciable amount of time. The term stability is commonly used because coordination compounds are stable in one reagent but dissociate or dissolve in the presence of another regent. It is also possible that the term stability can be referred as an action of heat or light or compound. The stability of complex [13] is expressed qualitatively in terms of thermodynamic stability and kinetic stability.
In a chemical reaction, chemical equilibrium is a state in which the concentration of reactants and products does not change over time. Often this condition occurs when the speed of forward reaction becomes the same as the speed of reverse reaction. It is worth noting that the velocities of the forward and backward reaction are not zero at this stage but are equal.
If hydrogen and iodine are kept together in molecular proportions in a closed process vessel at high temperature (500°C), the following action begins:
In this activity, hydrogen iodide is formed by combining hydrogen and iodine, and the amount of hydrogen iodide increases with time. In contrast to this action, if the pure hydrogen iodide gas is heated to 500°C in the reaction, the compound is dissolved by reverse action, which causes hydrogen iodide to dissolve into hydrogen and iodine, and the ratio of these products increases over time. This is expressed in the following reaction:
For the formation of metal chelates, the thermodynamic technique provides a very significant information. Thermodynamics is a very useful technique in distinguishing between enthalpic effects and entropic effects. The bond strengths are totally effected by enthalpic effect, and this does not make any difference in the whole solution in order/disorder. Based on thermodynamics the chelate effect below can be best explained. The change of standard Gibbs free energy for equilibrium constant is response:
Where:
R = gas constant
T = absolute temperature
At 25°C,
ΔG = (− 5.708 kJ mol−1) · log β.
The enthalpy term creates free energy, i.e.,
For metal complexes, thermodynamic stability and kinetic stability are two interpretations of the stability constant in the solution. If reaction moves from reactants to products, it refers to a change in its energy as shown in the above equation. But for the reactivity, kinetic stability is responsible for this system, and this refers to ligand species [14].
Stable and unstable are thermodynamic terms, while labile and inert are kinetic terms. As a rule of thumb, those complexes which react completely within about 1 minute at 25°C are considered labile, and those complexes which take longer time than this to react are considered inert. [Ni(CN)4]2− is thermodynamically stable but kinetically inert because it rapidly exchanges ligands.
The metal complexes [Co(NH3)6]3+ and such types of other complexes are kinetically inert, but these are thermodynamically unstable. We may expect the complex to decompose in the presence of acid immediately because the complex is thermodynamically unstable. The rate is of the order of 1025 for the decomposition in acidic solution. Hence, it is thermodynamically unstable. However, nothing happens to the complex when it is kept in acidic solution for several days. While considering the stability of a complex, always the condition must be specified. Under what condition, the complex which is stable or unstable must be specified such as acidic and also basic condition, temperature, reactant, etc.
A complex may be stable with respect to a particular condition but with respect to another. In brief, a stable complex need not be inert and similarly, and an unstable complex need not be labile. It is the measure of extent of formation or transformation of complex under a given set of conditions at equilibrium [15].
Thermodynamic stability has an important role in determining the bond strength between metal ligands. Some complexes are stable, but as soon as they are introduced into aqueous solution, it is seen that these complexes have an effect on stability and fall apart. For an example, we take the [Co (SCN)4]2+ complex. The ion bond of this complex is very weak and breaks down quickly to form other compounds. But when [Fe(CN)6]3− is dissolved in water, it does not test Fe3+ by any sensitive reagent, which shows that this complex is more stable in aqueous solution. So it is indicated that thermodynamic stability deals with metal-ligand bond energy, stability constant, and other thermodynamic parameters.
This example also suggests that thermodynamic stability refers to the stability and instability of complexes. The measurement of the extent to which one type of species is converted to another species can be determined by thermodynamic stability until equilibrium is achieved. For example, tetracyanonickelate is a thermodynamically stable and kinetic labile complex. But the example of hexa-amine cobalt(III) cation is just the opposite:
Thermodynamics is used to express the difference between stability and inertia. For the stable complex, large positive free energies have been obtained from ΔG0 reaction. The ΔH0, standard enthalpy change for this reaction, is related to the equilibrium constant, βn, by the well thermodynamic equation:
For similar complexes of various ions of the same charge of a particular transition series and particular ligand, ΔS0 values would not differ substantially, and hence a change in ΔH0 value would be related to change in βn values. So the order of values of ΔH0 is also the order of the βn value.
Kinetic stability is referred to the rate of reaction between the metal ions and ligand proceeds at equilibrium or used for the formation of metal complexes. To take a decision for kinetic stability of any complexes, time is a factor which plays an important role for this. It deals between the rate of reaction and what is the mechanism of this metal complex reaction.
As we discuss above in thermodynamic stability, kinetic stability is referred for the complexes at which complex is inert or labile. The term “inert” was used by Tube for the thermally stable complex and for reactive complexes the term ‘labile’ used [16]. The naturally occurring chlorophyll is the example of polydentate ligand. This complex is extremely inert due to exchange of Mg2+ ion in the aqueous media.
The nature of central atom of metal complexes, dimension, its degree of oxidation, electronic structure of these complexes, and so many other properties of complexes are affected by the stability constant. Some of the following factors described are as follows.
In the coordination chemistry, metal complexes are formed by the interaction between metal ions and ligands. For these type of compounds, metal ions are the coordination center, and the ligand or complexing agents are oriented surrounding it. These metal ions mostly are the transition elements. For the determination of stability constant, some important characteristics of these metal complexes may be as given below.
