Staging by TNM.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"1170",leadTitle:null,fullTitle:"Maxillofacial Surgery",title:"Maxillofacial Surgery",subtitle:null,reviewType:"peer-reviewed",abstract:"Oral and maxillofacial surgery is a specialty rooted in dentistry and forged in academic medical centers in departments of surgery, as the surgical specialty well equipped to care for conditions of the mouth, jaws, head and neck. 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It is intended to be used also by the medical doctors, animal owners, consumers of food of animal origin, etc. The book has five sections: "Introduction," "Use of Antibiotics in Animals," "Antibiotics and Nutrition," "Probiotics," and "Antimicrobial Resistance." Each of the sections discusses about one side of the antibiotic usage. Each group of authors has dedicated their work to one of the topics with key roles of antibiotics in the health of animals and public health in general. This book is a work of scientists and researchers in the topic of antibiotic use, and with this book, we hope to open new questions and deepen the research on roles of antibiotics in everyday life.',isbn:"978-953-51-3751-1",printIsbn:"978-953-51-3750-4",pdfIsbn:"978-953-51-4053-5",doi:"10.5772/intechopen.68438",price:119,priceEur:129,priceUsd:155,slug:"antibiotic-use-in-animals",numberOfPages:164,isOpenForSubmission:!1,hash:"330ad6b360324a533411aa736563fbee",bookSignature:"Sara Savic",publishedDate:"January 31st 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6179.jpg",keywords:null,numberOfDownloads:10065,numberOfWosCitations:30,numberOfCrossrefCitations:20,numberOfDimensionsCitations:39,numberOfTotalCitations:89,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 20th 2017",dateEndSecondStepPublish:"May 11th 2017",dateEndThirdStepPublish:"September 25th 2017",dateEndFourthStepPublish:"November 5th 2017",dateEndFifthStepPublish:"January 4th 2018",remainingDaysToSecondStep:"4 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",biography:"Sara Savić, Ph.D., DVM, is a researcher, working in a diagnostic laboratory within the Scientific Veterinary Institute 'Novi Sad” from Novi Sad, Serbia.\r\n Her main work is based on the diagnostic procedures for zoonotic diseases and vector-borne zoonoses. Dr. Savić has completed her Ph.D. degree on Diagnostics of Lyme disease in dogs and ticks, after which her interests and career went toward One Health issues. \r\nThe significance of multidisciplinary, transdisciplinary, and interdisciplinary work has become most interesting during the past decade. Her expertise is in bacterial and parasitic vector-borne zoonoses, especially in blood parasites. Dr. Savić has published over 100 publications so far as a leading author or as a co-author, in different scientific journals and proceedings from different scientific meetings.",institutionString:"Scientific Veterinary Institute",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1387",title:"Holistic Veterinary Medicine",slug:"holistic-veterinary-medicine"}],chapters:[{id:"58700",title:"Introductory Chapter: Antibiotic Use in Animals Today",slug:"introductory-chapter-antibiotic-use-in-animals-today",totalDownloads:636,totalCrossrefCites:0,authors:[{id:"239551",title:"Dr.",name:"Sara",surname:"Savic",slug:"sara-savic",fullName:"Sara Savic"}]},{id:"57280",title:"Necessary Usage of Antibiotics in Animals",slug:"necessary-usage-of-antibiotics-in-animals",totalDownloads:1396,totalCrossrefCites:2,authors:[{id:"207381",title:"Associate Prof.",name:"Mohamed Bedair M.",surname:"Ahmed",slug:"mohamed-bedair-m.-ahmed",fullName:"Mohamed Bedair M. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65946",title:"The Role of Pulmonary Rehabilitation in Patients with Idiopathic Pulmonary Fibrosis",doi:"10.5772/intechopen.84283",slug:"the-role-of-pulmonary-rehabilitation-in-patients-with-idiopathic-pulmonary-fibrosis",body:'\nIdiopathic pulmonary fibrosis (IPF) is a chronic disease that affects exclusively the lung, with an unknown etiology and a fast-progressive irreversible evolution, therefore disabling the adult. For most of the patients, the average survival is approximately 3–5 years from diagnosis [1, 2]. With an unpredictable but progressive evolution (slower, stable, or accelerated decline from patient to patient), the disease is characterized by a chronic presence of symptoms, specifically the exertional dyspnea, low tolerance to effort, and the deterioration of the quality of life [1, 2, 3, 4]. The diagnosis of the disease is often delayed and not reported until advanced stages [5]. A hope to halt the progression of the disease occurred with the demonstration of the reduction in the functional decline of the new pharmacological agents, pirfenidone and nintedanib, without claiming to cure the disease [1, 2, 3, 4, 5]. IPF remains a life-threatening illness in which the patient is fighting for survival as long as possible, striving to cope with the symptoms and the noticeable fatigue. Given that this is a fatal disease, some of the needs identified in patients with IPF and their families are easy access to information and IPF specialists, the existence of more treatment methods, emotional support, and access to end-of-life care [3].
\nThe indication of pulmonary rehabilitation (PR) for patients with IPF came from the positive results stemming from the exercise training program (ETP) in COPD. Thus, numerous clinical studies performed on patients with IPF proved that their health and wellness could be improved, at least for short periods, through ETP which are personalized and supervised by specialists [2].
\nPulmonary rehabilitation program (PRP) is an evidence-based recommendation for the non-pharmacological treatment of patients with chronic pulmonary diseases, especially for COPD, but also for interstitial lung diseases [1, 4]. PRP must be included in the integrative treatment of IPF, taking into consideration the severity of the disease, high mortality during exacerbations, a modest response to new drugs, and accelerated deterioration of lung function.
\nThe usual interstitial pneumonia (UIP) pattern (fibrosis with collagen and matrix deposition, the presence of fibroblastic foci and alveolar collapse, pulmonary heterogeneous architectural distortion and honeycombing presence) determines the main pathophysiological changes in IPF: loss of lung volume, decreased lung compliance, abnormal pulmonary gas exchange with oxygen diffusion limitation, low mixed venous oxygen content, circulatory impairments, and alveolar ventilation/perfusion (V′A/Q′) mismatching [6, 7].
\nPulmonary function tests reveal restrictive pulmonary dysfunction, indirect signs of increased elastic recoil, and decrease in diffusion capacity for carbon monoxide (DLCO). Pulse oximetry and arterial blood gases reveal hypoxemia initially only during exercise and, in advanced cases, as well during resting [2, 7]. Patients with IPF have reduced maximal or peak oxygen uptake (V’O2peak), peak work rate, and submaximal exercise endurance [7].
\nThe progressive installation of morphophysiopathological changes is reflected in the clinical symptoms of patients. The exertional dyspnea is the first and most important symptom of IPF patients. The more advanced the disease, the more severe the dyspnea is. The patients tend to be less physically active and more depressed [8]. The level of dyspnea is strongly correlated with the exercise capacity, the quality of life, and mortality [1, 8, 9]. Other associated symptoms are fatigue, dry cough, chest discomfort, and leg pain. These symptoms are mild or inconsistent at the beginning of the disease, but they get worse over time and lead to an impairment of daily activities [10]. Symptomology and physical inactivity are directly related to depression, quality of life (QoL), and increased mortality [10, 11].
\nConsequently, the most important mechanisms that limit effort capacity and change the IPF patient’s lifestyle, into a sedentary one, are inefficient breathing mechanics, abnormal pulmonary gas exchange, circulatory impairment, and exercise-induced hypoxemia [1, 7, 12, 13]. In time, progressive exercise-induced hypoxemia leads to respiratory and skeletal muscle dysfunction [1, 7]. Non-pharmacological interventions must take into account these mechanisms and create programs that seek to influence the patients’ outcomes positively. PR is a safe and effective non-pharmacological treatment [14].
\nThe official ERS/ARS statement define pulmonary rehabilitation as “Pulmonary rehabilitation is a comprehensive intervention based on a thorough patient assessment followed by patient tailored therapies that include, but are not limited to, exercise training, education, and behavior change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviors” [11].
\nPR decreases dyspnea, improves exercise capacity, and helps to cope with functional activities of daily life in IPF patients, even though the significance of these benefits is smaller and lasts for less time than in other chronic lung disease like COPD [15, 16, 17, 18, 19, 20].
\n\n
Decreasing symptoms, especially dyspnea
Increasing effort capacity
Enhancing the quality of life, health, and wellness
Improving muscle strength and endurance
Maintaining joint mobility
Increasing tolerance to physical activity with the improved cardiometabolic and respiratory profile
Improving well-being and cognitive functions
Decreasing depression and anxiety
Offer social and psychological support with the possibility of occupational and group therapy
Promoting pro-healthy behaviors, with decreasing effort deconditioning
The adaptation of pulmonary rehabilitation programs for IPF started from those applied to patients with COPD. It is advised to take into account the pathophysiology mechanisms particular to IPF and the clinical particularities of these patients. Patients have a respiratory pattern of frequent, superficial, and rapid breaths that worsen during exercise [7, 17, 18]. The frequent association of pulmonary hypertension (PH) aggravates the symptoms [1, 4]. An explanation for the positive results of PRP could be that repetitive ventilator stimulus during physical training sessions increases chest expansion and secondary pleural elasticity and pulmonary compliance while also improving V’A/Q‘ mismatch, increasing V’O2peak [13, 23]. Also, deep breathing exercises with stretching and the training of respiratory muscles, including the diaphragm, can help to reduce dyspnea [20, 23, 24].
\nBefore entering into a PRP, patients with IPF need to be assessed by the multidisciplinary team regarding clinical and functional status, imaging, effort tolerance, quality of life, physical activities of daily living (PADL), the presence of comorbidities, needs, and expectations from the pharmacological treatment. The evaluation of comorbidities such as coronary arterial disease, systemic and pulmonary hypertension, right and left ventricle dysfunction, and arrhythmias during exercise is critical. The additional impairment of the cardiovascular system decreases the effort capacity and worsens dyspnea and prognosis of patients [1, 2, 25]. This complex assessment also has the role in determining the type, intensity, and results of the PRP.
\nDyspnea is the most significant and disabling symptom for IPF patients. It can be objectively identified before, in the end, and at any time within PRP and can modulate the intensity of exercise. In studies targeting PR in IPF, dyspnea is quantified using one of the following scales:
\nThe Modified Medical Research Council (MMRC) scale is a well-known tool which assesses the dyspnea based on 5 degrees that are reported by the patient depending on his physical activity tolerance. It seems that dyspnea severity correlates with lung function parameters and Saint George Respiratory Questionnaire (SGRQ). The patient identifies the number that best matches his/her shortness of breath [26, 27, 28]. The standardized mean difference (SMD) for change in dyspnea in favor of exercise training (ET) is considered to be −0.66 (95% CI=1.05-0.28) [15]. MMRC dyspnea scales reflect the severity of the limitation of daily activity, pulmonary function, and quality of life and correlate with mortality. It can replace, where it is not possible to asses, the peripheral muscle strength, functional exercise capacity, and ADL performance [29].
