New therapies in thyroid cancer | Medicina Clínica (English Edition)

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(B) The RAI focuses on some lesions, but not on others. (C) Lesions lose the ability to concentrate RAI after previous evidence of iodine avid disease. (D) Lesions that progress within the last year despite concentrating RAI. RAI: radioactive iodine." ] ] ] "textoCompleto" => "IntroductionThe prognosis of differentiated thyroid carcinoma (DTC), which groups both papillary carcinoma (PTC) and follicular carcinoma (FC), is excellent. With proper treatment, survival rates at 10 years of 85% are reached for FC and 95% for PTC.<a class="elsevierStyleCrossRefs" href="#bib0190">1–3</a> Mortality is due, in most cases, to lung metastases with respiratory failure or compromised airway.<a class="elsevierStyleCrossRefs" href="#bib0205">4,5</a> However, despite its low mortality, persistence or recurrence of this cancer is common in up to 20–40% of patients; recurrence usually happens locally during the first decade after diagnosis. Similarly, the prognosis of patients diagnosed with medullary carcinoma (MC) in its early stages is good, with survival at 5 and 10 years ranging from 80 to 95% and 75 to 85%, respectively. However, 50% of patients with MC have cervical metastases at the time of diagnosis, and 15% are located at a distance.<a class="elsevierStyleCrossRef" href="#bib0215">6</a>Fortunately, DTC responds well to conventional therapy consisting of surgery often accompanied by a dose of radioactive iodine (RAI) and subsequent suppression of thyroid stimulating hormone (TSH).<a class="elsevierStyleCrossRefs" href="#bib0220">7,8</a> About two thirds of patients with distant metastases show significant uptake of RAI, of which only 40% will be cured.<a class="elsevierStyleCrossRefs" href="#bib0230">9,10</a> Therefore, almost half of patients with metastatic DTC do not respond adequately to RAI. Lack of response to RAI (or refractoriness) is inversely correlated with a survival of a life expectancy rate of 3–6 years.<a class="elsevierStyleCrossRef" href="#bib0240">11</a> In addition to the refractoriness to RAI, others are the factors that are associated with an adverse prognosis such as: an advanced age, aggressive histologic subtypes, poorly differentiated variants, large tumours, the presence of distant metastases at diagnosis or lesions that show a high uptake of 18Fluorodeoxyglucose in the positron emission tomography (18FDG-PET).<a class="elsevierStyleCrossRef" href="#bib0245">12</a>Therapeutic resources for patients with advanced DTC or MC are scarce. Experience with conventional chemotherapy, although meagre and poorly evaluated, has not shown convincing results. Therefore, these patients are optimal candidates for new therapies, regarding the discovery of new molecules with anti-oncogenic qualities. Within this area, tyrosine kinase inhibitors (TKI) currently play this role.Metabolic pathways in thyroid cancerIn thyroid cancer, aberrant mutated genes condition abnormal functioning of various tyrosine kinases with an overexpression of them and their receptors, as well as fibroblast, vascular endothelium, platelet derived, epidermal growth factors and others. Rearrangements of genes have also been described, resulting in the expression of chimeric proteins that affect the tyrosine kinase domain of Rearranged During Transfection (RET). The existence of mutations in BRAF-RAF genes is known, as well as RET/Papillary Thyroid Carcinoma rearrangements (RET/PTC). Both processes, coupled with the increased pathway activity of mitogen-activated protein kinase, lead to the upregulation of tumour cells and to the promotion of angiogenesis, proliferation and anti-apoptotic mechanisms.<a class="elsevierStyleCrossRefs" href="#bib0250">13,14</a> The percentage of these mutations also varies slightly as the DTC acquires aggressiveness.The study of metabolic pathways involved in the development of DTC has facilitated the identification of the cascade of kinases, mitogen-activated protein kinase pathway. This pathway may be affected in the DTC by activating mutations in the BRAF and RAS genes or rearrangement of RET/PTC. The RAS and BRAF mutations are commonly seen in poorly differentiated cancer. In PTC, the presence of translocations that generate RET/PTC oncogenes or RAS or BRAF mutations have been described in up to 70%. The V600E BRAF mutation has been associated with more aggressive PTC, an increased vascular invasion, extrathyroid extension and more advanced early stages upon diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0260">15,16</a>BRAF mutations have also been associated with of loss of ability to capture RAI.<a class="elsevierStyleCrossRef" href="#bib0270">17</a>RAS mutations have been observed in both the FC and the follicular variant of PTC. It has also been suggested that their presence may confer a worse long-term prognosis. Finally, all the familiar forms of MC are generated in activating RET mutations that are transmitted by autosomal dominant inheritance through the germ line.Suitable candidate patient selection for new therapiesThe patient with metastatic thyroid cancer should be monitored dynamically, valuing the functional and structural evolution of the disease along time according to their response to treatment. The functional response is determined by RAI uptake by the injury and by circulation of thyroglobulin (Tg) in the DTC. The markers in MC are calcitonin (Ct) and carcinoembryonic antigen. The structural response is determined by the volume or tumour load and its anatomical location, information provided by imaging tests: cervical ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI). The size of the macroscopic lesions should be evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST).<a class="elsevierStyleCrossRefs" href="#bib0275">18,19</a>The critical point for the selection of candidate patients with DTC for new therapies is the ability of lesions to respond to RAI. Sometimes there are DTC with visible metastases after administration of RAI that do not improve after several treatments. In other cases the metastases fail to capture RAI, showing a continuous rise of Tg concentration (functional discrepancy). In these patients, generally, a progress in the macroscopic lesion volume is also seen. In both situations, the possibility of treatment with RAI is low and an increase in dose may increase adverse effects, such as second solid tumours or leukaemia. Therefore, when a patient with DTC is classified as refractory to RAI, there is no indication to continue such treatment and an approach to treatment using new therapies available should be considered<a class="elsevierStyleCrossRef" href="#bib0285">20</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Assessment of candidate patient for new therapiesTo properly assess these patients, the extent and location of the disease should be known (through the use of RECIST) as well as the rate of progression. In addition, normal imaging tests (CT or MRI of the neck, thorax and abdomen) are also suggested as well as a bone scan and brain MRI. If possible, a 18FDG-PET is also advisable.<a class="elsevierStyleCrossRef" href="#bib0290">21</a>In general, patients selected are usually those where it can be seen that the disease has progressed in a certain period of time (usually the last 6 months). In these patients, the target lesions are indicated. These are generally measurable lesions with a diameter of more than 2cm (>1cm, if helical CT is used). Response to medication is evidenced by comparing reductions in the initial size and assessing the concentration of Tg of Ct tumour markers<a class="elsevierStyleCrossRef" href="#bib0295">22</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Approach for the patient with advanced thyroid cancerRefractory monitoring of the patientActive surveillance is key to the management of patients with advanced thyroid cancer. Monitoring should include carrying out a functional profile (thyroid hormones and tumour markers) and precise image tests (cervical ultrasound, 18FDG-PET/CT, MRI or CT) periodically. Generally, imaging tests are usually repeated every 3–12 months and tumour progression is evaluated according to RECIST. However, testing intervals are dictated by the disease's rate of progression. A patient's evolution will mark the opportunity to maintain a watchful wait or start systemic treatment with TKI.<a class="elsevierStyleCrossRef" href="#bib0300">23</a>Criteria for initiating systemic therapyTKI has allowed us to modify the evolution of those DTC that are refractory to treatment with RAI and MC in advanced stages. These therapies should only be indicated in patients with evident tumour progression or with the presence of symptoms due to the size of the tumour.<a class="elsevierStyleCrossRef" href="#bib0305">24</a> Patients with low tumour load (few lesions, metastases of less than 1cm, etc.), or without evidence of progression must be kept under an active surveillance. Therefore, stable patients whose lesions do not pose a clear vital risk, must wait before starting systemic treatment with TKI.In the event tumour progression is observed, candidate patients for treatment with TKI should meet the following characteristics:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Persistent and refractory disease to RAI ablation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</li><li class="elsevierStyleListItem" id="lsti0010">2.Multiple metastatic disease (macrometastases of diameter >1–2cm) with growth of >20% diameter in the last 12 months, objectified by an imaging test, or symptomatic disease that cannot be controlled with surgery or radiotherapy.</li><li class="elsevierStyleListItem" id="lsti0015">3.Good general condition (defined as Eastern Cooperative Oncology Group (ECOG)<2).