Ligands are oriented around the central metal ions in the metal complexes. The sizes of these metal ions determine the number of ligand species that will be attached or ordinated (dative covalent) in the bond formation. If the sizes of these metal ions are increased, the stability of coordination compound defiantly decreased. Zn(II) metal ions are the central atoms in their complexes, and due to their lower size (0.74A°) as compared to Cd(II) size (0.97A°), metal ions are formed more stable.
Hence, Al3+ ion has the greatest nuclear charge, but its size is the smallest, and the ion N3− has the smallest nuclear charge, and its size is the largest [17]. Inert atoms like neon do not participate in the formation of the covalent or ionic compound, and these atoms are not included in isoelectronic series; hence, it is not easy to measure the radius of this type of atoms.
The properties of stability depend on the size of the metal ion used in the complexes and the total charge thereon. If the size of these metal ions is small and the total charge is high, then their complexes will be more stable. That is, their ratio will depend on the charge/radius. This can be demonstrated through the following reaction:
An ionic charge is the electric charge of an ion which is formed by the gain (negative charge) or loss (positive charge) of one or more electrons from an atom or group of atoms. If we talk about the stability of the coordination compounds, we find that the total charge of their central metal ions affects their stability, so when we change their charge, their stability in a range of constant can be determined by propagating of error [18]. If the charge of the central metal ion is high and the size is small, the stability of the compound is high:
In general, the most stable coordination bonds can cause smaller and highly charged rations to form more stable coordination compounds.
When an electron pair attracts a central ion toward itself, a strong stability complex is formed, and this is due to electron donation from ligand → metal ion. This donation process is increasing the bond stability of metal complexes exerted the polarizing effect on certain metal ions. Li+, Na+, Mg2+, Ca2+, Al3+, etc. are such type of metal cation which is not able to attract so strongly from a highly electronegative containing stable complexes, and these atoms are O, N, F, Au, Hg, Ag, Pd, Pt, and Pb. Such type of ligands that contains P, S, As, Br and I atom are formed stable complex because these accepts electron from M → π-bonding. Hg2+, Pb2+, Cd2+, and Bi3+ metal ions are also electronegative ions which form insoluble salts of metal sulfide which are insoluble in aqueous medium.
Volatile ligands may be lost at higher temperature. This is exemplified by the loss of water by hydrates and ammonia:
The transformation of certain coordination compounds from one to another is shown as follows:
A ligand is an ion or small molecule that binds to a metal atom (in chemistry) or to a biomolecule (in biochemistry) to form a complex, such as the iron-cyanide coordination complex Prussian blue or the iron-containing blood-protein hemoglobin. The ligands are arranged in spectrochemical series which are based on the order of their field strength. It is not possible to form the entire series by studying complexes with a single metal ion; the series has been developed by overlapping different sequences obtained from spectroscopic studies [19]. The order of common ligands according to their increasing ligand field strength is
The above spectrochemical series help us to for determination of strength of ligands. The left last ligand is as weaker ligand. These weaker ligand cannot forcible binding the 3d electron and resultant outer octahedral complexes formed. It is as-
Increasing the oxidation number the value of Δ increased.
Δ increases from top to bottom.
However, when we consider the metal ion, the following two useful trends are observed:
Δ increases with increasing oxidation number.
Δ increases down a group. For the determination of stability constant, the nature of the ligand plays an important role.
The following factors described the nature of ligands.
The size and charge are two factors that affect the production of metal complexes. The less charges and small sizes of ligands are more favorable for less stable bond formation with metal and ligand. But if this condition just opposite the product of metal and ligand will be a more stable compound. So, less nuclear charge and more size= less stable complex whereas if more nuclear charge and small in size= less stable complex. We take fluoride as an example because due to their smaller size than other halide and their highest electro negativity than the other halides formed more stable complexes. So, fluoride ion complexes are more stable than the other halides:
As compared to S2− ion, O22− ions formed more stable complexes.
It is suggested by Calvin and Wilson that the metal complexes will be more stable if the basic character or strength of ligands is higher. It means that the donating power of ligands to central metal ions is high [20].
It means that the donating power of ligands to central metal ions is high. In the case of complex formation of aliphatic diamines and aromatic diamines, the stable complex is formed by aliphatic diamines, while an unstable coordination complex is formed with aromatic diamines. So, from the above discussion, we find that the stability will be grater if the e-donation power is greater.
Thus it is clear that greater basic power of electron-donating species will form always a stable complex. NH3, CN−, and F− behaved as ligands and formed stable complexes; on the other hand, these are more basic in nature.
We know that if the concentration of coordination group is higher, these coordination compounds will exist in the water as solution. It is noted that greater coordinating tendency show the water molecules than the coordinating group which is originally present. SCN− (thiocynate) ions are present in higher concentration; with the Co2+ metal ion, it formed a blue-colored complex which is stable in state, but on dilution of water medium, a pink color is generated in place of blue, or blue color complex is destroyed by [Co(H2O)6]2+, and now if we added further SCN−, the pink color will not appear:
Now it is clear that H2O and SCN− are in competition for the formation of Co(II) metal-containing complex compound. In the case of tetra-amine cupric sulfate metal complex, ammonia acts as a donor atom or ligand. If the concentration of NH3 is lower in the reaction, copper hydroxide is formed but at higher concentration formed tetra-amine cupric sulfate as in the following reaction:
For a metal ion, chelating ligand is enhanced and affinity it and this is known as chelate effect and compared it with non-chelating and monodentate ligand or the multidentate ligand is acts as chelating agent. Ethylenediamine is a simple chelating agent (Figure 1).