\nThe University of California, San Diego Shortness of Breath Questionnaire (UCSD SOB) uses a 24 questions questionnaire about the level of dyspnea during daily activities [30]. Five points represent a significant mean difference [31]. Dyspnea measured by UCSD SOB showed the strongest correlations with 6MWD [32].
\nThe Baseline Dyspnea Index (BDI)/Transition Dyspnea Index (TDI) assesses on a 5-degree scale (from 0 to 4), the daily dyspnea level in response to three categories of questions on functional impairment, the magnitude of task, and the magnitude of effort [26, 33, 34]. TDI records the changes from the initial value, the total score varying between −9 (worsening) and +9 (improvement). The significant minimal difference between TDI is 1 point [33, 34].
\nThe Modified Borg Scale (MBS) has 10 points (from 0 to 10), where participants choose descriptive terms that best suit their current state (0 = no dyspnea, 5 = moderate dyspnea, 10 = very severe dyspnea). It is used before and after performing a submaximal effort test such as 6MWT. The standardized significant mean difference (SMD) for change is 1 point [31]. During exercise training sessions in the PRP, the Borg scale is used as an essential tool to recommend workload [35].
\nIt was shown that there are correlations between clinical dyspnea rating and exercise capacity, exercised gas exchange and exercise capacity, and SGRQ in patients with IPF [26, 29, 36].
\nPulmonary function tests, including forced vital capacity (FVC), total lung capacity (TLC), maximal voluntary ventilation (FEV1 x 35), and diffusion capacity for carbon monoxide (DLCO), are important for stratifying the severity of the patient’s condition, but generally, PRP does not significantly influence the results of these tests [20]. The severity of dysfunction may guide the type and intensity of physical exercise and may be a warning about the risk of adverse effects (severe hypoxemia, hypotension, arrhythmias, etc.)
\nStandardized effort tests are important for choosing the intensity of training programs.
\nThe 6-minute walking test (6MWT) is a simple and safe tool used for IPF patients, where the subject moves in his rhythm [37]. It is performed according to ATS guidelines in a 30-m corridor [38]. 20–30 min of rest is recommended before and after the 6MWD test. The blood pressure, heart rate, respiratory frequency, oxygen saturation (SpO2), the severity of dyspnea, and fatigue are assessed by the modified Borg scale [38, 39]. SpO2 is recorded in the sitting position. It is recommended that the 6MWD test be performed with a SpO2 Holter, to record the length of the desaturation and the lowest value of oxygen [40]. It is always necessary to take into consideration the contraindications of walking tests and also the indications of interruption of the test. An important cessation criterion is a desaturation below 85% or tachycardia [80% of the theoretical maximum heart rate ( 220−age )], a situation easily met in IPF patients [1, 41]. The distance covered by the patient in 6 minutes is compared with the predicted value estimated by the formulas (women: 493 + (2.2 × height (cm)) − (0.93 × G (kg)) − 5.3 × age (years) and for the male + 17 m). The lower limit of normal 6MWD is the theoretical distance minus 100 m [42, 43, 44]. The 6-minute walk test distance (6MWD) does not correlate with sex, age, body mass index, and other medical comorbidities, but it is an independent predictor of survival rate, better than FVC and DLCO [37]. The 12-minute walk test is less used for IPF patients because it requires greater effort.
\nThe minimal clinical important significant difference (MCID) for 6MWD varies with the author, but a change of approximately 30 m is considered to be significant in IPF patients [32, 41, 44, 45].
\nCardiopulmonary exercise tests, when available, provide details on the mechanisms of effort intolerance. Measures of the anaerobic threshold, peak oxygen consumption (V′O2peak), and peak work rate (WR) are essential for determining the intensity of PRP and for assessing the benefits in dynamics. The SpO2, blood pressure, and 12-lead electrocardiogram are also recorded during these tests [46]. Cardiopulmonary stress tests are the gold standard for assessing the effort intolerance due to either lung, cardiac, or musculoskeletal pathologies. It is performed with a cycle ergometer or treadmill, but there is also a portable metabolic device. Cycle ergometry is the preferred method of being safer, with few movement artifacts, allowing a constant increase in workload, and is slightly influenced by weight [46, 47, 48]. Treadmill testing involves a kind of effort more common to patient’s daily activities (walking and running) and can train more muscle mass. Therefore, the V′O2peak is 5–10% higher than in cyclo-ergometry. Effort tests have a role in selecting patients for PRP and establishing rehabilitation design protocols, as well as evaluating outcomes [48].
\nIn patients with advanced IPF, it is not always possible to perform cyclo-ergometry. Volitional fatigue or increased oxygen desaturation (SpO2 < 80%) is quickly reached, and dizziness or mental confusion may also occur within 10–12 min of effort [48]. The incremental exercise testing shows decreased aerobic capacity (V′O2peak ~ 62% from predicted) and reduced maximal achievable workload in ILD. Other changes in IPF patients such as inefficient ventilation, desaturation, gas exchange abnormalities, circulator, and skeletal muscle dysfunction are reported [2]. These changes provoke a downward spiral of hypoxia, limited exercise capacity, deconditioning, shallow breathing pattern, and pulmonary hypertension [48].
\nDoppler-echocardiographic assessment of pulmonary artery systolic pressure should be assessed because a significant percentage of the IPF patients develop PH from early stages of the disease [10, 49]. It represents an important prognostic parameter [10, 49]. It usually replaces right heart catheterization, echocardiography being a noninvasive and widely available tool for screening PH. A substantial desaturation during exercise or a disproportionate exercise limitation related to the degree of lung restriction will increase the suspicion of PH [7, 10].
\nHRCT is the essential method to diagnose IPF. If the HRCT shows a pattern of usual interstitial pneumonia (UIP), this being the most characteristic to IPF, then its presence avoids invasive procedure such as lung biopsy. In the last few years, radiation-free techniques, such as the lung ultrasound, appear to be very sensitive in detecting fibrotic change or monitoring disease progression [50]. Imaging on HRCT is important and significant before a PRP, but its rehabilitation benefits are not assessed according to the initial findings.
\nPhysical activity of daily living (PADL) has a major impact on the quality of life and well-being of IPF patients and needs to be evaluated. PADL refers to volunteer movements that the patient performs at home, during professional or recreational activities that are energy-consuming. There is an inversely proportional relationship between PADL and sedentariness, reduced autonomy, disability, risk of hospitalization, and death [51]. Besides, the disease severity (dyspnea levels, SpO2 < 88%, DLCO < 40%, 6MWD, the extent of honeycombing on computed tomography, level of PH) was associated with lower physical activity among patients’ stable IPF [52].
\nPADL assessment is performed either by direct observation (time and staff consuming because it is individually applied), energy expenditure (for research calorimetry), questionnaires, and other devices with motion sensors (detect movement and quantify PADL: pedometers, accelerometers, or physical activity monitors). The questionnaires are subjective methods of evaluating the effects of the symptoms on the patient’s daily activities and quality of life, and they are instruments that are used in evaluating PRP [53]. Achieving progress through training programs can motivate the patient to pursue an active lifestyle for as long as possible. Pedometers measure only the distance covered daily (10,000 steps/day for a healthy lifestyle in the general population), but the effort intensity is better quantified by accelerometers [54]. These are preferred in sedentary or disabled patients, being more sensitive to the detection and description of movements. Daily activity can be quantified using the activity monitor for at least seven consecutive days from awakening to bed [2]. The intensity of physical activity is evaluated on a scale of 1–5, depending on the energy expenditure, expressed in the metabolic equivalent task (METS) [55].
\nThe questionnaires used in PADL evaluation for IPF are easy to apply, cheap, self-administered, validated (internal consistency and test-retest reliability) and correlate with the estimated energy consumption by the methods mentioned above. The most commonly used questionnaires in clinical studies, which are extrapolated to IPF patients, are as follows:
\nSelf-report 7-day short form International Physical Activity Questionnaire (IPAQ) [2, 56] consists of nine items which evaluate the level of physical activity that is quantified in METS for the effort intensity: vigorous (8 METS), moderate (4 METS), walking (3.3 METS), and sitting times. The total score is the sum of all types of activities (the number of minutes spent/day) multiplied by the level of energy (MET) and multiplied by the amount of time spent/week [(MET)-min/week] [55]. An active patient is considered to perform 600 METS-min/week (150 min/week × 4METS moderate intensity activity) [54, 57]. IPAQ ≤ 417 (MET-min/week) ∆SpO2 < 10 (%) represents the cutoff which predicts mortality in patients with IPF [2]. However, there were differences between the self-reported patient score on the questionnaire and the accelerometer’s results, depending on sex, age, education level, and body mass index (BMI). There is also a short form for this IPAQ [58].
\nBarthel index (BI) is based on basic physical activities for self-grooming, such as feeding, toilet use, bladder and bowel control, walking, dressing, bathing, brushing, or ascending and descending stairs. The total scores vary between 0 and 70; higher scores are associated with more active subjects. A change in the BI score after 1 month of ET4 was arbitrarily classified as mild (a decrease of <10 points), moderate (10–15 points), or severe (>15 points) [59]. This index reflects the independence levels in PADL in IPF patients.
\nIn Baecke questionnaire, the score reflects the level of energy consumed performing professional activities, sports, and entertainment and is also adapted for the elderly, obese, and Parkinson’s disease or cardiovascular patients [60].
\nStanford Seven-Day Physical Activity and Stanford Usual Activity questionnaires are applied during an interview. The first one relates to the time spent doing physical activities and sleeping for the past 7 days. The second focuses on moderate and intense activities in the last 3 months [61].
\nThe PADL level is positively influenced by supervised PRP that lasts at least 7–8 weeks.
\nThe quality of life questionnaire has been developed and validated extrapolating those applied to COPD patients, given the lack of a specific disease-specific questionnaire for IPF [56].
\nSt. George Respiratory Questionnaire and St. George Respiratory Questionnaire IPF-specific version (SGRQ-I) consist of 50 items referring to three categories: symptoms (8 items), activity (16 items), and impact (26 items) [36, 62, 63]. The total score varies from 0 to 100 points. Higher scores reveal a poorer health-related quality of life. SGRQ-I is reliable and comparable to the original SGRQ [64]. The SGRQ score was significantly correlated with FVC, FEV1 (%), 6MWD, and MRC. On the other hand, it did not show a significant correlation with DLCO or the level of desaturation at 6MWD, compared with CAT questionnaire [64].