</li><li class="elsevierStyleListItem" id="lsti0020">4.No specific contraindications associated with each TKI (e.g. poorly controlled hypertension [HTN], ischaemic heart disease in last 6 months, recent bleeding, active fistulas, etc.).</li><li class="elsevierStyleListItem" id="lsti0025">5.Adherence to prescribed treatment and the possibility of close clinical monitoring by units that have the means and appropriate professionals.</li></ul>Likewise, it would also be pertinent to have access to the molecular profiling of the patients’ tumours, which will facilitate a convenient and homogenised definition of the most appropriate systemic treatment, personalising the selection of medications. Adapting the therapeutic molecule to the mutations that have been found in the tumour would also be pertinent, and this criterion should prevail over the histology.Clinical evaluation prior to initiation of treatment with tyrosine kinase inhibitorsBefore starting treatment, a detailed medical history should be performed, assessing and excluding the existence of active bleeding, major surgery, fistulas and cardiovascular disease (ischaemic heart disease and stroke) within the last 6 months. Possible contraindications should be reviewed prior to initiation of treatment: uncontrolled hypertension or heart failure, chronic renal failure, heart rhythm abnormalities or history of previous bradyarrhythmias, hepatic failure, hyper- or hyperbilirubinemia. In addition, the functional status of the patient should be evaluated using validated scales (ECOG). Subsequent to that, a physical examination including weight, height, blood pressure should be performed, paying special attention to heart rate, cardiac and pulmonary auscultation as well as a complete examination of skin, hair and nails.A complete blood count, and plasma biochemistry analysis (glucose, urea, creatinine, electrolytes, transaminases, phosphorus metabolism) and urinary tests should be requested (recent proteinuria), coagulation study and hormonal determinations: TSH, free thyroxine (free T4), free triiodothyronine (free T3), vitamin D, Tg, anti-Tg antibodies, Ct, carcinoembryonic antigen. An electrocardiogram (ECG) should be available as well as an echocardiographic study if there is alteration.Therapy with TKI should not be considered in patients at high risk of developing adverse effects associated with the treatment or poor functional condition prior to treatment.Treatment with tyrosine kinase inhibitors in patients with advanced thyroid cancerNumerous TKIs have been used in thyroid cancer and four of them have passed phase III clinical trials, having been approved for the treatment of DTC and MC by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Sorafenib and lenvatinib have been approved for use in DTC, while cabozantinib and vandetanib have been for MC. However, there is no clear recommendation specifying which particular medication should be used. It has been found that these medications are generally partially selective, able to inhibit multiple kinases and often acting in several signalling pathways. Due to the existing structural similarity between kinases that activate the RET pathway and growth factors of vascular endothelium, many molecules are capable of inhibiting both pathways. Therefore, the decision to initiate a systemic treatment or include a patient in a clinical trial should be based on various parameters such as tumour load, progression of the disease, existing symptoms or the risk of complications.<a class="elsevierStyleCrossRef" href="#bib0310">25</a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the main existing TKI.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>All TKI have, in varying degrees, anti-tumour effects. In most cases they are able to stabilise the disease over time or promote partial responses. Complete responses are anecdotal as they are fundamentally tumourostatic acting medication (and to a lesser extent tumouricidal). In many cases disease-free survivals are achieved, but to date a clear increase in overall survival of patients has not yet been achieved.<a class="elsevierStyleCrossRef" href="#bib0315">26</a>Clinical monitoring of the patient undergoing treatment with tyrosine kinase inhibitorsPatients undergoing treatment with TKI should be evaluated regularly; initially on a weekly basis and then monthly. A complete history and physical examination should be performed which includes the determination of laboratory values (blood count, thyroid function, tumour markers, general biochemistry, liver and kidney function) adjusting the dose of levothyroxine as needed. In monitoring by ECG, special attention must be paid to the QT interval and an echocardiogram should be performed if there is suspicion of heart failure or abnormal ECG.Imaging tests (CT, MRI, 18FDG-PET/CT and bone scan) should be performed every 2–3 months with the focus on the cervical, thoracic and abdominal regions to assess response to treatment using RECIST criteria.The frequency of subsequent revisions is marked by the response. The terms can be spaced in cases where there has been a satisfactory response. It is important to note that some patients will have mixed responses: partial responses in certain metastatic lesions, while others will progress.<a class="elsevierStyleCrossRef" href="#bib0275">18</a> How to act, evaluate and treat these cases has not yet been defined.Evaluation of secondary effects and toxicity of treatment with tyrosine kinase inhibitorsSecondary effects of treatment with TKI are frequent, so treating these patients in referral centres that have multidisciplinary teams with resources and professionals from different medical specialties is preferable. The most common secondary effects are hypertension, skin lesions, diarrhoea, anorexia, fatigue, neutropenia and hypertransaminasemia.Within the cardiovascular secondary effects, HTN is the most common, with a prevalence in almost 25% of the patients treated. Changes in the ECG include increased QT interval, Torsades de Pointes syndrome or sudden death. An ECG before starting and after treatment is fundamental, especially in patients treated with vandetanib. Previous history of bradyarrhythmias, heart failure or long QT syndrome contraindicates administration. Heart failure has been associated with sunitinib, so echocardiographic monitoring is recommended prior to treatment. Finally, the presence of arterial embolic effects has been associated to treatment with sorafenib and sunitinib.<a class="elsevierStyleCrossRef" href="#bib0320">27</a>Dermatologic secondary effects are frequent and numerous, hand–foot syndrome being particularly relevant with acute onset in the first 2–4 weeks of treatment. They are erythema and oedema type lesions on the extremities. The lesions may progress to blisters, necrosis, or scaly areas, with loss of the epidermis of the hands and feet. It can affect up to 30% of those treated with TKI,<a class="elsevierStyleCrossRef" href="#bib0325">28</a> requiring local topical treatments with emollients.Within haematologic effects, the presence of pancytopenias is observed in 20–30% of cases, so a blood count must be carried out before initiation of treatment. Patients who received prior radiation therapy are at increased risk of bone marrow depression. There have been reports of thrombotic events and bleeding (sometimes fatal) in all TKI, being contraindicated in patients with active surgical wounds, history of digestive or brain haemorrhage or uncontrolled haemoptysis, anticoagulated patients with a history of bleeding or major bleeding, occurring in the last 6 months. TKI must be suspended 7 days prior to surgery.<a class="elsevierStyleCrossRef" href="#bib0330">29</a>Metabolic and hormonal effects exist, with disorders in glucose metabolism (decreases in plasma glucose values in patients with type 2 diabetes), disorders of calcium metabolism, with episodes of hypocalcaemia in 10% of patients previously treated with calcium and vitamin D supplements, and disorders of thyroid function, with an increase of levothyroxine and occasionally, the appearance of thyrotoxicosis in patients treated with sunitinib for probable induction of thyroiditis.<a class="elsevierStyleCrossRefs" href="#bib0335">30,31</a>Also, the presence of hepatotoxicity has been observed, especially with sunitinib and pazopanib, presenting hypertransaminasemia requiring periodic enzymatic determination.<a class="elsevierStyleCrossRef" href="#bib0345">32</a> Finally, within existing renal disorders, all TKI can cause proteinuria, such that routine kidney function tests and urinalysis are required, they appear most frequently in those receiving pazopanib and lenvatinib. The presence of nephrotic syndrome would result in the discontinuation of treatment.<a class="elsevierStyleCrossRef" href="#bib0350">33</a>The occurrence of such adverse effects were often initially managed by reducing the dose of the medication. In general, the secondary effects of conventional treatments are subsidiary. Non-haematologic grade 1 and 2 adverse effects, if properly handled (antihypertensive therapy, dermatological topical treatments, etc.) allow maintaining treatment with TKI. If the right treatment were not available or not tolerated by the patient, reducing the dose would be necessary (by approximately 50% of the initial dose) and, if they persist, discontinue TKI. Non-haematologic grade 3 adverse effects are easily manageable (diarrhoea, etc.) requiring the temporary suspension of TKI, and then reintroducing it to half the usual dose. If there is a recurrence of the secondary effect after reintroducing the drug at lower doses, treatment would be completely suspended. As non-haematologic adverse effects grade 4 are potentially fatal, they require the final complete suspension of treatment with TKI.