Structure of ethylenediamine.
Due to the bidentate nature of ethylenediamine, it forms two bonds with metal ion or central atom. Water forms a complex with Ni(II) metal ion, but due to its monodentate nature, it is not a chelating ligand (Figures 2 and 3).
Structure of chelating configuration of ethylenediamine ligand.
Structure of chelate with three ethylenediamine ligands.
The dentate cheater of ligand provides bonding strength to the metal ion or central atom, and as the number of dentate increased, the tightness also increased. This phenomenon is known as chelating effect, whereas the formation of metal complexes with these chelating ligands is called chelation:
or
Some factors are of much importance for chelation as follows.
The sizes of the chelating ring are increased as well as the stability of metal complex decreased. According to Schwarzenbach, connecting bridges form the chelating rings. The elongated ring predominates when long bridges connect to the ligand to form a long ring. It is usually observed that an increased a chelate ring size leads to a decrease in complex stability.
He interpreted this statement. The entropy of complex will be change if the size of chelating ring is increased, i.e., second donor atom is allowed by the chelating ring. As the size of chelating ring increased, the stability should be increased with entropy effect. Four-membered ring compounds are unstable, whereas five-membered are more stable. So the chelating ring increased its size and the stability of the formed metal complexes.
The number of chelating rings also decides the stability of complexes. Non-chelating metal compounds are less stable than chelating compounds. These numbers increase the thermodynamic volume, and this is also known as an entropy term. In recent years ligands capable of occupying as many as six coordination positions on a single metal ion have been described. The studies on the formation constants of coordination compounds with these ligands have been reported. The numbers of ligand or chelating agents are affecting the stability of metal complexes so as these numbers go up and down, the stability will also vary with it.
For the Ni(II) complexes with ethylenediamine as chelating agent, its log K1 value is 7.9 and if chelating agents are trine and penten, then the log K1 values are 7.9 and 19.3, respectively. If the metal ion change Zn is used in place of Ni (II), then the values of log K1 for ethylenediamine, trine, and penten are 6.0, 12.1, and 16.2, respectively. The log βMY values of metal ions are given in Table 1.
Metal ion | log βMY (25°C, I = 0.1 M) |
---|---|
Ca2+ | 11.2 |
Cu2+ | 19.8 |
Fe3+ | 24.9 |
Metal ion vs. log βMY values.
Ni(NH3)62+ is an octahedral metal complex, and at 25 °C its log β6 value is 8.3, but Ni(ethylenediamine)32+ complex is also octahedral in geometry, with 18.4 as the value of log β6. The calculated stability value of Ni(ethylenediamine)32+ 1010 times is more stable because three rings are formed as chelating rings by ethylenediamine as compared to no such ring is formed. Ethylenediaminetetraacetate (EDTA) is a hexadentate ligand that usually formed stable metal complexes due to its chelating power.
A special effect in molecules is when the atoms occupy space. This is called steric effect. Energy is needed to bring these atoms closer to each other. These electrons run away from near atoms. There can be many ways of generating it. We know the repulsion between valence electrons as the steric effect which increases the energy of the current system [21]. Favorable or unfavorable any response is created.
For example, if the static effect is greater than that of a product in a metal complex formation process, then the static increase would favor this reaction. But if the case is opposite, the skepticism will be toward retardation.
This effect will mainly depend on the conformational states, and the minimum steric interaction theory can also be considered. The effect of secondary steric is seen on receptor binding produced by an alternative such as:
Reduced access to a critical group.
Stick barrier.
Electronic resonance substitution bond by repulsion.
Population of a conformer changes due to active shielding effect.
The macrocyclic effect is exactly like the image of the chelate effect. It means the principle of both is the same. But the macrocyclic effect suggests cyclic deformation of the ligand. Macrocyclic ligands are more tainted than chelating agents. Rather, their compounds are more stable due to their cyclically constrained constriction. It requires some entropy in the body to react with the metal ion. For example, for a tetradentate cyclic ligand, we can use heme-B which forms a metal complex using Fe+2 ions in biological systems (Figure 4).
Structure of hemoglobin is the biological complex compound which contains Fe(II) metal ion.
The n-dentate chelating agents play an important role for the formation of more stable metal complexes as compared to n-unidentate ligands. But the n-dentate macrocyclic ligand gives more stable environment in the metal complexes as compared to open-chain ligands. This change is very favorable for entropy (ΔS) and enthalpy (ΔH) change.
There are so many parameters to determination of formation constants or stability constant in solution for all types of chelating agents. These numerous parameters or techniques are refractive index, conductance, temperature, distribution coefficients, refractive index, nuclear magnetic resonance volume changes, and optical activity.
Solubility products are helpful and used for the insoluble salt that metal ions formed and complexes which are also formed by metal ions and are more soluble. The formation constant is observed in presence of donor atoms by measuring increased solubility.
To determine the solubility constant, it involves the distribution of the ligands or any complex species; metal ions are present in two immiscible solvents like water and carbon tetrachloride, benzene, etc.
In this method metal ions or ligands are present in solution and on exchanger. A solid polymers containing with positive and negative ions are ion exchange resins. These are insoluble in nature. This technique is helpful to determine the metal ions in resin phase, liquid phase, or even in radioactive metal. This method is also helpful to determine the polarizing effect of metal ions on the stability of ligands like Cu(II) and Zn(II) with amino acid complex formation.