\nMedical Outcomes Short-Form 36 (SF-36) is a generic health-related quality of life questionnaire. It consists of eight multidimension items as general health, vitalities, physical functioning, physical role/problems, body pain, emotional roles/problems, social functioning, and mental health. Each of the dimensions is scored from 0 to 100. Higher scores indicate a better health-related quality of life [65].
\nThe Hospital Anxiety and Depression Scale (HADS) can be applied in any disabling chronic disease which leads to impairment of the psychic/emotional status of patients [66].
\nThe Chronic Respiratory Disease Questionnaire (CRDQ) refers to dyspnea, fatigability, emotional impact, and self-control [67].
\nCOPD assessment test (CAT) was compared with other instruments applied to patients with IPF showing good psychometric properties among ILD patients. It is a self-administered questionnaire with eight items, each scored on a scale from 1 to 5. There is a strong correlation between the CAT score and SGRQ score, indicating that it can be used for health-related quality of life assessment among patients with IPF. Furthermore, CAT showed higher correlations with the physiological parameters than the SGRQ [67].
\nThe Tool to Assess Quality of Life in Idiopathic Fibrosis (ATAQ-IPF) is an extensive, 74 items, a disease-specific instrument which measures the symptoms adequately, sleep, emotions, relationships, therapies, finances, and many others. The score correlates with disease severity, but future studies are needed [8].
\nThe King’s Brief Interstitial Lung Disease (K-BILD) questionnaire is a validated and responsive questionnaire for longitudinal assessment of ILD patients’ quality of life. A score change of 5 units is significant [68].
\nIn muscle strength assessment, types of muscular impairment refer to mass (of different anatomical sites: biceps, triceps, etc.), strength, endurance, and performance [69]. Peripheral muscle force measurement may be important in PRP for understanding the impact of the disease on muscle mass, identifying patients at risk for physical impairment, and identifying those who can benefit from the prescription of an individualized resistance training program. Peripheral muscular dysfunction is a consequence of sedentary lifestyle, adopted by patients to avoid the symptoms and systemic effects of the disease (inflammation, hypoxemia, nutritional deficiency, corticosteroid side effects, electrolyte imbalances). Commonly, quadriceps muscle dysfunction is used for the assessment of peripheral muscle strength. The tests that are used may be volitional (volitional techniques: identification of the maximum weight that the patient can lift, manual muscle testing with MRC scale, or by dynamometers: handheld and computerized) or non-volitional (electrical stimulation of involuntary muscle contraction). The quadriceps maximal isometric voluntary contraction (QMVC) or predictive formulas (different equations for predicting quadriceps muscle strength) are described in literature, especially in studies on patients with COPD [70, 71, 72]. It is considered that patients have quadriceps muscle weakness if the value is <80% of predicted [73]. Knee extensor and elbow flexor strength could be measured with handheld dynamometer [69].
\n\n
6MWD is an independent and discriminating predictor of mortality among patients with IPF, more accurate than FVC or DLCO [74, 75]:
Basal value <250 m correlates with twofold increase in mortality, and if it is less than 207 m, patients have a more than fourfold greater mortality rate.
A decrease of SpO2 < 88% during 6MWT is marker for increased mortality.
A decrease in the walking distance within 6 months, greater than 50 m, would increase the mortality rate by three times.
A delayed heart rate return in 1 minute after the end of the 6MWD test and a variation <13 beats/min are strongly correlated with increased mortality.
Daily life physical activity level [76, 77, 78]:
IPF patients are highly sedentary, having a daily physical activity level which is 35% lower than healthy sedentary controls.
A value under 3.287 steps/day on accelerometers was associated with a poorer prognosis and three times higher risk for death for IPF patients.
Peripheral muscle dysfunction related with a decrease of the physical activity level of daily life and exercise limitation is associated with reduced survival.
PRP for IPF patients include several types of exercises, such as aerobic, resistance, flexibility, balance training, and respiration technique. Their selection is based on the everyday lifestyle of each patient, preferences, disease severity, and the advantages of where the PRP will take place:
“Inpatient” rehabilitation centers are a more appropriate method for the supervised exercise programs taking into account the symptoms and the risk of severe effort desaturation that may occur. The advantage is that during exercise sessions, patients are monitored for blood pressure, heart rate, SpO2, and symptoms, and the urgent treatment is available in case of complications [79, 80].
“Outpatient”-based programs take place in the patient’s home under the assistance of a healthcare professional with expertise in exercise training.
Home-based rehabilitation programs are an alternative to in-/outpatient programs. They are easy to perform, practical, cheap, and equally as effective, but unfortunately have a lower adherence rate and less improvements, so it is necessary to be supervised by phone calls [12, 78, 79, 81].
Combined programs start in a specialized structure and continues at home after the patients are familiar with the type and intensity of exercise [83].
PRP includes physical training, patient education, and nutritional and psychological support [11]. Regardless of the type of PRP, it is beneficial to start it as soon as possible. We will keep in mind that the intensity of rehabilitation depends on the severity of functional impairment and is personalized to each patient. The physical therapist starts from breath retraining and relaxing postures which increase chest expansion and relax the inspiratory muscles (Jacobson, Schultz technique). They reinforce proper breathing patterns (diaphragm) and include exercises that tonify respiratory and skeletal muscle (endurance and resistance) in order to increase patients’ exercise capacity [2].
\nThe main objective of these training programs is teaching patients how to perform a series of structured and repetitive exercises that improve or maintain their physical fitness and decrease the respiratory discomfort [82].
\nEducating patients about pursuing an active lifestyle even in the presence of IPF should be based on information about the types of exercises that can be performed, the regularity and duration of each session, and general instructions on how and what to follow through the program. During the follow-up with their patients, the doctor may be confronted with various questions, doubts, and anxiety from the patients. In the early stages of the disease, when the symptoms are not disabling, the patient’s motivation to follow a PRP is low. In advanced stages, the motivation is stronger because dyspnea limits exercise capacity and daily activities. According to several studies, the PRP with greatest benefits have 6–12 weeks programs, with 2–3 sessions per week of 30 minutes duration. The exercise intensity is determined by patients’ walking speed on 6MWD (starting at 70–80%), or by the maximum workload on cycle ergometer test (50–60% or more of peak WR on CPET for cycling), maximum heart rate (up to 80%), or on the intensity of symptoms on the Borg scale (to reach a score above 5–7). The effort intensity can also be calculated from an average heart rate ± 5 beats, obtained in the last 3 minutes of the effort test [2, 21, 33, 84].
\nA comprehensive training program should include several types of exercises: breathing and balance exercises, aerobic, endurance, and flexibility (stretching) [2, 12, 20, 33, 84].
\nFor increasing the endurance to effort, aerobic exercises can be used to train different muscle groups, depending on the patients’ preferences and physical resources. Aerobic exercises can include walking, stair climbing, treadmill walking, leg cycling, semi-recumbent cycling, or step climbing on an ergometer adapted for lower limbs [16]. Resistance training refers to the increase in muscle strength and can be achieved by performing repeated exercises for upper and lower limbs, arm raising, knee-extension, sit-to-stand, and strength training using elastic bands. In these types of exercises, the muscles work against an external force applied by a device from the physiotherapy room or against their own body weight. They can also use weights. These exercises are grouped in 2–4 sets, with 10–15 repetitions, followed by breaks of 45–60 s. Each set of exercises targets specific muscle groups [85]. These exercises are recommended due to the fact that IPF patients have reduced muscle mass, strength, and endurance, compared with healthy subjects. They develop atrophy and muscle weakness, especially in lower limbs [86, 87]. Stretching exercises are activities designed to maintain or increase joint mobility and muscle relaxation. Strength training targets major muscle groups of the upper and lower body. There is a wide range of exercises that could be applied by physiotherapist [88]:
Shoulder wheel
Multiple movements of shoulder by changing his position as abduction, externally rotates the shoulder, flexion, and extension
Sitting or standing biceps curls
Mid-back rowing
Shoulder flexion or extension
Sitting or standing chest presses and triceps extensions
Lower body exercises: standing hip abduction and extension
Seated knee flexion and extension
Internal and external rotations of the abducted shoulder with the elbow flexed 90 degrees
Wall push-ups
Chair squat
Dumbbells shoulder press
Dumbbells biceps curls
Dumbbells arm extension
Abdominal curl-ups
Seated single leg hamstring stretch
Standing quadriceps stretch
Chest stretch
Overhead reach stretch and wall cat stretch
For strength training there are three types of therapeutic bands that can be used: yellow, followed by red, and then green.
\nRespiratory muscle training or breathing exercises are extremely important, especially for patients with advanced disease, because they focus on diaphragm training, by teaching patients abdominal breathing techniques [79, 89].
\nThere are no strictly standardized protocols for the PRP, allowing an experienced physiotherapist to tailor the patient’s training structure in order to maximize the benefits.
\nThe structure of a rehabilitation program should be seen as a multistage process:
Firstly, the patient learns different types of exercise and different techniques, which can be divided into four categories (aerobic, endurance, flexibility, and breathing). Their intensity should be adapted to the severity of patient’s pulmonary impairment, typically 50–60% of the work peak rate for aerobic exercise and 70–80% of the walking speed in 6MWT for endurance exercises (bicycle, treadmill, walking). The program can start with breathing exercises or balance training, continued by aerobic exercise and resistance training. Exercises should primarily focus on increasing the strength and the muscle mass of the lower limbs and diaphragm. The interval technique can also be used, allowing the patient to rest between exercises. In patients who experience desaturations (SpO2 < 85%) during training, oxygen supplementation should be considered in order to maintain SpO2 above 88% [21]. During a program of 2–3 sessions/week, for 4–6 weeks, under the supervision of a physiotherapist, a patient can learn and become adequately trained to pass into the second phase.
In the continuation and improvement phase, subjects can progressively increase both the frequency (3–4 times/week), duration, and intensity of the sessions. The aerobic program can be extended to 20–50 min and can be performed at an intensity of 60–85% of the work peak rate. The resistance training can last between 20 and 30 min, with an intensity of 80–100% from the average walking speed obtained in the 6MWD test. Also, the programs recommend including 10–15 min of stretching and a minimum of 5 min of diaphragmatic or pursed lip breathing [90].
The maintenance phase is important for preserving the benefits of a PRP, for decreasing the anxiety and depression level, and for increasing the quality of life. It is recommended to maintain the types and the intensity of exercises that will lead to a level of fatigue between 5 and 7 on the Borg scale.