<a class="elsevierStyleCrossRef" href="#bib0355">34</a>Haematological adverse effects of grade 1 and 2 does not need treatment to be modified, however grade 3 and 4 neutropenia and thrombocytopenia and grade 4 anaemias oblige suspension of treatment and an assessment of possible secondary causes should be carried out (myelodysplasias), especially if there is a history of RAI at high doses or prior radiotherapy<a class="elsevierStyleCrossRef" href="#bib0360">35</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Actions against the development of resistance to tyrosine kinase inhibitorsAfter a favourable initial response, the patient can acquire a resistance to TKI, which in many cases supposes the progression of a new tumour. Little is known about the causes of these resistances. Two types are distinguished: primary, which has existed since the beginning of treatment, and secondary, which occurs after treatment due to the activation of compensatory activating routes that avoid the existing pharmacological blockade. It has been suggested that the genetic heterogeneity in many DTC/MC assumes that certain genetic alterations exist only in a sub-clonal fraction of tumour cells. This fact, along with the presence of secondary effects requiring suspension of treatment, leads us to consider the characteristics of second-line medications, often being a fundamentally palliative action.<a class="elsevierStyleCrossRef" href="#bib0365">36</a>Second-line treatment with tyrosine kinase inhibitorsThe optimal strategy of sequential or simultaneous TKI use has not yet been well defined. In general, patients who have not responded nor tolerated it, and those who have had a new TKI added to their treatment will show worse results than those obtained in the first line of treatment. Before the use of TKI in second line treatment, the cause of failure in the initial therapy must be analysed. If the failure is attributed to toxicity, the secondary effect profile of the new TKI must be different from the initial TKI. If the cause has been tumour progression, the molecular target profile of the new TKI must be different.<a class="elsevierStyleCrossRef" href="#bib0370">37</a> Therefore, it is unlikely that a single TKI can achieve a curative action. In order to draw valid conclusions, it is essential that candidate patients for second or third line treatment are enrolled in clinical trials.Special considerations for treatment with tyrosine kinase inhibitorsPatients with advanced thyroid neoplasms, either refractory DTC or metastatic MC should be monitored by a multidisciplinary team. The moment to start treatment with these substances should be carefully considered because secondary effects are significant and cloud the quality of life of patients without having so far shown that they prolong survival. Therefore, whether the patient meets the criteria for inclusion should be verified and potential candidates should be carefully selected among patients who have an advanced and progressive disease in which the benefit of treatment outweighs the deterioration that occurs. The results obtained so far do not show that any particular drug is significantly superior over others and hope seems to be more powerful than reality. For this reason, in many cases the choice of compound will depend on various factors such as the patient's condition, their access to clinical trials and the possibility of requesting the use of TKI within the modality of compassionate use. For patients with few metastatic lesions, or who follow an indolent clinical course, the prudent option would be to offer other treatment options.Conflict of interestJCG has participated as an advisor for AstraZeneca, Bayer HealthCare and Genzyme, and has received fees from Genzyme and Merck.PLM declares no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Metabolic pathways in thyroid cancer" ] 2 => array:3 [ "identificador" => "sec0015" "titulo" => "Suitable candidate patient selection for new therapies" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Assessment of candidate patient for new therapies" ] ] ] 3 => array:3 [ "identificador" => "sec0025" "titulo" => "Approach for the patient with advanced thyroid cancer" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Refractory monitoring of the patient" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Criteria for initiating systemic therapy" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Clinical evaluation prior to initiation of treatment with tyrosine kinase inhibitors" ] ] ] 4 => array:3 [ "identificador" => "sec0045" "titulo" => "Treatment with tyrosine kinase inhibitors in patients with advanced thyroid cancer" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Clinical monitoring of the patient undergoing treatment with tyrosine kinase inhibitors" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Evaluation of secondary effects and toxicity of treatment with tyrosine kinase inhibitors" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Actions against the development of resistance to tyrosine kinase inhibitors" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Second-line treatment with tyrosine kinase inhibitors" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Special considerations for treatment with tyrosine kinase inhibitors" ] ] ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflict of interest" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-10-01" "fechaAceptado" => "2015-11-11" "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: López Mondéjar P, Galofré JC. Nuevas terapias en el cáncer de tiroides. Med Clin (Barc). 2016;146:324–329." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2817 "Ancho" => 1658 "Tamanyo" => 266475 ] ] "descripcion" => array:1 [ "en" => "The patient is deemed to be refractory to RAI when they meet any of the following conditions: (A) Metastatic lesions that do not capture RAI in the initial treatment. (B) The RAI focuses on some lesions, but not on others. (C) Lesions lose the ability to concentrate RAI after previous evidence of iodine avid disease. (D) Lesions that progress within the last year despite concentrating RAI. RAI: radioactive iodine." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Category \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target lesions \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-target lesions \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Complete response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Target lesions have disappeared \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The disappearance of all lesions and normalisation of tumour markers \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Partial response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Decrease of at least 30% of the diameter of the largest target lesions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stable disease (incomplete response) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A sufficient reduction has not been observed to be partial response, nor an increase to be progressive disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The persistence of one or more non-target lesions and/or maintenance of the concentration of tumour markers above the normal range \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Progressive disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increase of at least 20% of the diameter of the largest target lesions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The appearance of one or more new lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1122975.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Criteria for evaluation of lesions." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "DTC, differentiated thyroid cancer; MC, medullary cancer; EGF, epidermal growth factor; HBP, high blood pressure; IC, heart failure; PDGF-Rβ, platelet-derived growth factor receptors; RET, Rearranged during transfection; RET/PTC, Rearranged during transfection/papillary thyroid carcinoma; VEGF-R, vascular endothelial growth factor receptor." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Compound \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Commercial name \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Targets \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Indication \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse effects \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Axitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inlyta® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 1, 2 and 3, PDGF-Rβ, c-Kit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HTN, IC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cabozantinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cometriq® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 1 y 2, PDGF-Rβ, RET, c-Kit, c-MET \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">140mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diarrhoea, HTN \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lenvatinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lenvima® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 1, 2 and 3, RET, c-KIT, PDGF-Rβ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HTN, proteinuria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pazopanib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Votrient® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 1, 2 and 3, c-Kit, PDGF-R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">800mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cutaneous \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Selumetinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MEK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">75mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dermatological \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nexavar® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 1, 2 and 3, RET/PTC, BRAF, PDGF-Rβ, c-KIT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">400mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dermatological \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sunitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sutent® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 2, RET/PET, c-Kit, PDGF-Rβ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vandetanib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Caprelsa®, Zactima® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VEGF-R 2 and 3, RET, EGF-R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">300mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arrhythmias \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vemurafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Zelboraf® \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">BRAF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">960mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Liver \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1122976.