At the equilibrium free metal and ions are present in the solution, and using the different electrometric techniques as described determines its stability constant.
This method is based upon the titration method or follows its principle. A stranded acid-base solution used as titrate and which is titrated, it may be strong base or strong acid follows as potentiometrically. The concentration of solution using 103− M does not decomposed during the reaction process, and this method is useful for protonated and nonprotonated ligands.
This is the graphic method used to determine the stability constant in producing metal complex formation by plotting a polarograph between the absences of substances and the presence of substances. During the complex formation, the presence of metal ions produced a shift in the half-wave potential in the solution.
If a complex is relatively slow to form and also decomposes at measurable rate, it is possible, in favorable situations, to determine the equilibrium constant.
This involves the study of the equilibrium constant of slow complex formation reactions. The use of tracer technique is extremely useful for determining the concentrations of dissociation products of the coordination compound.
This method is based on the study of the effect of an equilibrium concentration of some ions on the function at a definite organ of a living organism. The equilibrium concentration of the ion studied may be determined by the action of this organ in systems with complex formation.
The solution of 25 ml is adopted by preparing at the 1.0 × 10−5 M ligand or 1.0 × 10−5 M concentration and 1.0 × 10−5 M for the metal ion:
The solutions containing the metal ions were considered both at a pH sufficiently high to give almost complete complexation and at a pH value selected in order to obtain an equilibrium system of ligand and complexes.
In order to avoid modification of the spectral behavior of the ligand due to pH variations, it has been verified that the range of pH considered in all cases does not affect absorbance values. Use the collected pH values adopted for the determinations as well as selected wavelengths. The ionic strengths calculated from the composition of solutions allowed activity coefficient corrections. Absorbance values were determined at wavelengths in the range 430–700 nm, every 2 nm.
For a successive metal complex formation, use this method. If ligand is protonate and the produced complex has maximum number of donate atoms of ligands, a selective light is absorbed by this complex, while for determination of stability constant, it is just known about the composition of formed species.
Bjerrum (1941) used the method stepwise addition of the ligands to coordination sphere for the formation of complex. So, complex metal–ligand-n forms as the following steps [22]. The equilibrium constants, K1, K2, K3, … Kn are called stepwise stability constants. The formation of the complex metal-ligandn may also be expressed by the following steps and equilibrium constants.
Where:
M = central metal cation
L = monodentate ligand
N = maximum coordination number for the metal ion M for the ligand
If a complex ion is slow to reach equilibrium, it is often possible to apply the method of isotopic dilution to determine the equilibrium concentration of one or more of the species. Most often radioactive isotopes are used.
This method was extensively used by Werner and others to study metal complexes. In the case of a series of complexes of Co(III) and Pt(IV), Werner assigned the correct formulae on the basis of their molar conductance values measured in freshly prepared dilute solutions. In some cases, the conductance of the solution increased with time due to a chemical change, e.g.,
It is concluded that the information presented is very important to determine the stability constant of the ligand metal complexes. Some methods like spectrophotometric method, Bjerrum’s method, distribution method, ion exchange method, electrometric techniques, and potentiometric method have a huge contribution in quantitative analysis by easily finding the stability constants of metal complexes in aqueous solutions.
All the authors thank the Library of University of Delhi for reference books, journals, etc. which helped us a lot in reviewing the chapter.
License
\n\nBook Chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen maintains a very flexible Copyright Policy that ensures that there is no copyright transfer to the publisher. Therefore, Authors retain exclusive copyright to their work. All Monographs are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0).
\n\n',metaTitle:"Open Access Statement",metaDescription:"Book chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0)",metaKeywords:null,canonicalURL:"/page/open-access-statement/",contentRaw:'[{"type":"htmlEditorComponent","content":"Formats
\\n\\nBased on your preferences and the stage of your scientific projects, you have multiple options for publishing your scientific research with IntechOpen:
\\n\\nPeer Review Policies
\\n\\nAll scientific Works are subject to Peer Review prior to publishing.
\\n\\n\\n\\nCosts
\\n\\nThe Open Access publishing model followed by IntechOpen eliminates subscription charges and pay-per-view fees, thus enabling readers to access research at no cost to themselves. In order to sustain these operations, and keep our publications freely accessible, we levy an Open Access Publishing Fee on all manuscripts accepted for publication to help cover the costs of editorial work and the production of books.
\\n\\n\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is dedicated to ensuring the long-term preservation and availability of the scholarly research it publishes.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Formats
\n\nBased on your preferences and the stage of your scientific projects, you have multiple options for publishing your scientific research with IntechOpen:
\n\nPeer Review Policies
\n\nAll scientific Works are subject to Peer Review prior to publishing.
\n\n\n\nCosts
\n\nThe Open Access publishing model followed by IntechOpen eliminates subscription charges and pay-per-view fees, thus enabling readers to access research at no cost to themselves. In order to sustain these operations, and keep our publications freely accessible, we levy an Open Access Publishing Fee on all manuscripts accepted for publication to help cover the costs of editorial work and the production of books.
\n\n\n\nDigital Archiving Policy
\n\nIntechOpen is dedicated to ensuring the long-term preservation and availability of the scholarly research it publishes.