Each patient should be reassessed at 3–6 months, in terms of effort tolerance, quality of life, disease progression, and response to pharmacological treatment.
\nIn brief, a supervised training program for patients with IPF should recommend:
4–6 weeks, 2–3 sessions/week
Aerobic effort 20–40 min
Stretching 10–15 min
Breathing techniques 5–10 min
Adjusting the work intensity so it can be tolerable for the patient
Oxygen supplementation for patients who desaturate (SpO2 85–88%)
Intervals between exercises allowing better oxygenation
Patient reassessment at the end of the 6 weeks
In a comprehensive PRP, patient’s education begins from understanding the patient’s needs and providing detailed information regarding the nature and expected course of the disease, solutions for symptoms management, benefits and side effects of treatments (depression, anxiety, obesity, diabetes, cardiovascular disease), the indication of oxygen supplementation, energy conservation techniques, relaxation and recreation methods, stress management, coping techniques for anxiety and depression, smoking cessation, and solutions for the improvement of quality of life. Medical education sessions usually precede exercise training sessions. This will be individualized for each patient, ensuring optimal communication between the patient and the multidisciplinary team. Educational assessment begins with the identification of difficulties, focusing on the change of the health-related behavior. Goals need to be established in the short, medium, and long term, to increase the patient’s motivation to follow a PRP. Educational therapy plays a role in the relief of symptoms and quality of life improvement, optimizing the benefits of a PRP [11].
\nNutritional support refers to weight control and a balanced diet, with obesity or weight loss being associated with a poor prognosis. Adipose mass can be evaluated pre- and post-PR, using different skinfold calipers for the analysis of body composition by skinfold thickness measurements [91].
\nDue to the life-threatening course of the disease, the psychological support should be considered for each patient. The dialog among the patient, the patient’s family, and healthcare professionals can decrease the depression and anxiety in more than 50% of ILD patients [56].
\nStudies conducted support the beneficial effects of PR programs, at the end of which patients with IPF present [15, 19, 33]:
Improvement in functional capacity
Improvement in 6MWD results over SMD: 35.63 m (95% CI 16.02–55.23 m)
Improvement in V′O2 peak at 6WMD 1.46 mL/kg/min−1 (95% CI 0.54–2.39 mL/kg/min−1)
Increased physical activity levels (IPAQ)
Significant reduction in dyspnea: SMD −0.68 (95% CI −1.12 to −0.25)
Improvement in wellness and health-related quality of life, especially for those with severe disease SMD 0.59 (95% CI 0.14–1.03)
Increased muscular fitness
Quality of the evidence regarding the impact of PR programs in IPF patients after Dowman et al. [15]:
Change in 6-min walk distance—moderate ⊕⊕⊕⊝
Change in V′O2 peak uptake at cardiopulmonary exercise test—low ⊕⊕⊝⊝
Change in maximum ventilation cardiopulmonary exercise test—low ⊕⊕⊝⊝
Change in dyspnea score MMRC Dyspnea Scale—low ⊕⊕⊝⊝
Change in quality of life CRDQ (total score)—low ⊕⊕⊝⊝
Month survival—low ⊕⊕⊝⊝
A follow-up was performed 8–12 weeks after end of rehabilitation.
\nThe review used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) to evaluate the study results: “Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate” [15].
\nThe increase in effort capacity is directly related to training frequency, three to five sessions per week being optimal and fewer than two sessions being unlikely to produce meaningful change [92].
\nIt is considered that a PR has been beneficial if there has been an increase of more than 50 m at 6MWD test (31–81 m gained in PR in different clinical trials) and a minimum amount of physical activity at 200 METS-min/week [10 min × 4METS (moderate intensity in the IPAQ questionnaire) × 5 times/week. Longer programs and more frequent sessions (12 or more) appear to have a greater benefit; however these benefits can be lost after 3–6 months, if the training does not continue and patients fail to maintain an active lifestyle [11]. There are discrepancies in the outcome of the studies, in patients who have undergone a pulmonary rehabilitation program, discussing the responder or non-responder label depending on whether or not the walking distance of 6MWD or V′O2 has improved. Non-responders are considered patients whose result of 6MWT did not rise above or equal to 30 m after PR (30 m considered as MCID) [93]. Also, the responders had FEV1 and TLC raised after the rehabilitation program and significantly increased V′O2 peak, carbon dioxide output (VCO2), and minute ventilation (VE) in the 6MWT post-PR test, while non-responders showed greater desaturation during exercise [93].
\nThe different results of the studies can be explained by:
Training programs with differences in intensity, duration, and type of administration (inpatient/outpatient, supervised/unsupervised)
Small numbers of participants
Methodological limitation: methods of randomization (uncontrolled studies or nonrandomized, unblinded study)
Limitations of retrospective studies
Different control batches (other types of ILD, sham, etc.)
Patients entering PR at different stages of severity
Inclusion and exclusion criteria
No follow-up data after exercise training
Different outcomes
Conforming to the International Society for Heart and Lung Transplantation (ISHLT), this pulmonary transplantation is performed for a variety of advanced lung diseases, IPF, together with COPD, being the most common indication. However, in posttransplant survival, IPF is associated with the worst prognosis. For patients with IPF, transplantation and supplemental oxygen were the only treatments strongly recommended by the latest ATS consensus document. A transplant discussion is recommended from the moment the positive diagnosis is confirmed due to low survival [94, 95].
\nMedical and surgical interventions in transplants have progressed in the last few years. All of these lead to a changing demographic of patients undergoing lung transplantation, including older subjects with multiple comorbidities, respiratory failure, and even those who require bridging to transplantation [95]. To ensure a high rate of posttransplant survival, both in the short and long term, these patients must be physically and psychologically trained for this complex process. PRP plays an essential role in pulmonary transplantation, both by optimizing physical function prior to surgical intervention and by facilitating posttransplant recovery. Although these PRP are mandatory in most transplant centers, to date there is no international pulmonary rehabilitation guideline for this patient category [95].
\nPhysiotherapists working with lung transplant candidates and recipients need expertise both in general exercise training principles and in pre- and posttransplant rehabilitation, complications, oxygen titration, and side effects of medications. They should be able to adapt exercise programs according to the lung function changes and according to episodic illnesses (exacerbation) [95, 96].
\nPrior to transplant, patients should attend PRP and benefit from exercise training, aerobic, resistance, and flexibility, with or without oxygen support, in the tolerance limit. In early posttransplant period, mobility is advised even in ICU and in acute hospitalization, for the progression to independent function (transfers, walking, self-care, climbing stairs). In the next phase (1–6 month), they should gradually perform balance training, aerobic, resistance, and flexibility exercises, as tolerated. Oxygen can be supplemented to support exercise. In the long term (>6 months), patients should be included in home and community PR programs for maintaining and improving the benefits of this intervention [96]. All these aspects are the premises for a better prognosis and lower costs for the healthcare system.
\n\n
A multidisciplinary team that includes a respiratory specialist and a clinical psychotherapist should manage and supervise the inclusion in a PR program of patients with IPF and the structure and monitoring of the patients’ exercise training sessions.
In patients with severe IPF, it is preferred that programs are held in the hospital. In case programs are held at patient’s home, then high-intensity exercises that could lead to desaturation and worsening of symptoms should be avoided.
For long-term benefits, three to five sessions per week for a minimum of 6 weeks are optimal, less than two sessions being unlikely to produce significant change [92].
Initially, the interval training method is preferred, and in time, the duration of the exercises can be increased. A break and rest are mandatory when excessive fatigue and dyspnea appear [12].
The overall load increases gradually according to patient’s tolerance, the intensity of effort being adjusted to patients’ fatigue tolerance.
Additional oxygen can be used during exercise as it allows for an increased endurance and intensity of exercise levels [1].
Factors such as self-motivation, fear of adverse events, or comprehension may affect the ability to tolerate exercise training.
The pulmonary rehabilitation has become a clear indication as a non-pharmacological therapy for patients diagnosed with IPF. The benefits of pulmonary rehabilitation programs are reduced respiratory symptoms, especially dyspnea, and increased exercise tolerance and level of physical activity. All these lead to a lower level of anxiety and depression and therefore increased quality of life. These benefits are sustained in short term, 3–6 months. They can be maintained for a longer period if the patient has a responsible behavior and an active lifestyle.
\nOsteosarcoma is a primary malignant bone tumor that develops from primitive mesenchymal stem cells capable of differentiating into bone, cartilage, or fibrous tissue [1].
\nOsteosarcoma accounts for 3% of all malignant tumors, 35–50% of all malignant bone tumors in pediatric patients. The frequency of occurrence is 4 cases per 1 million children and adolescents per year. About 60% of cases of osteosarcoma detection are recorded at the age of 10–20 years (mainly in the prepubertal and pubertal periods). The gender ratio (boys/girls) is 1.3–1.6:1 [2].In 50% of cases, the tumor is located in the projection of the knee joint (distal femur, proximal tibial bone). The third place in terms of frequency of occurrence is the lesion of the proximal metadiaphysis of the humerus. The defeat of the axial skeleton (pelvis, spinal column) is detected in 12% of cases [3, 4, 5].
\nIn the treatment of children with osteosarcoma, chemotherapy is the main method. Nonadjuvant and adjuvant chemotherapy courses are important. In the middle of the twentieth century, when the main treatment was surgical, the frequency of relapse and metastasis was extremely high. Increased patient survival is due precisely to the intensification of chemotherapeutic treatment, which has reduced the frequency of relapses and metastasis.
\nA localized (locally advanced) variant of osteosarcoma, which occurs in 80% of cases and a disseminated (primary metastatic) variant, which occurs in 20% of cases, are distinguished [3, 6].
\n\n
low grade, central osteosarcoma
classic (conventional) version of osteosarcoma:
chondroblastic osteosarcoma
fibroblastic osteosarcoma
osteoblastic osteosarcoma
osteosarcoma, unspecified accuracy
telangiectatic osteosarcoma
small cell osteosarcoma
high degree of malignancy, superficial osteosarcoma.
\n
T—primary tumor
Tx—the primary tumor cannot be determined [7].
T0—no signs of primary tumor.
T1—the largest tumor size ≤8 cm.
T2—the largest tumor size>8 cm.
T3—several unrelated tumors in the primary zone of bone damage.
N—regional lymph nodes:
Nx—the presence of metastatic lesions in the regional lymph nodes cannot be determined.
N0—no regional metastases in the lymph nodes.
N1—regional lymph node metastases.
M—distant metastases:
Mx—the presence of distant metastases could not be determined or the study was not conducted.