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of tyrosine kinase inhibitors." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "iv, intravenous; DBP, diastolic blood pressure; SBP, systolic blood pressure." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Toxicity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">0 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 1 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 2 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 3 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 4 \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anorexia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Loss of appetite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Decreased oral intake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Accurate nutrition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bleeding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mild; does not require intervention \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Accurate intervention \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Transfusion or haemostasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diarrhoea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><4stools/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4–6stools/day; requires iv fluids <24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>7stools/day; iv fluids >24h; hospitalisation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dry mouth \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Symptomatic without causing alteration of diet \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Symptomatic specifying increase in liquids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Symptoms that prevent eating properly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dysphagia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Can eat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cannot eat; iv fluids <24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Iv fluids 24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Asthenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mild \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Severe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prostration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fever/rigour \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38–39°C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39.1–40°C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>40°C for <24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>40°C for >24h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hand–foot syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Does not interfere with daily activities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Interferes with daily activities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ulcer, peeling, severe pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Steven–Johnson syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SBP 120–139mmHg or DBP 80–89mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SBP 140–160mmHg or DBP 90–99mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SBP >160mmHg or DBP >100mmHg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support (e.g., hypertensive crisis) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mucositis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mucosal erythema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Patchy mucosal ulceration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Extensive ulceration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tissue necrosis; life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nausea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Loss of appetite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Decreased intake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Accurate nutrition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rash \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maculopapular \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rash on <50% body \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rash on ≥50% body \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Exfoliative or ulcerative dermatitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mild \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Severe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unbearable \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vomiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">An episode/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–5 episodes/24h, iv fluids <24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥6/24h; iv fluids >24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weakness \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mild \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">With exercise \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Life support \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight loss \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5–10% of baseline weight; surgery not indicated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–20% of baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≥20% of baseline \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertransaminasemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1–3 increase normal value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3–8 increase normal value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>8 increase normal value \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyperbilirubinemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.5–2 increase normal value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2–3 increase normal value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">>3 increase normal value \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1122977.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Adverse effects of tyrosine kinase inhibitors." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib0190" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Morbidity and mortality in folicular thyroid cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L.J. 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Diagnosis and treatment

New therapies in thyroid cancer

Nuevas terapias en el cáncer de tiroides

Pedro López Mondéjara,

Corresponding author

pedrolopezmondejar@hotmail.com

Corresponding author.

, Juan Carlos Galofréb,c

a Sección Endocrinología y Nutrición, Hospital General Universitario Alicante, Alicante, Spain

b Departamento de Endocrinología y Nutrición, Clínica Universidad de Navarra, Pamplona, Spain

c Instituto de Investigación en la Salud de Navarra (IdiSNA)

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The patient is deemed to be refractory to RAI when they meet any of the following conditions&#58; &#40;A&#41; Metastatic lesions that do not capture RAI in the initial treatment&#46; &#40;B&#41; The RAI focuses on some lesions&#44; but not on others&#46; &#40;C&#41; Lesions lose the ability to concentrate RAI after previous evidence of iodine avid disease&#46; &#40;D&#41; Lesions that progress within the last year despite concentrating RAI&#46; RAI&#58; radioactive iodine&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The prognosis of differentiated thyroid carcinoma &#40;DTC&#41;&#44; which groups both papillary carcinoma &#40;PTC&#41; and follicular carcinoma &#40;FC&#41;&#44; is excellent&#46; With proper treatment&#44; survival rates at 10 years of 85&#37; are reached for FC and 95&#37; for PTC&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">1&#8211;3</span></a> Mortality is due&#44; in most cases&#44; to lung metastases with respiratory failure or compromised airway&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">4&#44;5</span></a> However&#44; despite its low mortality&#44; persistence or recurrence of this cancer is common in up to 20&#8211;40&#37; of patients&#59; recurrence usually happens locally during the first decade after diagnosis&#46; Similarly&#44; the prognosis of patients diagnosed with medullary carcinoma &#40;MC&#41; in its early stages is good&#44; with survival at 5 and 10 years ranging from 80 to 95&#37; and 75 to 85&#37;&#44; respectively&#46; However&#44; 50&#37; of patients with MC have cervical metastases at the time of diagnosis&#44; and 15&#37; are located at a distance&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Fortunately&#44; DTC responds well to conventional therapy consisting of surgery often accompanied by a dose of radioactive iodine &#40;RAI&#41; and subsequent suppression of thyroid stimulating hormone &#40;TSH&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">7&#44;8</span></a> About two thirds of patients with distant metastases show significant uptake of RAI&#44; of which only 40&#37; will be cured&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">9&#44;10</span></a> Therefore&#44; almost half of patients with