\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:5703},{group:"region",caption:"Middle and South America",value:2,count:5174},{group:"region",caption:"Africa",value:3,count:1690},{group:"region",caption:"Asia",value:4,count:10246},{group:"region",caption:"Australia and Oceania",value:5,count:889},{group:"region",caption:"Europe",value:6,count:15653}],offset:12,limit:12,total:117317},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"17"},books:[],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:9},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:14},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:6},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:4},{group:"topic",caption:"Engineering",value:11,count:16},{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:5},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:57},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:5},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{group:"topic",caption:"Robotics",value:22,count:1},{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:0},popularBooks:{featuredBooks:[{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5146},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editedByType:"Edited by",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editedByType:"Edited by",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8063",title:"Food Security in Africa",subtitle:null,isOpenForSubmission:!1,hash:"8cbf3d662b104d19db2efc9d59249efc",slug:"food-security-in-africa",bookSignature:"Barakat Mahmoud",coverURL:"https://cdn.intechopen.com/books/images_new/8063.jpg",editedByType:"Edited by",editors:[{id:"92016",title:"Dr.",name:"Barakat",middleName:null,surname:"Mahmoud",slug:"barakat-mahmoud",fullName:"Barakat Mahmoud"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10118",title:"Plant Stress Physiology",subtitle:null,isOpenForSubmission:!1,hash:"c68b09d2d2634fc719ae3b9a64a27839",slug:"plant-stress-physiology",bookSignature:"Akbar Hossain",coverURL:"https://cdn.intechopen.com/books/images_new/10118.jpg",editedByType:"Edited by",editors:[{id:"280755",title:"Dr.",name:"Akbar",middleName:null,surname:"Hossain",slug:"akbar-hossain",fullName:"Akbar Hossain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editedByType:"Edited by",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editedByType:"Edited by",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1083",title:"Medical Oncology",slug:"medical-oncology",parent:{title:"Oncology",slug:"medicine-oncology"},numberOfBooks:15,numberOfAuthorsAndEditors:436,numberOfWosCitations:226,numberOfCrossrefCitations:131,numberOfDimensionsCitations:346,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"medical-oncology",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"8025",title:"Cancer Immunotherapy and Biological Cancer Treatments",subtitle:null,isOpenForSubmission:!1,hash:"e9953ff7bc3b22ae75810e286dd86b73",slug:"cancer-immunotherapy-and-biological-cancer-treatments",bookSignature:"Hilal Arnouk",coverURL:"https://cdn.intechopen.com/books/images_new/8025.jpg",editedByType:"Edited by",editors:[{id:"76431",title:"Dr.",name:"Hilal",middleName:null,surname:"Arnouk",slug:"hilal-arnouk",fullName:"Hilal Arnouk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6127",title:"Cancer Causing Substances",subtitle:null,isOpenForSubmission:!1,hash:"174eb39b8b0e84934f4a958e6d4de827",slug:"cancer-causing-substances",bookSignature:"Faik Atroshi",coverURL:"https://cdn.intechopen.com/books/images_new/6127.jpg",editedByType:"Edited by",editors:[{id:"65639",title:"Dr.",name:"Faik",middleName:null,surname:"Atroshi",slug:"faik-atroshi",fullName:"Faik Atroshi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4756",title:"New Aspects in Molecular and Cellular Mechanisms of Human Carcinogenesis",subtitle:null,isOpenForSubmission:!1,hash:"3d0f53df3dd15a086df1fc78bd2aaed7",slug:"new-aspects-in-molecular-and-cellular-mechanisms-of-human-carcinogenesis",bookSignature:"Dmitry Bulgin",coverURL:"https://cdn.intechopen.com/books/images_new/4756.jpg",editedByType:"Edited by",editors:[{id:"93072",title:"Dr.",name:"Dmitry",middleName:null,surname:"Bulgin",slug:"dmitry-bulgin",fullName:"Dmitry Bulgin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4537",title:"Updates on Cancer Treatment",subtitle:null,isOpenForSubmission:!1,hash:"e4d069af27b0dd4f600d1ae75aee66cd",slug:"updates-on-cancer-treatment",bookSignature:"Leticia B. A. Rangel and Ian Victor Silva",coverURL:"https://cdn.intechopen.com/books/images_new/4537.jpg",editedByType:"Edited by",editors:[{id:"60359",title:"Dr.",name:"Letícia",middleName:null,surname:"Rangel",slug:"leticia-rangel",fullName:"Letícia Rangel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3462",title:"Neoadjuvant Chemotherapy",subtitle:"Increasing Relevance in Cancer