M0—distant metastases are absent.
M1—there are distant metastases.
M1a—in the lungs.
M1b—another localization.
G—degree of differentiation:
Gx—the degree of differentiation could not be determined or the study was not conducted.
G1—well differentiated.
G2—moderately differentiated.
G3—poorly differentiated.
G4—undifferentiated.
G1–2—low degree of malignancy.
G3–4—a high degree of malignancy.
TX | \nPrimary tumor cannot be assessed | \n
T0 | \nNo evidence of primary tumor | \n
T1 | \nTumor confined to one pelvic segment with no extraosseous extension | \n
T1a | \nTumor ≤8 cm in greatest dimension | \n
T1b | \nTumor >8 cm in greatest dimension | \n
T2 | \nTumor confined to one pelvic segment with extraosseous extension or two segments without extraosseous extension | \n
T2a | \nTumor ≤8 cm in greatest dimension | \n
T2b | \nTumor >8 cm in greatest dimension | \n
T3 | \nTumor spanning two pelvic segments with extraosseous extension | \n
T3a | \nTumor ≤8 cm in greatest dimension | \n
T3b | \nTumor >8 cm in greatest dimension | \n
T4 | \nTumor spanning three pelvic segments or crossing the sacroiliac joint | \n
T4a | \nTumor involves sacroiliac joint and extends medial to the sacral neuroforamen | \n
T4b | \nTumor encasement of external iliac vessels or presence of gross tumor thrombus in major pelvic vessels | \n
NX | \nRegional lymph nodes cannot be assessed. Because of the rarity of lymph node involvement in bone sarcomas, the designation NX may not be appropriate, and cases should be considered N0 unless clinical node involvement clearly is evident | \n
N0 | \nNo regional lymph node metastasis | \n
N1 | \nRegional lymph node metastasis | \n
cM0 | \nNo distant metastasis | \n
cM1 | \nDistant metastasis | \n
cM1a | \nLung | \n
cM1b | \nBone or other distant sites | \n
pM1 | \nDistant metastasis, microscopically confirmed | \n
cM1a | \nLung, microscopically confirmed | \n
cM1b | \nBone or other distant sites. Microscopically confirmed | \n
Staging according to the TNM classification is presented in Table 1.
\nStage | \nTNM | \nDegree of malignancy | \n
---|---|---|
IA | \nT1 N0 M0 | \nLow | \n
IB | \nT2 N0 M0 | \nLow | \n
IIA | \nT1 N0 M0 | \nHigh | \n
IIB | \nT2 N0 M0 | \nHigh | \n
III | \nT3 N0 M0 | \nAny | \n
IVA | \nAny Т N0 M1a | \nAny | \n
IVB | \nAny Т N1 Any М Any Т Any N М1b | \nAny Any | \n
Staging by TNM.
The methods of treatment of osteosarcoma over the past 30 years have not changed. There are five main drugs (cisplatin, adriamycin, methotrexate, ifosfamide, and etoposide) that have been used in various combinations and doses [8, 9, 10, 11, 12, 13].
\nThe rates of treatment outcome in the world remain at about the same level. In patients with a localized variant of osteosarcoma, 5-year overall survival (OS) does not exceed 75% and 5-year event-free survival (EFS)—62% (Table 2).
\nTherapy program | \n5-year overall survival, % | \n5-year event-free survival, % | \n
---|---|---|
IOR/OS2 the Istituto Ortopedico Rizzoli [14] | \n75 | \n63 | \n
ISG/OS1 (Italian Sarcoma Group) [15] | \n74 | \n64 | \n
ISG/SSG1 (Italian and Scandinavian Sarcoma Group) [16] | \n77 | \n64 | \n
COSS 88/96 (Cooperative Osteosarcoma Study Group) [17] | \n79 | \n\n |
SSG XIV (Scandinavian Sarcoma Group) [18] | \n\n | 65 | \n
NECO93J/95J (Neoadjuvant Chemotherapy for Osteosarcoma) [19] | \n78 | \n65 | \n
BOTG III/IV (Brazilian Osteosarcoma Treatment Group) [20] | \n61 | \n45 | \n
POG8651 (Pediatric Oncology Group) [21] | \n78 | \n65 | \n
SFOP94 (Société Française d’Oncologie Pédiatrique) [22] | \n76 | \n62 | \n
St.Jude CRH OS91 (Children Research Hospital) [23] | \n74 | \n65 | \n
St.Jude CRH OS99 (Children Research Hospital) [24] | \n79 | \n67 | \n
INT0133-COG (+MTP/-MTP) Children’s Oncology Group [25] | \n78/70 | \n67/61 | \n
MSKC NY (+PAM) Memorial Sloan-Kettering Cancer Center, NY [26] | \n94 | \n72 | \n
COG INT0133, CCG7943, AOST0121 [27] | \n47 | \n22 | \n
ISG/SSG II (Italian and Scandinavian Sarcoma Group) [28] | \n55 | \n46 | \n
EURAMOS1 [29, 30] | \n75 | \n59 | \n
The results of the treatment of pediatric patients with localized osteosarcoma.
In patients with primary metastatic osteosarcoma, the results are much worse, despite attempts to use high doses of drugs, including high-dose polychemotherapy with transplantation of autologous hematopoietic stem cells. At the same time, the 5-year OS does not exceed 35% on average and the 5-year EFS–25% (Table 2).
\nThe most significant interest in the treatment of children with a localized version of osteosarcoma are the studies of the Italian and Scandinavian groups (Italian and Scandinavian sarcoma group–ISG/SSGI, SSG XIV), the French Pediatric Oncological Group (Societe Francaise d’Oncologie Pediatrique–SFOP OS94), and EURAMOS1.
\nFerrari et al. showed the data of the joint study of the Italian and Scandinavian groups (ISG/SSG I), which was conducted from 1997 to 2000. The study included 182 patients.
\nA special feature of neoadjuvant chemotherapy was the use of two courses of monotherapy with high-dose ifosfamide (in a course dose of 15 g/m2) and two courses of MAR (methotrexate (M) 12 g/m2, adriamycin (A) 75 mg/m2, and cisplatin (P) 120 mg/m2) in alternating mode. Adjuvant chemotherapy started at week 14. In this case, the course dose of adriamycin was increased to 90 mg/m2, the dose of cisplatin to 150 mg/m2, and a high-dose ifosfamide was administered in PIM chemotherapy courses (cisplatin, ifosfamide, and methotrexate) and PAI (cisplatin, adriamycin, and ifosfamide).
\nAfter removal of the primary tumor focus, a good histological response (therapeutic pathomorphism of grade 3–4) was achieved in 63% of patients, a poor histological response (treatment pathomorphism of grade 1–2) in 37%. At the same time, the 5-year OV and EFS accounted for 77 and 64%. Consequently, the use of high-dose ifosfamide in an alternating mode with the MAP scheme led to an increase in the frequency of achieving a good histological response, but did not affect the rates of OS and EFS [15, 16, 31].
\nSmeland et al. presented the data of the study of the Scandinavian Group (SSG XIV), which was conducted from 2001 to 2005. The study included 63 patients.
\nNeoadjuvant chemotherapy consisted of two courses of IDA. High-dose ifosfamide (in the course dose of 10 g/m2) was used in monotherapy in patients with a poor histological response to treatment, only after five courses of MAP.
\nAfter removal of the primary tumor lesion, a good histological response was achieved in 45% of patients and a poor histological response in 55%. At the same time, the 5-year OV and BSV accounted for 76–65% and the 5-year EFS in the group with a good histological response for 89%, with a poor histological response 48%. Consequently, the use of ifosfamide after MAP courses in the adjuvant mode did not lead to an increase in OS and EFS, and the frequency of achieving a good histological response was lower than in studies in which the MAP scheme was used in alternating mode with ifosfamide [18].
\nLe Deley et al. presented the results of the randomized SFOP OS94 study, which was conducted from 1994 to 2001. The study included 239 patients (120 in group A and 119 in group B).
\nNeoadjuvant therapy included seven courses of high-dose methotrexate and two courses of monotherapy with adriamycin (in a course dose of 70 mg/m2) in group A or seven courses of high-dose methotrexate and two courses of IE (ifosfamide (I) 12 g/m2 and etoposide (E) 300 mg/m2) in group B. In the adjuvant mode, chemotherapy was replaced with IE courses in group A, and AP in group B for patients with a poor histological response detected after removal of the primary focus. The operative stage of treatment was carried out at 12 and 14 weeks in groups A and B, respectively.
\nA good histological response was achieved in group A in 43% of patients, in group B in 64%, poor histological response in group A in 57%, and in group B in 36% (p = 0.009). The 5-year OS in group A was 75%, in group B—76%, the 5-year EFS in group A—58%, and in group B—66%. A 3-year EFS in group A in patients showed a good histological response for 82%, with a poor histological response for 49%, in group B—77 and 60%, respectively.
\nConsequently, the use of methotrexate, ifosfamide and etoposide in neoadjuvant chemotherapy led to a statistically significant increase in the frequency of achieving a good histological response, but not to an increase in OS and EFS [22].
\nOf particular interest in the treatment of children with primary metastatic osteosarcoma are the Pediatric Oncology Group (POG) IE and ISG/SSG II studies.
\nGoorin et al. presented the results of a phase II/III nonrandomized clinical trial of high-dose ifosfamide and etoposide in patients with primary metastatic osteosarcoma. The study included 43 patients.
\nNeoadjuvant chemotherapy was represented by two courses of IE (ifosfamide (I) 17.5 g/m2 and etoposide (E) 500 mg/m2). Removal of the primary tumor lesion was performed after two courses of IE at 7–8 weeks of therapy. The timing of the removal of metastatic foci was chosen individually during adjuvant chemotherapy, which included four courses of MAP chemotherapy and three courses of iE (with a course dose of ifosfamide (i) 12 g/m2) in an alternating mode.
\nA good histological response was achieved in 65% of patients and poor in 35%. However, the 2-year OS and EFS were 55 and 45%, respectively. Consequently, the use of high-dose ifosfamide in combination with etoposide therapy led to an increase in the frequency of achieving a good histological response, but not indicators of OS and EFS [32].
\nBoye et al. showed the results of the nonrandomized study ISG/SSG II, which was conducted from 1996 to 2004. The study included 57 patients with primary metastatic osteosarcoma.
\nNeoadjuvant chemotherapy included two courses of MAPI. Surgical removal of the primary tumor lesion was performed at week 14.