metastatic DTC do not respond adequately to RAI&#46; Lack of response to RAI &#40;or refractoriness&#41; is inversely correlated with a survival of a life expectancy rate of 3&#8211;6 years&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> In addition to the refractoriness to RAI&#44; others are the factors that are associated with an adverse prognosis such as&#58; an advanced age&#44; aggressive histologic subtypes&#44; poorly differentiated variants&#44; large tumours&#44; the presence of distant metastases at diagnosis or lesions that show a high uptake of <span class="elsevierStyleSup">18</span>Fluorodeoxyglucose in the positron emission tomography &#40;18FDG-PET&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Therapeutic resources for patients with advanced DTC or MC are scarce&#46; Experience with conventional chemotherapy&#44; although meagre and poorly evaluated&#44; has not shown convincing results&#46; Therefore&#44; these patients are optimal candidates for new therapies&#44; regarding the discovery of new molecules with anti-oncogenic qualities&#46; Within this area&#44; tyrosine kinase inhibitors &#40;TKI&#41; currently play this role&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Metabolic pathways in thyroid cancer</span><p id="par0020" class="elsevierStylePara elsevierViewall">In thyroid cancer&#44; aberrant mutated genes condition abnormal functioning of various tyrosine kinases with an overexpression of them and their receptors&#44; as well as fibroblast&#44; vascular endothelium&#44; platelet derived&#44; epidermal growth factors and others&#46; Rearrangements of genes have also been described&#44; resulting in the expression of chimeric proteins that affect the tyrosine kinase domain of Rearranged During Transfection &#40;RET&#41;&#46; The existence of mutations in BRAF-RAF genes is known&#44; as well as RET&#47;Papillary Thyroid Carcinoma rearrangements &#40;RET&#47;PTC&#41;&#46; Both processes&#44; coupled with the increased pathway activity of mitogen-activated protein kinase&#44; lead to the upregulation of tumour cells and to the promotion of angiogenesis&#44; proliferation and anti-apoptotic mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">13&#44;14</span></a> The percentage of these mutations also varies slightly as the DTC acquires aggressiveness&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The study of metabolic pathways involved in the development of DTC has facilitated the identification of the cascade of kinases&#44; mitogen-activated protein kinase pathway&#46; This pathway may be affected in the DTC by activating mutations in the <span class="elsevierStyleItalic">BRAF</span> and <span class="elsevierStyleItalic">RAS</span> genes or rearrangement of RET&#47;PTC&#46; The <span class="elsevierStyleItalic">RAS</span> and <span class="elsevierStyleItalic">BRAF</span> mutations are commonly seen in poorly differentiated cancer&#46; In PTC&#44; the presence of translocations that generate RET&#47;PTC oncogenes or <span class="elsevierStyleItalic">RAS</span> or <span class="elsevierStyleItalic">BRAF</span> mutations have been described in up to 70&#37;&#46; The V600E <span class="elsevierStyleItalic">BRAF</span> mutation has been associated with more aggressive PTC&#44; an increased vascular invasion&#44; extrathyroid extension and more advanced early stages upon diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">15&#44;16</span></a><span class="elsevierStyleItalic">BRAF</span> mutations have also been associated with of loss of ability to capture RAI&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">RAS</span> mutations have been observed in both the FC and the follicular variant of PTC&#46; It has also been suggested that their presence may confer a worse long-term prognosis&#46; Finally&#44; all the familiar forms of MC are generated in activating RET mutations that are transmitted by autosomal dominant inheritance through the germ line&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Suitable candidate patient selection for new therapies</span><p id="par0035" class="elsevierStylePara elsevierViewall">The patient with metastatic thyroid cancer should be monitored dynamically&#44; valuing the functional and structural evolution of the disease along time according to their response to treatment&#46; The functional response is determined by RAI uptake by the injury and by circulation of thyroglobulin &#40;Tg&#41; in the DTC&#46; The markers in MC are calcitonin &#40;Ct&#41; and carcinoembryonic antigen&#46; The structural response is determined by the volume or tumour load and its anatomical location&#44; information provided by imaging tests&#58; cervical ultrasound&#44; computed tomography &#40;CT&#41; or magnetic resonance imaging &#40;MRI&#41;&#46; The size of the macroscopic lesions should be evaluated according to the Response Evaluation Criteria In Solid Tumours &#40;RECIST&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The critical point for the selection of candidate patients with DTC for new therapies is the ability of lesions to respond to RAI&#46; Sometimes there are DTC with visible metastases after administration of RAI that do not improve after several treatments&#46; In other cases the metastases fail to capture RAI&#44; showing a continuous rise of Tg concentration &#40;functional discrepancy&#41;&#46; In these patients&#44; generally&#44; a progress in the macroscopic lesion volume is also seen&#46; In both situations&#44; the possibility of treatment with RAI is low and an increase in dose may increase adverse effects&#44; such as second solid tumours or leukaemia&#46; Therefore&#44; when a patient with DTC is classified as refractory to RAI&#44; there is no indication to continue such treatment and an approach to treatment using new therapies available should be considered<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">20</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Assessment of candidate patient for new therapies</span><p id="par0045" class="elsevierStylePara elsevierViewall">To properly assess these patients&#44; the extent and location of the disease should be known &#40;through the use of RECIST&#41; as well as the rate of progression&#46; In addition&#44; normal imaging tests &#40;CT or MRI of the neck&#44; thorax and abdomen&#41; are also suggested as well as a bone scan and brain MRI&#46; If possible&#44; a 18FDG-PET is also advisable&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In general&#44; patients selected are usually those where it can be seen that the disease has progressed in a certain period of time &#40;usually the last 6 months&#41;&#46; In these patients&#44; the <span class="elsevierStyleItalic">target</span> lesions are indicated&#46; These are generally measurable lesions with a diameter of more than 2<span class="elsevierStyleHsp" style=""></span>cm &#40;&#62;1<span class="elsevierStyleHsp" style=""></span>cm&#44; if helical CT is used&#41;&#46; Response to medication is evidenced by comparing reductions in the initial size and assessing the concentration of Tg of Ct tumour markers<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Approach for the patient with advanced thyroid cancer</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Refractory monitoring of the patient</span><p id="par0055" class="elsevierStylePara elsevierViewall">Active surveillance is key to the management of patients with advanced thyroid cancer&#46; Monitoring should include carrying out a functional profile &#40;thyroid hormones and tumour markers&#41; and precise image tests &#40;cervical ultrasound&#44; 18FDG-PET&#47;CT&#44; MRI or CT&#41; periodically&#46; Generally&#44; imaging tests are usually repeated every 3&#8211;12 months and tumour progression is evaluated according to RECIST&#46; However&#44; testing intervals are dictated by the disease&#39;s rate of progression&#46; A patient&#39;s evolution will mark the opportunity to maintain a watchful wait or start systemic treatment with TKI&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Criteria for initiating systemic therapy</span><p id="par0060" class="elsevierStylePara elsevierViewall">TKI has allowed us to modify the evolution of those DTC that are refractory to treatment with RAI and MC in advanced stages&#46; These therapies should only be indicated in patients with evident tumour progression or with the presence of symptoms due to the size of the tumour&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a> Patients with low tumour load &#40;few lesions&#44; metastases of less than 1<span class="elsevierStyleHsp" style=""></span>cm&#44; etc&#46;&#41;&#44; or without evidence of progression must be kept under an active surveillance&#46; Therefore&#44; stable patients whose lesions do not pose a clear vital risk&#44; must wait before starting systemic treatment with TKI&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In the event tumour progression is observed&#44; candidate patients for treatment with TKI should meet the following characteristics&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Persistent and refractory disease to RAI ablation &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Multiple metastatic disease &#40;macrometastases of diameter &#62;1&#8211;2<span class="elsevierStyleHsp" style=""></span>cm&#41; with growth of &#62;20&#37; diameter in the last 12 months&#44; objectified by an imaging test&#44; or symptomatic disease that cannot be controlled with surgery or radiotherapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Good general condition &#40;defined as Eastern Cooperative Oncology Group &#40;ECOG&#41;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">&#60;</span><span class="elsevierStyleHsp" style=""></span>2&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0085" class="elsevierStylePara elsevierViewall">No specific contraindications associated with each TKI &#40;e&#46;g&#46; poorly