Management",isOpenForSubmission:!1,hash:"4f88a3fde61b5535375bde00b9c13d1e",slug:"neoadjuvant-chemotherapy-increasing-relevance-in-cancer-management",bookSignature:"Maurie M. Markman",coverURL:"https://cdn.intechopen.com/books/images_new/3462.jpg",editedByType:"Edited by",editors:[{id:"162295",title:"Dr.",name:"Maurie",middleName:null,surname:"Markman",slug:"maurie-markman",fullName:"Maurie Markman"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3273",title:"Cancer Treatment",subtitle:"Conventional and Innovative Approaches",isOpenForSubmission:!1,hash:"cdd9872a05001212b3583bff95bae979",slug:"cancer-treatment-conventional-and-innovative-approaches",bookSignature:"Letícia Rangel",coverURL:"https://cdn.intechopen.com/books/images_new/3273.jpg",editedByType:"Edited by",editors:[{id:"60359",title:"Dr.",name:"Letícia",middleName:null,surname:"Rangel",slug:"leticia-rangel",fullName:"Letícia Rangel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3002",title:"Oncogenomics and Cancer Proteomics",subtitle:"Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer",isOpenForSubmission:!1,hash:"bc8990331803d9e6084b367163dcf218",slug:"oncogenomics-and-cancer-proteomics-novel-approaches-in-biomarkers-discovery-and-therapeutic-targets-in-cancer",bookSignature:"César López-Camarillo and Elena Aréchaga-Ocampo",coverURL:"https://cdn.intechopen.com/books/images_new/3002.jpg",editedByType:"Edited by",editors:[{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",slug:"cesar-lopez-camarillo",fullName:"Cesar Lopez-Camarillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3291",title:"T-Cell Leukemia",subtitle:"Characteristics, Treatment and Prevention",isOpenForSubmission:!1,hash:"fb2dc976b5929dc5fa310da0c658e55e",slug:"t-cell-leukemia-characteristics-treatment-and-prevention",bookSignature:"Mariko Tomita",coverURL:"https://cdn.intechopen.com/books/images_new/3291.jpg",editedByType:"Edited by",editors:[{id:"49567",title:"Dr.",name:"Mariko",middleName:null,surname:"Tomita",slug:"mariko-tomita",fullName:"Mariko Tomita"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2610",title:"Carcinogenesis",subtitle:null,isOpenForSubmission:!1,hash:"61e4a760de592236762035553ff855e9",slug:"carcinogenesis",bookSignature:"Kathryn Tonissen",coverURL:"https://cdn.intechopen.com/books/images_new/2610.jpg",editedByType:"Edited by",editors:[{id:"145170",title:"Dr.",name:"Kathryn",middleName:null,surname:"Tonissen",slug:"kathryn-tonissen",fullName:"Kathryn Tonissen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1898",title:"Cancer Management",subtitle:null,isOpenForSubmission:!1,hash:"877784b1af60471e118fade16d5c50d1",slug:"cancer-management",bookSignature:"Doaa Hashad",coverURL:"https://cdn.intechopen.com/books/images_new/1898.jpg",editedByType:"Edited by",editors:[{id:"110869",title:"Dr.",name:"Doaa",middleName:null,surname:"Hashad",slug:"doaa-hashad",fullName:"Doaa Hashad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1756",title:"Carcinogen",subtitle:null,isOpenForSubmission:!1,hash:"4ec4fd67f39ca00211fc40e7b563d684",slug:"carcinogen",bookSignature:"Margarita Pesheva, Martin Dimitrov and Teodora Stefkova Stoycheva",coverURL:"https://cdn.intechopen.com/books/images_new/1756.jpg",editedByType:"Edited by",editors:[{id:"115544",title:"Dr.",name:"Margarita",middleName:null,surname:"Pesheva",slug:"margarita-pesheva",fullName:"Margarita Pesheva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1001",title:"Tumor Microenvironment and Myelomonocytic Cells",subtitle:null,isOpenForSubmission:!1,hash:"a2392066cd104cd48f3b296bf72b97a6",slug:"tumor-microenvironment-and-myelomonocytic-cells",bookSignature:"Subhra K. Biswas",coverURL:"https://cdn.intechopen.com/books/images_new/1001.jpg",editedByType:"Edited by",editors:[{id:"69842",title:"Dr.",name:"Subhra",middleName:"K.",surname:"Biswas",slug:"subhra-biswas",fullName:"Subhra Biswas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:15,mostCitedChapters:[{id:"44364",doi:"10.5772/55795",title:"Hyperthermia: Cancer Treatment and Beyond",slug:"hyperthermia-cancer-treatment-and-beyond",totalDownloads:3175,totalCrossrefCites:17,totalDimensionsCites:34,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Ahmed Bettaieb, Paulina K. Wrzal and Diana A. Averill-Bates",authors:[{id:"61148",title:"Prof.",name:"Diana",middleName:null,surname:"Averill-Bates",slug:"diana-averill-bates",fullName:"Diana Averill-Bates"},{id:"62367",title:"Dr.",name:"Ahmed",middleName:null,surname:"Bettaieb",slug:"ahmed-bettaieb",fullName:"Ahmed Bettaieb"},{id:"62368",title:"Dr.",name:"Paulina",middleName:null,surname:"K. Wrzal",slug:"paulina-k.