\nIn the adjuvant mode, two courses of ACyVP (adriamycin (A) 90 mg/m2, cyclophosphamide (Cy) 4 g/m2, and vepesid (VP) 600 mg/m2) and two courses of high-dose chemotherapy VPCarbo (vepesid (VP) 600 mg/m2 and carboplatin (Carbo) 1.5 g/m2) with the support of autologous hematopoietic stem cells. Surgical removal of the primary tumor lesion was performed at week 14.
\nA good histological response was achieved in 29% of patients and poor in 71%. The 5-year OM and BSV were 31 and 27%, respectively [28].
\nMarina et al. presented the results of the EURAMOS1 study in patients with a poor histological response after neoadjuvant MAP chemotherapy. Within the protocol, patients are randomly assigned to the MAP treatment lines (methotrexate (M) 12 g/m2, adriamycin (A) 75 mg/m2, and cisplatin (P) 120 mg/m2) and MAPIE (ifosfamide (I) 14 g/m2 and etoposide 500 mg/m2). In the age group up to 30 years, the MAPIE line of therapy was carried out in 310 patients, the MAPIE line in 308 patients, in the age group up to 20 years—259 (84%) and 271 (88%) patients. Groups of patients are statistically significantly comparable by sex, age, localization of the primary tumor lesion, the presence of metastatic lesions, and the histological variant of the tumor.
\nIn the group of 541 patients with a localized version of osteosarcoma, 247 events were identified, 118 in patients who received the MAP therapy line and 129 in patients who received the MAPIE therapy line. At the same time, the 3-year EFS was 60 and 57%. In the group of patients with primary metastatic osteosarcoma, 3-year EFS was 24 and 18%, for MAP and MAPIE, respectively. Therefore, this study showed that the use of alternating chemotherapy courses for MAP, IE, and Ai in an adjuvant regimen did not lead to an increase in EFS indices [33].
\nTreatment outcomes for children with primary metastatic osteosarcoma remain extremely low and the optimal therapeutic strategy is unknown.
\nNew programs are being developed around the world taking into account the molecular biological features of tumor cells that determine sensitivity to chemotherapy (ERCC1 to cisplatin, TOPO2α to anthracyclines and etoposide, MGMT to epigenetic therapy and cisplatin, RFC1 to methotrexate) [34, 35, 36, 37, 38, 39] and invasive and metastatic potential of a tumor (stem cell markers—CD133, OCT4; transcription factors—p-STAT3, C-MYC; cytokine-associated signaling pathways—ErbB2, VEGFR1, VEGFR2, PDGFRα, and PDGFRβ) [40, 41, 42, 43].
\nCui et al. presented the results of a study to determine the expression of MGMT protein (methylguanine–DNA–methyltransferase) and MGMT gene methylation in patients with osteosarcoma in the age group up to 40 years (mean age 17 years) who were treated with cisplatin in single mode, in a course dose of 120 mg/m2 Determination of MGMT protein expression in immunohistochemical (IHC) study was performed in biopsy tumor material in 76 patients and MGMT gene methylation in 51 patients. The result of IHC was considered positive with a high level of expression—more than 30% (3+), with an average level of expression—20–30% (2+), and with a low level of expression—10–20% (1+). MGMT protein expression was detected in 52 (68%) patients, low expression level in 27 (35%), medium level in 18 (24%), and high level in 7 (9%).
\nA statistically significant relationship was established between the presence of MGMT protein expression and an increase in the frequency of a poor histological response (p = 0.004). The expression level above 20% was detected in 22 out of 43 (51%) patients in the group of patients with 1–2°of therapeutic pathomorphosis and only in 3 out of 33 (9%) patients in the group with 3–4° of therapeutic pathomorphosis.
\nMethylation of the promoter portion of the MGMT gene was observed in 12 of 51 (23.5%) patients and the lack of expression of MGMT protein in 14 of 51 (27.5%) patients. A statistically significant relationship between the absence of methylation and the presence of MGMT protein expression (p < 0.001) was established. In the group of patients with 1–2 degrees of therapeutic pathomorphosis, the absence of MGMT gene methylation was detected in 36 of 38 (94.7%) patients and with 3–4 degrees of therapeutic pathomorphosis in 3 of 13 (23%) patients (p < 0.001).
\nConsequently, the data obtained indicate the formation of tumor resistance to treatment with an alkylating agent—cisplatin in patients whose biopsy material revealed the absence of methylation of the promoter portion of the MGMT gene and the presence of expression of the MGMT protein [34, 35].
\nPitano-Garcia et al. (Spain sarcoma group) conducted a study to determine the expression of RFC1 micro-RNA (reduced folate carrier 1, a transmembrane protein that provides folate and methotrexate transport to the cell) by real-time polymerase chain reaction (PCR) in a tumor substrate in children with osteosarcoma.
\nIn 34 samples, biopsy tumor material in 14 children and metastatic foci tumor material in 20 children were analyzed. In 13 of 14 (92.9%) biopsy specimens and in 11 of 20 (68.8%) metastatic specimens, a low level of RFC1 expression was detected.
\nA poor histological response after neoadjuvant chemotherapy (three courses of intravenous administration of doxorubicin at a dose of 75 mg/m2, three courses of intraarterial administration of cisplatin at a dose of 105 mg/m2, four courses of intravenous administration of methotrexate at a dose of 14 g/m2) in 45% of cases. The biopsy tumor substrate in this group of patients was characterized by a low level of expression of RFC1 micro-RNA in 90% of cases compared to 60% in patients with a good histological response (p = 0.053). The average level of expression was statistically significantly lower in the biopsy material than in the metastatic tumor foci (p = 0.024) [38, 44].
\nTherefore, in this study, there was a tendency to an increase in the frequency of detection of low expression levels of RFC1 micro-RNA in patients with a poor histological response.
\nHattinger et al. (Italian sarcoma group) presented the results of the study, the purpose of which was to determine the prognostic significance of ERCC1 protein expression (excision repair crosscomplementation group 1) in biopsy tumor material in patients with localized osteosarcoma, who underwent programmed treatment of ISG/OS-oss and ISG/SSG1. A tumor sample was considered positive in the presence of a score of 2–3: score 1 (1–10% of positive nuclei), score 2 (11–50% of positive nuclei), and score 3 (more than 50% of positive nuclei).
\nERCC1-positive tumor (score 2–3) was detected in 30 patients (30%). During the ISG/OS-oss program in groups of patients with ERCC1-negative/score 1 and ERCC1-positive (score 2–3), the 5-year-old OS and BSV tumor variants were 91, 38, and 57, 25% (p = 0.001; p = 0.042), with the ISG/SSG1 program–82, 64, and 69, 36% (p = 0.022; p = 0.028), and with both therapy programs–82, 50 and 62, 34% (p < 0.001; p = 0.006). Consequently, a statistically significant relationship has been established between the ERCC1-positive variant of the tumor and lower rates of 5-year OS and BSV [36].
\nNguyen et al. (SFOP) presented the results of a study to determine the prognostic significance of TOP2A protein expression (topoisomerase DNA 2 alfa) and the presence of rearrangement of the TOP2A gene in biopsy tumor material in 105 children with osteosarcoma treated with the SFOP protocol OS94. Patients with a primary metastatic osteosarcoma variant accounted for 17%. After neoadjuvant chemotherapy, a good histological response was detected in 56 patients (53%) and a poor histological response in 49 (47%). Real-time PCR amplification of the TOP2A gene and the TOP2A gene deletion were detected in 21 (21.2%) and 25 (25.3%) patients. In 53 children (53.5%), rearrangements of the TOP2A gene were not detected. A statistically significant relationship was established between the presence of the TOP2A gene rearrangement (amplification and deletion) and the presence of a good histological response after neoadjuvant polychemotherapy (p = 0.004). There was also a tendency to achieve lower rates of 5-year OM and BSV in patients whose tumor cells had amplified the TOP2A gene (p = 0.09 and 0.06). The expression of the TOR2A protein was determined in 17 patients by immunohistochemistry. Medium (2+) and high (3+) levels of expression were detected in all patients; expression was above 30% in 12 of 17 children (70.5%). There is no statistically significant relationship between the expression of the TOR2A protein above 30% and the presence of amplification or deletion of the TOP2A gene (p > 0.05) due to an insufficient number of observations [37].
\nXiao et al. presented the results of a study of a personalized approach to the prescription of chemotherapy depending on the presence or absence of markers of drug resistance in 28 patients with localized osteosarcoma. The average age in the patient group was 20.1 g. To determine the sensitivity to chemotherapy, the following markers were used: for doxorubicin–expression of TOP2A micro-RNA, mutation of the ABCB1 gene, and mutation of the GSTP1 gene; for cisplatin–expression of microcryptal ERCC1, BRCA1, and mutation of genes XRCC1-exon6 and XRCC1-exon10, and for ifosfamide–mutation of CYP2C9 * 3.
\nAt the same time, a high level of sensitivity to ifosfamide was detected in all patients (100%), to cisplatin in 11 out of 28 (39.2%), to doxorubicin in 6 out of 28 (21.4%); medium and high levels of sensitivity to cisplatin in 17 of 28 (60.7%), to doxorubicin in 20 of 28 (71.4%). Chemotherapy, taking into account the sensitivity of the tumor to drugs, was performed in 8 of 28 patients (28.5%). In this group, only one relapse of the disease was detected, while in the rest of the 20 patients, four relapses of the disease were detected: in one case, progression during neoadjuvant chemotherapy and in another case, fatal outcome from toxicity of therapy. The average duration of observation for groups was not indicated, and no statistically significant difference was obtained due to the insufficient number of observations [39].
\nIn addition, the study of markers of stem tumor cells CD133 (Prominin 1) and Octamer-binding transcription factor 4 (OCT4), as well as the transcription factors signal transducer and activator of transcription 3 (STAT3), and myelocytomatosis viral oncogene homolog (C-MYC), which determines the invasive and metastatic potential of a tumor [45, 46, 47].
\nSo in the work of He et al., there was a significant correlation between the expression of CD133 in tumor cells and a higher frequency of metastatic lesions, a lower median of overall survival. A CD133-positive variant was detected in 46 of 70 (65.7%) patients, in 6 out of 16 (37.5%) in the group with a localized osteosarcoma variant, and in 40 out of 54 (74%) in the group with the primary metastatic osteosarcoma (p = 0.002). The median overall survival rate was statistically significantly lower in the group with CD133-positive tumor (p = 0.000). When conducting the study “Transwell invasion,” a significantly higher invasive potential of the CD133-positive variant of the tumor was established (p < 0.05). Real-time PCR established a higher level of expression of micro-RNA OCT4 in a CD133-positive variant of the tumor (p < 0.05) [41].