controlled hypertension &#91;HTN&#93;&#44; ischaemic heart disease in last 6 months&#44; recent bleeding&#44; active fistulas&#44; etc&#46;&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5&#46;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Adherence to prescribed treatment and the possibility of close clinical monitoring by units that have the means and appropriate professionals&#46;</p></li></ul></p><p id="par0095" class="elsevierStylePara elsevierViewall">Likewise&#44; it would also be pertinent to have access to the molecular profiling of the patients&#8217; tumours&#44; which will facilitate a convenient and homogenised definition of the most appropriate systemic treatment&#44; personalising the selection of medications&#46; Adapting the therapeutic molecule to the mutations that have been found in the tumour would also be pertinent&#44; and this criterion should prevail over the histology&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical evaluation prior to initiation of treatment with tyrosine kinase inhibitors</span><p id="par0100" class="elsevierStylePara elsevierViewall">Before starting treatment&#44; a detailed medical history should be performed&#44; assessing and excluding the existence of active bleeding&#44; major surgery&#44; fistulas and cardiovascular disease &#40;ischaemic heart disease and stroke&#41; within the last 6 months&#46; Possible contraindications should be reviewed prior to initiation of treatment&#58; uncontrolled hypertension or heart failure&#44; chronic renal failure&#44; heart rhythm abnormalities or history of previous bradyarrhythmias&#44; hepatic failure&#44; hyper- or hyperbilirubinemia&#46; In addition&#44; the functional status of the patient should be evaluated using validated scales &#40;ECOG&#41;&#46; Subsequent to that&#44; a physical examination including weight&#44; height&#44; blood pressure should be performed&#44; paying special attention to heart rate&#44; cardiac and pulmonary auscultation as well as a complete examination of skin&#44; hair and nails&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A complete blood count&#44; and plasma biochemistry analysis &#40;glucose&#44; urea&#44; creatinine&#44; electrolytes&#44; transaminases&#44; phosphorus metabolism&#41; and urinary tests should be requested &#40;recent proteinuria&#41;&#44; coagulation study and hormonal determinations&#58; TSH&#44; free thyroxine &#40;free T4&#41;&#44; free triiodothyronine &#40;free T3&#41;&#44; vitamin D&#44; Tg&#44; anti-Tg antibodies&#44; Ct&#44; carcinoembryonic antigen&#46; An electrocardiogram &#40;ECG&#41; should be available as well as an echocardiographic study if there is alteration&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Therapy with TKI should not be considered in patients at high risk of developing adverse effects associated with the treatment or poor functional condition prior to treatment&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment with tyrosine kinase inhibitors in patients with advanced thyroid cancer</span><p id="par0115" class="elsevierStylePara elsevierViewall">Numerous TKIs have been used in thyroid cancer and four of them have passed phase III clinical trials&#44; having been approved for the treatment of DTC and MC by both the European Medicines Agency &#40;EMA&#41; and the Food and Drug Administration &#40;FDA&#41;&#46; Sorafenib and lenvatinib have been approved for use in DTC&#44; while cabozantinib and vandetanib have been for MC&#46; However&#44; there is no clear recommendation specifying which particular medication should be used&#46; It has been found that these medications are generally partially selective&#44; able to inhibit multiple kinases and often acting in several signalling pathways&#46; Due to the existing structural similarity between kinases that activate the RET pathway and growth factors of vascular endothelium&#44; many molecules are capable of inhibiting both pathways&#46; Therefore&#44; the decision to initiate a systemic treatment or include a patient in a clinical trial should be based on various parameters such as tumour load&#44; progression of the disease&#44; existing symptoms or the risk of complications&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">25</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the main existing TKI&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">All TKI have&#44; in varying degrees&#44; anti-tumour effects&#46; In most cases they are able to <span class="elsevierStyleItalic">stabilise the disease</span> over time or promote <span class="elsevierStyleItalic">partial responses</span>&#46; <span class="elsevierStyleItalic">Complete responses</span> are anecdotal as they are fundamentally tumourostatic acting medication &#40;and to a lesser extent tumouricidal&#41;&#46; In many cases <span class="elsevierStyleItalic">disease</span>-<span class="elsevierStyleItalic">free survivals</span> are achieved&#44; but to date a clear increase in <span class="elsevierStyleItalic">overall survival</span> of patients has not yet been achieved&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">26</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical monitoring of the patient undergoing treatment with tyrosine kinase inhibitors</span><p id="par0125" class="elsevierStylePara elsevierViewall">Patients undergoing treatment with TKI should be evaluated regularly&#59; initially on a weekly basis and then monthly&#46; A complete history and physical examination should be performed which includes the determination of laboratory values &#40;blood count&#44; thyroid function&#44; tumour markers&#44; general biochemistry&#44; liver and kidney function&#41; adjusting the dose of levothyroxine as needed&#46; In monitoring by ECG&#44; special attention must be paid to the QT interval and an echocardiogram should be performed if there is suspicion of heart failure or abnormal ECG&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Imaging tests &#40;CT&#44; MRI&#44; 18FDG-PET&#47;CT and bone scan&#41; should be performed every 2&#8211;3 months with the focus on the cervical&#44; thoracic and abdominal regions to assess response to treatment using RECIST criteria&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The frequency of subsequent revisions is marked by the response&#46; The terms can be spaced in cases where there has been a satisfactory response&#46; It is important to note that some patients will have mixed responses&#58; partial responses in certain metastatic lesions&#44; while others will progress&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> How to act&#44; evaluate and treat these cases has not yet been defined&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Evaluation of secondary effects and toxicity of treatment with tyrosine kinase inhibitors</span><p id="par0140" class="elsevierStylePara elsevierViewall">Secondary effects of treatment with TKI are frequent&#44; so treating these patients in referral centres that have multidisciplinary teams with resources and professionals from different medical specialties is preferable&#46; The most common secondary effects are hypertension&#44; skin lesions&#44; diarrhoea&#44; anorexia&#44; fatigue&#44; neutropenia and hypertransaminasemia&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Within the cardiovascular secondary effects&#44; <span class="elsevierStyleItalic">HTN</span> is the most common&#44; with a prevalence in almost 25&#37; of the patients treated&#46; <span class="elsevierStyleItalic">Changes in the ECG</span> include increased QT interval&#44; <span class="elsevierStyleItalic">Torsades de Pointes</span> syndrome or sudden death&#46; An ECG before starting and after treatment is fundamental&#44; especially in patients treated with vandetanib&#46; Previous history of bradyarrhythmias&#44; heart failure or long QT syndrome contraindicates administration&#46; <span class="elsevierStyleItalic">Heart failure</span> has been associated with sunitinib&#44; so echocardiographic monitoring is recommended prior to treatment&#46; Finally&#44; the presence of <span class="elsevierStyleItalic">arterial embolic effects</span> has been associated to treatment with sorafenib and sunitinib&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">27</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Dermatologic secondary effects are frequent and numerous&#44; <span class="elsevierStyleItalic">hand&#8211;foot syndrome</span> being particularly relevant with acute onset in the first 2&#8211;4 weeks of treatment&#46; They are erythema and oedema type lesions on the extremities&#46; The lesions may progress to blisters&#44; necrosis&#44; or scaly areas&#44; with loss of the epidermis of the hands and feet&#46; It can affect up to 30&#37; of those treated with TKI&#44;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">28</span></a> requiring local topical treatments with emollients&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Within haematologic effects&#44; the presence of <span class="elsevierStyleItalic">pancytopenias</span> is observed in 20&#8211;30&#37; of cases&#44; so a blood count must be carried out before initiation of treatment&#46; Patients who received prior radiation therapy are at increased risk of bone marrow depression&#46; There have been reports of thrombotic events and bleeding &#40;sometimes fatal&#41; in all TKI&#44; being contraindicated in patients with active surgical wounds&#44; history of digestive or brain haemorrhage or uncontrolled haemoptysis&#44; anticoagulated patients with a history of bleeding or major bleeding&#44; occurring in the last 6 months&#46; TKI must be suspended 7 days prior to surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">29</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Metabolic and hormonal effects exist&#44; with <span class="elsevierStyleItalic">disorders in glucose metabolism</span> &#40;decreases in