-wrzal",fullName:"Paulina K. Wrzal"}]},{id:"24601",doi:"10.5772/22656",title:"Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies",slug:"combination-chemotherapy-in-cancer-principles-evaluation-and-drug-delivery-strategies",totalDownloads:4370,totalCrossrefCites:1,totalDimensionsCites:31,book:{slug:"current-cancer-treatment-novel-beyond-conventional-approaches",title:"Current Cancer Treatment",fullTitle:"Current Cancer Treatment - Novel Beyond Conventional Approaches"},signatures:"Ana Catarina Pinto, João Nuno Moreira and Sérgio Simões",authors:[{id:"48598",title:"Prof.",name:"Sergio",middleName:null,surname:"Simoes",slug:"sergio-simoes",fullName:"Sergio Simoes"},{id:"54753",title:"Dr.",name:"Ana",middleName:null,surname:"Pinto",slug:"ana-pinto",fullName:"Ana Pinto"},{id:"54754",title:"Prof.",name:"Joăo",middleName:null,surname:"Moreira",slug:"joao-moreira",fullName:"Joăo Moreira"}]},{id:"43632",doi:"10.5772/53110",title:"The Importance of Cancer Cell Lines as in vitro Models in Cancer Methylome Analysis and Anticancer Drugs Testing",slug:"the-importance-of-cancer-cell-lines-as-in-vitro-models-in-cancer-methylome-analysis-and-anticancer-d",totalDownloads:4189,totalCrossrefCites:12,totalDimensionsCites:31,book:{slug:"oncogenomics-and-cancer-proteomics-novel-approaches-in-biomarkers-discovery-and-therapeutic-targets-in-cancer",title:"Oncogenomics and Cancer Proteomics",fullTitle:"Oncogenomics and Cancer Proteomics - Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer"},signatures:"Daniela Ferreira, Filomena Adega and Raquel Chaves",authors:[{id:"155129",title:"Prof.",name:"Raquel",middleName:null,surname:"Chaves",slug:"raquel-chaves",fullName:"Raquel Chaves"},{id:"157394",title:"M.Sc.",name:"Daniela",middleName:"Perneta",surname:"Ferreira",slug:"daniela-ferreira",fullName:"Daniela Ferreira"},{id:"157395",title:"Dr.",name:"Filomena",middleName:null,surname:"Adega",slug:"filomena-adega",fullName:"Filomena Adega"}]}],mostDownloadedChaptersLast30Days:[{id:"42589",title:"Anticancer Properties of Cardiac Glycosides",slug:"anticancer-properties-of-cardiac-glycosides",totalDownloads:3270,totalCrossrefCites:2,totalDimensionsCites:5,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Varisa Pongrakhananon",authors:[{id:"60007",title:"Prof.",name:"Varisa",middleName:null,surname:"Pongrakhananon",slug:"varisa-pongrakhananon",fullName:"Varisa Pongrakhananon"}]},{id:"44364",title:"Hyperthermia: Cancer Treatment and Beyond",slug:"hyperthermia-cancer-treatment-and-beyond",totalDownloads:3175,totalCrossrefCites:17,totalDimensionsCites:34,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Ahmed Bettaieb, Paulina K. Wrzal and Diana A. Averill-Bates",authors:[{id:"61148",title:"Prof.",name:"Diana",middleName:null,surname:"Averill-Bates",slug:"diana-averill-bates",fullName:"Diana Averill-Bates"},{id:"62367",title:"Dr.",name:"Ahmed",middleName:null,surname:"Bettaieb",slug:"ahmed-bettaieb",fullName:"Ahmed Bettaieb"},{id:"62368",title:"Dr.",name:"Paulina",middleName:null,surname:"K. Wrzal",slug:"paulina-k.-wrzal",fullName:"Paulina K. Wrzal"}]},{id:"43632",title:"The Importance of Cancer Cell Lines as in vitro Models in Cancer Methylome Analysis and Anticancer Drugs Testing",slug:"the-importance-of-cancer-cell-lines-as-in-vitro-models-in-cancer-methylome-analysis-and-anticancer-d",totalDownloads:4189,totalCrossrefCites:12,totalDimensionsCites:31,book:{slug:"oncogenomics-and-cancer-proteomics-novel-approaches-in-biomarkers-discovery-and-therapeutic-targets-in-cancer",title:"Oncogenomics and Cancer Proteomics",fullTitle:"Oncogenomics and Cancer Proteomics - Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer"},signatures:"Daniela Ferreira, Filomena Adega and Raquel Chaves",authors:[{id:"155129",title:"Prof.",name:"Raquel",middleName:null,surname:"Chaves",slug:"raquel-chaves",fullName:"Raquel Chaves"},{id:"157394",title:"M.Sc.",name:"Daniela",middleName:"Perneta",surname:"Ferreira",slug:"daniela-ferreira",fullName:"Daniela Ferreira"},{id:"157395",title:"Dr.",name:"Filomena",middleName:null,surname:"Adega",slug:"filomena-adega",fullName:"Filomena Adega"}]},{id:"56652",title:"Heavy Metals and Cancer",slug:"heavy-metals-and-cancer",totalDownloads:1205,totalCrossrefCites:3,totalDimensionsCites:3,book:{slug:"cancer-causing-substances",title:"Cancer Causing Substances",fullTitle:"Cancer Causing Substances"},signatures:"Austin Carver and Vincent S. Gallicchio",authors:[{id:"169299",title:"Dr.",name:"Vincent",middleName:null,surname:"Gallicchio",slug:"vincent-gallicchio",fullName:"Vincent Gallicchio"},{id:"215100",title:"Mr.",name:"Austin",middleName:null,surname:"Carver",slug:"austin-carver",fullName:"Austin Carver"}]},{id:"42057",title:"Conventional Cancer Treatment",slug:"conventional-cancer-treatment",totalDownloads:1917,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Isabella dos Santos Guimarães*, Renata Dalmaschio Daltoé*, Alice\nLaschuk Herlinger, Klesia Pirola Madeira, Taciane Ladislau, Iuri\nCordeiro Valadão, Paulo Cilas Morais Lyra Junior, Sarah Fernandes\nTeixeira, Gustavo Modesto Amorim, Diandra Zipinotti dos Santos,\nKarina Rangel Demuth and Leticia Batista Azevedo Rangel",authors:[{id:"60339",title:"Prof.",name:"Renata",middleName:null,surname:"Dalto�",slug:"renata-dalto",fullName:"Renata