\nLi et al. in an experimental model on cell lines showed that about 80% of cells in a CD133-positive variant of the tumor are in the G0/G1 phases of the cell cycle (p < 0.01). Also, real-time PCR revealed a significantly higher level of expression of the multidrug-resistant gene (MDR1) in the CD133-positive variant of the tumor (p < 0.05) [48].
\nIn the studies presented, He and Li et al., the mechanisms of drug resistance, invasion, and metastasis in case of CD133-positive variant of the tumor were established.
\nIn the works of Tu et al., the significance of activation of the IL6R/STAT3/p-STAT3tyr705 mesenchymal stem cell signaling pathway to increase the metastatic potential of tumor cells was exemplified by the example of cell lines (Saos 2 and U2-OS). The relationship between the increased expression of p-STAT3tyr705 and increased expression of the drug resistance markers multidrug resistance protein (MRP) and MDR1 has been established. An increase in sensitivity to doxorubicin, but not to cisplatin, was also noted with inhibition of this signaling pathway [43, 49].
\nHan et al. using cell lines (MG63 and SAOS2) as an example showed that an increase in C-MYC expression leads to activation of the MEK–ERK signaling pathway and an increase in the expression of MMP2 and MMP9, which enhance the invasive and metastatic potential of a tumor [50].
\nWu et al. investigated the prognostic significance of C-MYC expression in biopsy tumor material in 56 children with osteosarcoma who were treated with methotrexate, cisplatin, and adriamycin. Expression of the C-MYC protein was detected in 48 of 56 (85.7%) patients. A statistically significant relationship was established between the presence of C-MYC expression and a decrease in the apoptotic index (p < 0.05). In addition, in the group of patients with C-MYC-positive variant of the tumor and the intensity of expression, at 2+ and 3+, a significantly lower 3-year-old OM was established (p < 0.05) [51].
\nConsequently, in the works of Tu, Han, and Wu et al., the significance of transcription factors in the development of drug resistance, invasion, and metastasis of the tumor has been established.
\nInnovative therapeutic approaches are used mainly in patients with metastatic osteosarcoma, relapse, and refractory course of the disease. Currently, the following key areas are distinguished: (1) the use of monoclonal antibody preparations, (2) tumor-modifying therapy using nitrogen-containing bisphosphonates, (3) the use of chemotherapeutic drugs that affect various cellular signaling pathways (multikinase inhibitors and mTOR inhibitors), and (4) the use of drugs that promote the activation of tumor-associated macrophages.
\nRossi et al. presented the results of a study aimed at determining the expression of vascular endothelial growth factor (VEGF) in a biopsy tumor substrate and in tumor material after neoadvanting chemotherapy (two courses of MAP) in 16 patients with localized osteosarcoma, who received programmed treatment using the SSG XIV protocol. Four levels of expression were evaluated: negative and low–at an expression level <25%, medium—at 25–50% (1+), high—at 50–75% (2+), and very high—at>75% (3+). Medium and high levels of VEGF expression in biopsy tumor material were detected in 11 (6 in medium and 5 in high) out of 16 patients (68.7%). After neoadjuvant chemotherapy and the removal of the primary tumor site, VEGF expression was established in all samples, and there was an increase in expression in samples that were positive in the initial study.
\nHigh and very high levels of expression, increased expression after neoadjuvant chemotherapy was statistically significantly correlated with the localization of the primary tumor lesion in the femur (p = 0.02), with the appearance of local recurrence (p = 0.04) and/or early metastatic lesions in the lungs (p = 0.04), with a fatal outcome from the refractory course of the disease (p = 0.04).
\nTherefore, the presence of VEGF expression in the biopsy material and an increase in the expression of VEGF after neoadjuvant chemotherapy are factors for poor prognosis of the disease [42]. But this study requires the continuation of the fact that it includes a small number of patients.
\nIn addition, Ohba et al. showed in an in vivo experiment using human osteosarcoma cell lines (TE85 and 143B) the mechanism of autocrine stimulation of tumor transformation and proliferation using the example of the VEGF/VEGFR signaling pathway. In this study, the expression of VEGF-A and VEGFR micro-RNA was evaluated [52].
\nCurrently, little experience has been gained with the use of the drug bevacizumab in children with osteosarcoma.
\nBevacizumab (Avastin) is a partially humanized monoclonal antibody to VEGF-A, IgG1, which realizes its activity through a second type of immunopathological reaction (antibody-mediated complement-dependent cytotoxicity and antibody-mediated cell-dependent cytotoxicity) [53].
\nTurner et al. (St. Jude Children’s research hospital) presented preliminary results of using bevacizumab in combination with neoadjuvant chemotherapy (two courses of IDA) in 27 children with osteosarcoma. The drug was used at a dose of 15 mg/kg. There are three introductions for neoadjuvant chemotherapy. A satisfactory toxicity profile has been established. The study NCT00667342 continues [54, 55].
\nBack in 1999, employees of the Memorial Sloan-Kettering Cancer Center presented the results of a study assessing the effect of ErbB2 expression (Erb-B2 receptor tyrosine kinase 2) on the nature of the histological response after neoadjuvant polychemotherapy and on the rates of OS and BSV. The study included 53 patients. ErbB2 overexpression was detected in 42% of patients in the entire study group, in 50% with metastatic variant and in 76% at the time of detection of relapse or refractory course of the disease, and also statistically significantly correlated with poor histological response (p = 0.02) and BSV (p = 0.05). The 5-year BSV in patients with a localized version of osteosarcoma and ErbB2-positive status was 47%, with ErbB2-negative status—79% [40].
\nConflicting data on the prognostic significance of ErbB2-positive status in patients with localized osteosarcoma were obtained.
\nIn 2002, the Japanese Osteosarcoma Group (Japanese Osteosarcoma Group) published the results of a study that included 155 patients with localized osteosarcoma from 1984 to 1995. At the same time, 5-year BSV in patients with ErbB2-positive status was 45%, with ErbB2-negative status—72% [56].
\nIn 2014, the Children Oncology Group (COG) presented completely different results of the study, which from 1999 to 2002 included 135 patients with localized osteosarcoma. Only 13% of patients showed ErbB2-positive status. The 5-year RR in patients with ErbB2-positive status was 73%, and with the ErbB2-negative status—72%, the 5-year RR was 59 and 69%, respectively. No statistically significant difference in survival was observed [57].
\nThus, it was confirmed that ErbB2 can be considered as a potential target for targeted therapy in metastatic variant, relapse, and refractory course of the disease.
\nCOG presented the results of a phase 2 clinical trial of the drug Trastuzumab (Herceptin) in combination with MAPIE polychemotherapy in 96 patients with primary metastatic osteosarcoma. This study was conducted from 2001 to 2005.
\nTrastuzumab is a partially humanized IgG1κ monoclonal antibody to ErbB2, which also realizes its activity through a second type of immunopathological reaction (antibody-mediated complement-dependent cytotoxicity and antibody-mediated cell-dependent cytotoxicity). The drug was administered at a dose of 4 mg/kg in the first week, and then 2 mg/kg 1 time per week (34 in total) only in patients in whose tumor substrate ErbB2 expression was detected.
\nSurgical removal of the primary tumor lesion was performed at week 11. Adjuvant chemotherapy began at week 13.
\nIn the group with trastuzumab, a good histological response was detected in 56% of patients and without trastuzumab, it was 40%, a poor histological response of 44–60%, respectively. At the same time, the 3-year OS and BSV in the group of patients who received treatment with trastuzumab accounted for 59 and 32%, and in the group of patients who received treatment without trastuzumab for 50 and 32%. Consequently, the use of trastuzumab with polychemotherapy MAPIE led to an increase in the frequency of achieving a good histological response, but not to an increase in the rates of OS and EFS [58].
\nOf particular interest is tumor-modifying therapy using nitrogen-containing bisphosphonates. Currently, the following mechanisms of action of nitrogen-containing bisphosphonates have been identified, which are represented by the activation of tumor cell apoptosis by the caspase mechanism (indirectly through protein Rb and P53) and without the participation of the caspase mechanism (an increase in AIF—apoptosis of the inducing factor); increased expression of TNF-related apoptosis-inducing ligand–death receptor 5 (TRAIL-DR5, TRAIL-induced apoptosis); reduction of receptor activator of nuclear factor kappa-B ligand (RANKL) expression–ligand of nuclear factor activation receptor kB in osteosarcoma cells, which leads to suppression of tumor cell proliferation, osteoclast activity, changes in the tumor microenvironment, bone resorption, and risk of metastasis; γδT activation of cellular cytotoxicity; and tumor activation of associated macrophages [59, 60, 61, 62].
\nIn addition, the potentiating effect of nitrogen-containing bisphosphonates on cisplatin and adriamycin has been confirmed [63].
\nCurrently, a rather small experience has been gained in using these drugs in children with osteosarcoma.
\nMeyers et al. published the results of a study on the combined use of pamidronate with MAP chemotherapy. The study included 40 patients, 32 in the age group under 18, 29 with a localized version of osteosarcoma, and 11 with a primary metastatic option of osteosarcoma.
\nIn accordance with the program, pamidronate was administered once a month at a dose of 2 mg/kg 48–72 h after adriamycin, methotrexate, a total of 12 administrations.
\nSurgical removal of the primary tumor lesion was performed at week 11. Adjuvant chemotherapy began at week 13. Removal of metastatic foci was carried out individually at the stage of adjuvant therapy.
\nThe frequency of achieving a good and poor histological response is not indicated. However, relatively high rates of 5-year OS and EFS were obtained: 93 and 72% in patients with localized osteosarcoma and 64 and 45% in patients with metastatic osteosarcoma [26].
\nCOG presented the results of the pilot protocol AOST06P1 aimed at studying the combined use of zoledronic acid with MAPIE polychemotherapy in children with the primary metastatic osteosarcoma. This study included 24 patients. Zoledronic acid was administered at a dose of 1.2–3.5 mg/m2 in each course of chemotherapy.
\nThe maximum tolerated dose of zoledronic acid was established, which was 2.3 mg/m2. Indicators of a 2-year OV and EFS were 60 and 32%, respectively [63].
\nPiperno-Neumann et al. presented the results of a phase 3 randomized study OS 2006, the purpose of which was to identify the potentiating effect of zoledronic acid when used together with polychemotherapy MIE and MAP.
\nThe study included 217 children, 107 in the control group, and 110 in the group with zoledronic acid. Groups of patients were statistically significantly comparable by sex, age, foci of primary and metastatic lesions, and histological variant of the tumor.
\nZoledronic acid was administered at a dose of 0.05 mg/kg (maximum dose of 4 mg) with each course of chemotherapy (IE and AP).