plasma glucose values in patients with type 2 diabetes&#41;&#44; <span class="elsevierStyleItalic">disorders of calcium metabolism</span>&#44; with episodes of hypocalcaemia in 10&#37; of patients previously treated with calcium and vitamin D supplements&#44; and <span class="elsevierStyleItalic">disorders of thyroid function</span>&#44; with an increase of levothyroxine and occasionally&#44; the appearance of thyrotoxicosis in patients treated with sunitinib for probable induction of thyroiditis&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">30&#44;31</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Also&#44; the presence of <span class="elsevierStyleItalic">hepatotoxicity</span> has been observed&#44; especially with sunitinib and pazopanib&#44; presenting hypertransaminasemia requiring periodic enzymatic determination&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">32</span></a> Finally&#44; within existing renal disorders&#44; all TKI can cause <span class="elsevierStyleItalic">proteinuria</span>&#44; such that routine kidney function tests and urinalysis are required&#44; they appear most frequently in those receiving pazopanib and lenvatinib&#46; The presence of <span class="elsevierStyleItalic">nephrotic syndrome</span> would result in the discontinuation of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">33</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The occurrence of such adverse effects were often initially managed by reducing the dose of the medication&#46; In general&#44; the secondary effects of conventional treatments are subsidiary&#46; Non-haematologic grade 1 and 2 adverse effects&#44; if properly handled &#40;antihypertensive therapy&#44; dermatological topical treatments&#44; etc&#46;&#41; allow maintaining treatment with TKI&#46; If the right treatment were not available or not tolerated by the patient&#44; reducing the dose would be necessary &#40;by approximately 50&#37; of the initial dose&#41; and&#44; if they persist&#44; discontinue TKI&#46; Non-haematologic grade 3 adverse effects are easily manageable &#40;diarrhoea&#44; etc&#46;&#41; requiring the temporary suspension of TKI&#44; and then reintroducing it to half the usual dose&#46; If there is a recurrence of the secondary effect after reintroducing the drug at lower doses&#44; treatment would be completely suspended&#46; As non-haematologic adverse effects grade 4 are potentially fatal&#44; they require the final complete suspension of treatment with TKI&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">34</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Haematological adverse effects of grade 1 and 2 does not need treatment to be modified&#44; however grade 3 and 4 neutropenia and thrombocytopenia and grade 4 anaemias oblige suspension of treatment and an assessment of possible secondary causes should be carried out &#40;myelodysplasias&#41;&#44; especially if there is a history of RAI at high doses or prior radiotherapy<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">35</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Actions against the development of resistance to tyrosine kinase inhibitors</span><p id="par0180" class="elsevierStylePara elsevierViewall">After a favourable initial response&#44; the patient can acquire a resistance to TKI&#44; which in many cases supposes the progression of a new tumour&#46; Little is known about the causes of these resistances&#46; Two types are distinguished&#58; <span class="elsevierStyleItalic">primary</span>&#44; which has existed since the beginning of treatment&#44; and <span class="elsevierStyleItalic">secondary</span>&#44; which occurs after treatment due to the activation of compensatory activating routes that avoid the existing pharmacological blockade&#46; It has been suggested that the genetic heterogeneity in many DTC&#47;MC assumes that certain genetic alterations exist only in a sub-clonal fraction of tumour cells&#46; This fact&#44; along with the presence of secondary effects requiring suspension of treatment&#44; leads us to consider the characteristics of second-line medications&#44; often being a fundamentally palliative action&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Second-line treatment with tyrosine kinase inhibitors</span><p id="par0185" class="elsevierStylePara elsevierViewall">The optimal strategy of sequential or simultaneous TKI use has not yet been well defined&#46; In general&#44; patients who have not responded nor tolerated it&#44; and those who have had a new TKI added to their treatment will show worse results than those obtained in the first line of treatment&#46; Before the use of TKI in second line treatment&#44; the cause of failure in the initial therapy must be analysed&#46; If the failure is attributed to toxicity&#44; the secondary effect profile of the new TKI must be different from the initial TKI&#46; If the cause has been tumour progression&#44; the molecular target profile of the new TKI must be different&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a> Therefore&#44; it is unlikely that a single TKI can achieve a curative action&#46; In order to draw valid conclusions&#44; it is essential that candidate patients for second or third line treatment are enrolled in clinical trials&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Special considerations for treatment with tyrosine kinase inhibitors</span><p id="par0190" class="elsevierStylePara elsevierViewall">Patients with advanced thyroid neoplasms&#44; either refractory DTC or metastatic MC should be monitored by a multidisciplinary team&#46; The moment to start treatment with these substances should be carefully considered because secondary effects are significant and cloud the quality of life of patients without having so far shown that they prolong survival&#46; Therefore&#44; whether the patient meets the criteria for inclusion should be verified and potential candidates should be carefully selected among patients who have an advanced and progressive disease in which the benefit of treatment outweighs the deterioration that occurs&#46; The results obtained so far do not show that any particular drug is significantly superior over others and hope seems to be more powerful than reality&#46; For this reason&#44; in many cases the choice of compound will depend on various factors such as the patient&#39;s condition&#44; their access to clinical trials and the possibility of requesting the use of TKI within the modality of <span class="elsevierStyleItalic">compassionate use</span>&#46; For patients with few metastatic lesions&#44; or who follow an indolent clinical course&#44; the prudent option would be to offer other treatment options&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interest</span><p id="par0195" class="elsevierStylePara elsevierViewall">JCG has participated as an advisor for AstraZeneca&#44; Bayer HealthCare and Genzyme&#44; and has received fees from Genzyme and Merck&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">PLM declares no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Metabolic pathways in thyroid cancer"
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          "titulo" => "Approach for the patient with advanced thyroid cancer"
          "secciones" => array:3 [
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              "identificador" => "sec0030"
              "titulo" => "Refractory monitoring of the patient"
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              "titulo" => "Criteria for initiating systemic therapy"
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              "identificador" => "sec0040"
              "titulo" => "Clinical evaluation prior to initiation of treatment with tyrosine kinase inhibitors"
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          "titulo" => "Treatment with tyrosine kinase inhibitors in patients with advanced thyroid cancer"
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              "titulo" => "Clinical monitoring of the patient undergoing treatment with tyrosine kinase inhibitors"
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              "titulo" => "Evaluation of secondary effects and toxicity of treatment with tyrosine kinase inhibitors"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; L&#243;pez Mond&#233;jar P&#44; Galofr&#233; JC&#46; Nuevas terapias en el c&#225;ncer de tiroides&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;324&#8211;329&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The patient is deemed to be refractory to RAI when they meet any of the following conditions&#58; &#40;A&#41; Metastatic lesions that do not capture RAI in the initial treatment&#46; &#40;B&#41; The RAI focuses on some lesions&#44; but not on others&#46; &#40;C&#41; Lesions lose the ability to concentrate RAI after previous evidence of iodine avid disease&#46; &#40;D&#41; Lesions that progress within the last year despite concentrating RAI&#46; RAI&#58; radioactive iodine&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Category&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Non-target lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Complete response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Target lesions have disappeared&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The disappearance of all lesions and normalisation of tumour markers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Partial response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decrease of at least 30&#37; of the diameter of the largest target lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stable disease &#40;incomplete response&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A sufficient reduction has not been observed to be partial response&#44; nor an increase to be progressive disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The persistence of one or