Dalto�"},{id:"60359",title:"Dr.",name:"Letícia",middleName:null,surname:"Rangel",slug:"leticia-rangel",fullName:"Letícia Rangel"},{id:"96614",title:"Dr.",name:"Klesia",middleName:"Pirola",surname:"Madeira",slug:"klesia-madeira",fullName:"Klesia Madeira"},{id:"96615",title:"MSc.",name:"Alice",middleName:null,surname:"Herlinger",slug:"alice-herlinger",fullName:"Alice Herlinger"},{id:"165908",title:"BSc.",name:"Taciane",middleName:null,surname:"Ladislau",slug:"taciane-ladislau",fullName:"Taciane Ladislau"},{id:"165909",title:"BSc.",name:"Isabella",middleName:null,surname:"Guimarães",slug:"isabella-guimaraes",fullName:"Isabella Guimarães"},{id:"165910",title:"Ms.",name:"Sarah",middleName:null,surname:"Teixeira",slug:"sarah-teixeira",fullName:"Sarah Teixeira"},{id:"165911",title:"Mr.",name:"Paulo",middleName:null,surname:"Lyra-Junior",slug:"paulo-lyra-junior",fullName:"Paulo Lyra-Junior"},{id:"165912",title:"Mr.",name:"Iuri",middleName:null,surname:"Valadão",slug:"iuri-valadao",fullName:"Iuri Valadão"},{id:"165918",title:"MSc.",name:"Gustavo",middleName:null,surname:"Amorim",slug:"gustavo-amorim",fullName:"Gustavo Amorim"},{id:"165919",title:"Ms.",name:"Diandra",middleName:null,surname:"Santos",slug:"diandra-santos",fullName:"Diandra Santos"},{id:"165920",title:"Dr.",name:"Karina",middleName:"Rangel",surname:"Demuth",slug:"karina-demuth",fullName:"Karina Demuth"}]},{id:"34380",title:"Monocyte Subsets and Their Role in Tumor Progression",slug:"monocyte-subsets-and-their-role-in-tumor-progression",totalDownloads:3261,totalCrossrefCites:3,totalDimensionsCites:5,book:{slug:"tumor-microenvironment-and-myelomonocytic-cells",title:"Tumor Microenvironment and Myelomonocytic Cells",fullTitle:"Tumor Microenvironment and Myelomonocytic Cells"},signatures:"Andrea Doseff and Arti Parihar",authors:[{id:"92127",title:"Dr",name:"Andrea",middleName:null,surname:"Doseff",slug:"andrea-doseff",fullName:"Andrea Doseff"},{id:"127683",title:"Dr.",name:"Arti",middleName:null,surname:"Parihar",slug:"arti-parihar",fullName:"Arti Parihar"}]},{id:"44365",title:"Immunotherapy of Urinary Bladder Carcinoma: BCG and Beyond",slug:"immunotherapy-of-urinary-bladder-carcinoma-bcg-and-beyond",totalDownloads:1963,totalCrossrefCites:4,totalDimensionsCites:13,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Yi Luo, Eric J. Askeland, Mark R. Newton, Jonathan R. Henning and\nMichael A. O’Donnell",authors:[{id:"46467",title:"Prof.",name:"Yi",middleName:null,surname:"Luo",slug:"yi-luo",fullName:"Yi Luo"},{id:"95257",title:"Dr.",name:"Jonathan",middleName:null,surname:"Henning",slug:"jonathan-henning",fullName:"Jonathan Henning"},{id:"95258",title:"Prof.",name:"Michael",middleName:null,surname:"O'Donnell",slug:"michael-o'donnell",fullName:"Michael O'Donnell"},{id:"155748",title:"Dr.",name:"Eric",middleName:null,surname:"Askeland",slug:"eric-askeland",fullName:"Eric Askeland"},{id:"155749",title:"Dr.",name:"Mark",middleName:null,surname:"Newton",slug:"mark-newton",fullName:"Mark Newton"}]},{id:"41975",title:"Targeted Cancer Therapy by Dendritic Cell Vaccine",slug:"targeted-cancer-therapy-by-dendritic-cell-vaccine",totalDownloads:2202,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Hiroyuki Abe, Touko Shimamoto, Shinichiro Akiyama and Minako\nAbe",authors:[{id:"62629",title:"Prof.",name:"Hiroyuki",middleName:null,surname:"Abe",slug:"hiroyuki-abe",fullName:"Hiroyuki Abe"}]},{id:"43863",title:"Definitive Chemo-Radiotherapy for Resectable Esophageal Cancer — Unresolved Problems Remain",slug:"definitive-chemo-radiotherapy-for-resectable-esophageal-cancer-unresolved-problems-remain",totalDownloads:1398,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Shouji Shimoyama",authors:[{id:"59239",title:"Dr.",name:"Shouji",middleName:null,surname:"Shimoyama",slug:"shouji-shimoyama",fullName:"Shouji Shimoyama"}]},{id:"44356",title:"Supportive and Palliative Care in Solid Cancer Patients",slug:"supportive-and-palliative-care-in-solid-cancer-patients",totalDownloads:1370,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"cancer-treatment-conventional-and-innovative-approaches",title:"Cancer Treatment",fullTitle:"Cancer Treatment - Conventional and Innovative Approaches"},signatures:"Bassam Abdul Rasool Hassan, Zuraidah Binti Mohd Yusoff,\nMohamed Azmi Hassali and Saad Bin Othman",authors:[{id:"155124",title:"Dr.",name:"Bassam",middleName:"Abdul Rasool",surname:"Hassan",slug:"bassam-hassan",fullName:"Bassam Hassan"}]}],onlineFirstChaptersFilter:{topicSlug:"medical-oncology",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:"profile.detail",path:"/profiles/169789/veronica-cardoso",hash:"",query:{},params:{id:"169789",slug:"veronica-cardoso"},fullPath:"/profiles/169789/veronica-cardoso",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var t;(t=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(t)}()