\nNeoadjuvant chemotherapy consisted of two courses of IE (ifosfamide (I) 12 g/m2, etoposide 300 mg/m2) and seven administrations of high-dose methotrexate ((M) 12 g/m2). Surgical removal of the primary tumor lesion was performed at week 14. Adjuvant chemotherapy included two courses of MIE in the group with a good histological response and five courses of MAP in the group with a poor histological response. A good histological response after neoadjuvant polychemotherapy was achieved in 73% of patients. However, there was no statistically significant difference in achieving a good histological response, in terms of OS and BSV in groups of patients who received programmed treatment with or without zoledronic acid. The number of events in the group with zoledronic acid was 42% (47/110) and in the group without zoledronic acid was 31% (34/107). Consequently, this study shows the high effectiveness of chemotherapy courses with IE in combination with methotrexate in the neoadjuvant regimen. The presence of the potentiating effect of zoledronic acid has not been proven [64].
\nIn the treatment of refractory forms of osteosarcoma, drugs are also used that affect various cellular signaling pathways. Understanding the mechanisms of tumor activation opens up the possibility of using multikinase and mammalian target of rapamycin complex (mTOR) inhibitors.
\nTakagi and Peng et al. in an in vitro experiment on cell lines (SaOS2, MG63, HOS), pathogenetic mechanisms of cytokine-induced tumor transformation and proliferation were shown through the activation of VEGF/VEGFR/PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase)/AKT (protein kinase B) and the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathways [65, 66]. The most studied drugs from this group are currently sorafenib (nexavar) and everolimus (afinitor) [67]. Sorafenib is a nonselective multikinase inhibitor that inhibits the activity of various cellular signaling pathways, in particular VEGFR1, VEGFR2, PDGFRα, and PDGFRβ, while everolimus is an mTOR inhibitor [68].
\nYmera et al. of the Italian Sarcoma Group published the results of a preclinical study (in vitro and in vivo), which noted the mutually potentiating antitumor effect of everolimus and sorafenib on osteosarcoma cell lines (KHOS, MNNG-HOS, and U2OS). The effect of everolimus and sorafenib on mTORC1/mTORC2 is manifested in a decrease in the expression of mTORC1 and an increase in the expression of mTORC2, which provides proapoptotic and antiproliferative effects. With the combined use of everolimus and sorafenib, there is a decrease in the expression of both mTORC1 and mTORC2 [69].
\nFrom 2008 to 2009, Grignani et al. of the Italian Sarcoma Group conducted a second phase of clinical trials of the drug sorafenib in patients with relapse and refractory osteosarcoma. The study included 35 patients with osteosarcoma in the age group over 14 years. Partial response was achieved in 5 (14%) patients and stabilization of the disease in 12 (34%) patients. The overall response rate was 48%. At the same time, 4-month progression-free survival was 45% (15 out of 35) [70].
\nFrom 2011 to 2013, Grignani et al. conducted a second phase of clinical trials of a combination of drugs of everolimus and sorafenib in patients with relapse and refractory osteosarcoma after performing standard polychemotherapy MAP (study NCT01804374). The study included 38 patients over the age of 18 years. Everolimus was administered in a dose of 5 mg once a day and sorafenib 400 mg two times a day. The duration of chemotherapy was 28 days. Partial response was achieved in 4 (10%) patients and stabilization of the disease in 20 (53%) patients. The overall response rate is 63%. This figure is 15% more than in the study, where sorafenib was used in monomode. A 4-month progression-free survival was 58% and for 6-month, it was 45% (17 out of 38) [71].
\nThus, taking into account the data of studies in 2008 (application of sorafenib in mono mode) and 2011 (using a combination of sorafenib with everolimus), it can be said that the combination of sorafenib with everolimus leads to an increase in the overall response rate and an increase in survival rate without disease progression within 6 months. However, by the year, this difference disappears.
\nAt ASCO 2016, preliminary results were presented in a pilot study of the use of everolimus/sorafenib in children with relapse and refractory osteosarcoma, which was carried out at the Institute of Pediatric Oncology and Hematology N.N. Blokhin Medical Research Center of Oncology from 2013 to 2016. This protocol included 14 patients. The first line of therapy is represented by the program “Osteosarcoma 2006” in seven patients and “Osteosarcoma 2014” in seven patients. All patients underwent therapy, which included doxorubicin, cisplatin, high-dose methotrexate, high-dose ifosfamide, and gemcitabine and docetaxel.
\nThe number of courses of therapy for everolimus/sorafenib ranged from 2 to 18. The toxicity of therapy was erythema cutaneous in all patients (100%), palmar and plantar syndrome in 1 (7%), and mucositis 1–2 in 4 (28.5%). Hematologic toxicity did not exceed 1–2 degree in all patients. A transient increase in transaminases up to five norms in all patients (100%) was also noted.
\nPartial response to treatment was achieved in 5 of 14 (35.7%) patients and stabilization of the disease in 9 (64.3%). The overall response rate was 100%. Survival without disease progression for more than 6 months was detected in 6 out of 14 (43%) patients. The mean follow-up was 7 ± 1.2 months. The maximum period without progression of the disease is 18.4 months.
\nThe findings suggest that everolimus/sorafenib combination resulted in a partial response in 35.7% of cases with a satisfactory toxicity profile [72].
\nCompared to international data (Italian sarcoma group) in the presented study, the achievement of a partial response, stabilization of the disease, and the overall response rate were significantly higher.
\nCurrently, a number of studies aimed at studying the role of tumor-associated macrophages. Activation of tumor-associated macrophages can be achieved through the use of preparations of liposomal tripeptides (mifamurtide) and interferon preparations (interferon alpha-2A).
\nMeyers et al. presented the results of the randomized study CCG 7921/POG 9351, which was conducted from 1993 to 1997. The study included 662 patients with a localized version of osteosarcoma.
\nA feature of line A therapy was the use of two courses of neoadjuvant chemotherapy for MAP, and in line B therapy, two courses of neoadjuvant chemotherapy MAi, alternating courses of MAR and MAi at the stage of adjuvant chemotherapy, was used. Surgical removal of the primary tumor lesion was performed at week 10. Mifamurtide (MTP) was administered at a dose of 2 mg/m2 two times a week for 12 weeks, and then once a week for 24 weeks in accordance with randomization.
\nThe mechanism of action of mythamurtide (MTP) is to activate monocytes/macrophages with antitumor activity, which is realized by binding to specific receptors toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 receptor (NOD2), followed by altering the activity of cellular signal pathways (ERK1/2—extracellular-signal regulated kinase 1/2), NF-kB—nuclear factor kappa-B, and AP1—adapter protein 1 [73].
\nAfter removal of the primary tumor focus, a good histological response in group A was achieved in 42% of patients and in group B in 48%, and a poor histological response in group A was 58% and in group B was 52%. At the same time, the 6-year-old RH was 74%, without the use of MTP was 70% and with the MTP was 78%; BSV was 64%, without the use of MTR was 61% and with MTP was 67%. In group A: OS without the use of MTR was 71% and with MTR was 75%; BSV without MTR was 64% and with MTR was 63%. In group B: OS without the use of MTR was 71% and with MTR was 75%; BSV without MTR was 64% and with MTR was 63%. The addition of MTP to polychemotherapy led to a statistically significant increase in the 6-year OS from 70 to 78% (p = 0.03), and there was also a tendency to an increase in BSV, mainly in group B (p = 0.08) [25].
\nKubo et al. published the results of a pilot study that determined the prognostic significance of the expression level of interferon α/β receptors in 40 patients with localized osteosarcoma who received treatment according to the NECO95J program. Expression of interferon α/β receptors was detected in 45% of patients. When conducting multivariate statistical analysis, a significant association was observed between the expression of interferon α/β receptors and 5-year-old OM and survival free of metastatic lesions (VSMP). The 5-year OM, in the presence of expression of the α/β interferon receptor in the tumor substrate, was 81%, with no expression, 47% (p = 0.043), and in the 5-year HSMP, it was 75 and 41% (p = 0.023). This study confirms the possibility of using interferon preparations in the treatment of osteosarcoma in patients with overexpression of α/β interferon receptors [74].
\nBielack et al. presented the results of the EURAMOS1 study in patients with a good histological response after neoadjuvant MAP chemotherapy. In the age group up to 30 years, the MAP line of therapy was carried out to 359 patients, the MAP INF line α–2b—to 357 patients, in the age group up to 20 years—333 (92.7%) and 332 (92.9%) patients. Groups of patients are statistically significantly comparable by sex, age, localization of the primary tumor lesion, the presence of metastatic lesions, and the histological variant of the tumor.
\nIn accordance with the program, pegylated INF–α–2b was administered at a dose of 0.5 mg/kg (at a maximum dose of 50 mg) once a week for 4 weeks, and then 1 mg/kg (at a maximum dose of 100 mg) 1 time per week (from 30 to 104 weeks of programmed treatment).
\nIn a group of 630 patients with a localized version of osteosarcoma, 135 events were detected: 72 in patients who received the MAP therapy line and 63 in patients who received the MAP INF therapy line–2b. At the same time, the 3-year EFS was 77 and 80%, respectively. Therefore, the use of INF–α–2b as maintenance therapy after MAP in patients with a good histological response did not lead to an increase in EFS [75].
\nThe data set out in paragraph 3 are summarized in Table 3.
\nAuthors | \nAgents | \n
---|---|
Ferrari S. | \nIfosfamide, adriamycin, cisplatin | \n
Le Deley M.C. | \nMethotrexate, adriamycin, ifosfamide, etoposide | \n
Cui Q. | \nCisplatin | \n
Pitano-Garcia A. | \nDoxorubicin, cisplatin | \n
Wu X. | \nMethotrexate, cisplatin, adriamycin | \n
Ohba T. | \nBevacizumab (Avastin) | \n
Children Oncology Group | \nTrastuzumab | \n
Trials/authors and agents.
Thus, the results of treatment of children with primary metastatic osteosarcoma, relapse, and refractory course of the disease remain unsatisfactory. Molecular biological factors that determine sensitivity to chemotherapy, invasive, and metastatic potential of the tumor, as well as the prognosis of the disease, among which special attention is deserved are as follows: expression of MGMT protein, methylation of the promoter part of the MGMT gene, expression of ERCC1 proteins, VEGF, CD133, p-STAT3tyr705, C-MYC, expression of RFC1 micro-RNA, and the presence of rearrangement of the TOR2A gene. It is important to note that there was no comprehensive assessment of the value of these markers for the histological response to neoadjuvant chemotherapy and survival rates in patients with osteosarcoma.
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