more non-target lesions and&#47;or maintenance of the concentration of tumour markers above the normal range&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Progressive disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increase of at least 20&#37; of the diameter of the largest target lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The appearance of one or more new lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">DTC&#44; differentiated thyroid cancer&#59; MC&#44; medullary cancer&#59; EGF&#44; epidermal growth factor&#59; HBP&#44; high blood pressure&#59; IC&#44; heart failure&#59; PDGF-R&#946;&#44; platelet-derived growth factor receptors&#59; RET&#44; Rearranged during transfection&#59; RET&#47;PTC&#44; Rearranged during transfection&#47;papillary thyroid carcinoma&#59; VEGF-R&#44; vascular endothelial growth factor receptor&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Compound&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Commercial name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Targets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Indication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Axitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inlyta<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 1&#44; 2 and 3&#44; PDGF-R&#946;&#44; c-Kit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HTN&#44; IC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cabozantinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cometriq<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 1 y 2&#44; PDGF-R&#946;&#44; RET&#44; c-Kit&#44; c-MET&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">140<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diarrhoea&#44; HTN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lenvatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lenvima<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 1&#44; 2 and 3&#44; RET&#44; c-KIT&#44; PDGF-R&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">HTN&#44; proteinuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pazopanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Votrient<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 1&#44; 2 and 3&#44; c-Kit&#44; PDGF-R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">800<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cutaneous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Selumetinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MEK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">75<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dermatological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nexavar<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 1&#44; 2 and 3&#44; RET&#47;PTC&#44; BRAF&#44; PDGF-R&#946;&#44; c-KIT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">400<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dermatological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sunitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sutent<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 2&#44; RET&#47;PET&#44; c-Kit&#44; PDGF-R&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vandetanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Caprelsa<span class="elsevierStyleSup">&#174;</span>&#44; Zactima<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGF-R 2 and 3&#44; RET&#44; EGF-R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arrhythmias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Zelboraf<span class="elsevierStyleSup">&#174;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DTC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">960<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">iv&#44; intravenous&#59; DBP&#44; diastolic blood pressure&#59; SBP&#44; systolic blood pressure&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Toxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Grade 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anorexia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of appetite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decreased oral intake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Accurate nutrition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Bleeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild&#59; does not require intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Accurate intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Transfusion or haemostasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleMonospace">&#60;</span>4<span class="elsevierStyleHsp" style=""></span>stools&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#8211;6<span class="elsevierStyleHsp" style=""></span>stools&#47;day&#59; requires iv fluids <span class="elsevierStyleMonospace">&#60;</span>24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;7<span class="elsevierStyleHsp" style=""></span>stools&#47;day&#59; iv fluids <span class="elsevierStyleMonospace">&#62;</span>24<span class="elsevierStyleHsp" style=""></span>h&#59; hospitalisation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dry mouth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Symptomatic without causing alteration of diet&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Symptomatic specifying increase in liquids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Symptoms that prevent eating properly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dysphagia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Can eat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cannot eat&#59; iv fluids &#60;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Iv fluids 24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Asthenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prostration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fever&#47;rigour&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38&#8211;39<span class="elsevierStyleHsp" style=""></span>&#176;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#46;1&#8211;40<span class="elsevierStyleHsp" style=""></span>&#176;C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;40<span class="elsevierStyleHsp" style=""></span>&#176;C for <span class="elsevierStyleMonospace">&#60;</span>24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;40<span class="elsevierStyleHsp" style=""></span>&#176;C for &#62;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hand&#8211;foot syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Does not interfere with daily activities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Interferes with daily activities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ulcer&#44; peeling&#44; severe pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Steven&#8211;Johnson syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SBP 120&#8211;139<span class="elsevierStyleHsp" style=""></span>mmHg or DBP 80&#8211;89<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SBP 140&#8211;160<span class="elsevierStyleHsp" style=""></span>mmHg or DBP 90&#8211;99<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SBP &#62;160<span class="elsevierStyleHsp" style=""></span>mmHg or DBP &#62;100<span class="elsevierStyleHsp" style=""></span>mmHg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support &#40;e&#46;g&#46;&#44; hypertensive crisis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Mucositis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mucosal erythema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Patchy mucosal ulceration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Extensive ulceration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tissue necrosis&#59; life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Loss of appetite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decreased intake&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Accurate nutrition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rash&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Maculopapular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rash on &#60;50&#37; body&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rash on &#8805;50&#37; body&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Exfoliative or ulcerative dermatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Unbearable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">An episode&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;5 episodes&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; iv fluids <span class="elsevierStyleMonospace">&#60;</span>24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;6&#47;24<span class="elsevierStyleHsp" style=""></span>h&#59; iv fluids &#62;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weakness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">With exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Life support&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Weight loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8211;10&#37; of baseline weight&#59; surgery not indicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;20&#37; of baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8805;20&#37; of baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertransaminasemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#8211;3 increase normal value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#8211;8 increase normal value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;8 increase normal value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyperbilirubinemia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;5&#8211;2 increase normal value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#8211;3 increase normal value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;3 increase normal value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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