Recommendations on the management of controversies in advanced castrate-resistant prostate cancer | Actas Urológicas Españolas (English Edition)

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However, there remain some uncertainties with regard to the management of the advanced disease in the castration-resistant phase, which starts with the complexity of its definition and variability in its interpretation.For these reasons, a group of experts made the decision to write this document of recommendations on the current management of castration-resistant prostate cancer (CRPC), with the aim to find the most efficient alternative, the best moment to act, and the greatest safety. This document is endorsed by the leading scientific societies and working groups involved in the current management of genitourinary tumors (the Spanish Association of Urology [AEU], the Uro-Oncology Group [GUO], and the Spanish Group of Genitourinary Oncology [SOGUG]). With the adaptation and implementation of this document of recommendations into clinical practice, we have, for the first time, a true roadmap of quality, efficiency, and safety of the management of patients with CRPC.Proposed definition of castration-resistant prostate cancer and hormone-refractory prostate cancerThe term hormone-refractory PCa (HRPC) has been used for many years to define the stage in which a patient with PCa undergoing androgen deprivation experiences a progression; however, recently, the term CRPC has been used more often. In the context of the HRPC-CRPC, there is a great heterogeneity of patients according to their clinical situation, PSA level, and presence or absence of metastatic spread. In this broad spectrum of patients, the estimated mean survival ranges from 4 years for patients with asymptomatic elevated PSA to 9–16 months of a symptomatic patient with extensive metastatic disease.The definition of resistance to castration involves biochemical and/or clinical progression (PSA) in a patient properly castrated. Therefore, the CRPC includes 2 essential conditions assessed by the panel of experts:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.Proper castration (in response to the serum testosterone level): although castration levels of testosterone with values between 20 and 50ng/dl<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> are assessed, the experts consider that, according to the scientific evidence available today, an appropriate level would be 30ng/dl.</li><li class="elsevierStyleListItem" id="lsti0010">2.A progression: in relation to the criteria of progression, the EAU guidelines consider the criteria established by the Prostate-Specific Antigen Working Group (PCWG2)<a class="elsevierStyleCrossRef" href="#bib0015">3</a> when a biochemical progression is detected. In the case that there may be clinical progressions without PSA elevation, the progression of bone lesions is considered, 2 or more on bone scan or soft-tissue injuries according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).<a class="elsevierStyleCrossRef" href="#bib0020">4</a> However, it is important to know that about 80% of these patients do not have bidimensional measurable disease, and possibly the only prognostic factor is different when there are only metastatic bone lesions or soft-tissue involvement.</li></ul>In view of these data, the definition of castration suggested is the one shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>So much for the consideration of CRPC; it would be from this moment when second-line hormonal maneuvers that will define whether PCa is still hormone sensitive (HSPC) can be started or if instead it can be regarded as as HRPC. The EAU guidelines consider that for the definition of CRPC, an antiandrogen (AA) deprivation of at least 4 weeks or performing a second hormonal manipulation and PSA progression are required.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The EAU guidelines also specify that in order to consider castration resistance at least one second-line hormonal maneuver is required. It is known that the lack of response to a second-line hormonal maneuver does not imply a lack of response to other hormonal maneuvers and it has been confirmed that, even after failure of chemotherapy (CT), the HRPC may still respond to hormone-based treatments such as androgen synthesis inhibitors through the CYP17 inhibitor pathway, like abiraterone, or the new anti-androgen receptor drugs, such as MDV3100.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>It is therefore suggested that the definition of HRPC (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) incorporates the concept of non-response to any hormonal maneuver.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Which and how many should be the second-line hormonal maneuvers?There are several second-line hormonal maneuvers following failure of androgen deprivation used as first-line therapy, according to the patient profile: withdrawal,<a class="elsevierStyleCrossRef" href="#bib0030">6</a> addition,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> or change<a class="elsevierStyleCrossRef" href="#bib0040">8</a> of the AA, adding high doses of bicalutamide,<a class="elsevierStyleCrossRef" href="#bib0045">9</a> ketoconazole,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> corticosteroids,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> or estrogens.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> The maneuvers described are sometimes used interchangeably as second or third hormonal lines. In a recent study in this regard there is a greater response rate to second and third hormonal lines after the withdrawal of the AA when there is response to previous maneuvers and even more if a steroidal AA is replaced by a non-steroidal one.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Evaluating the scientific evidence on these second hormonal maneuvers it is suggested that:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015">1.Removal of AA is an essential maneuver before any therapeutic decision, as well as adding an AA when the patient was initially treated with hormone monotherapy.</li><li class="elsevierStyleListItem" id="lsti0020">2.In patients with biochemical progression after the previous maneuvers, successive hormonal maneuvers could be provided, particularly where one response to the previous maneuvers would have been observed.</li><li class="elsevierStyleListItem" id="lsti0025">3.In asymptomatic patients in whom the second hormonal maneuvers fail, CT should be considered, although factors such as PSA kinetics can more accurately refine the candidate patient for CT.</li></ul>Which are the first-line recommendations and the prognostic tools in castration-resistant prostate cancer?PCa has traditionally been regarded as resistant to CT,<a class="elsevierStyleCrossRef" href="#bib0065">13</a> but the initial studies in the 90s<a class="elsevierStyleCrossRefs" href="#bib0070">14,15</a> that introduced mitoxantrone with low doses of corticosteroids as initial standard palliative treatment (TAX 327<a class="elsevierStyleCrossRef" href="#bib0080">16</a> and SWOG<a class="elsevierStyleCrossRef" href="#bib0085">17</a>) made the treatment with tri-weekly docetaxel plus prednisone the new standard first-line treatment for patients with CRPC.At what point should treatment with docetaxel begin?In clinical practice, the spectrum of patients who will benefit from treatment with CT is very varied. The recommendations should be individualized. CT must be offered within a multidisciplinary team and its potential benefits versus its side effects must be discussed individually with each patient.In patients with symptoms or objective progression of visceral and/or lymph node metastases, treatment with CT should not be delayed. In the asymptomatic patients, who have as the only criterion of progression elevated PSA levels, the second-line hormonal treatment could provide a similar benefit to the CT, leaving the benefit of the treatment with CT for a more advanced situation. However, the risk of progression of patients should be assessed. Those patients at greatest risk of a rapid progression should be selected as candidates for CT. In those patients in whom an hematologic toxicity greater than normality is predicted, or with initial deterioration of the general condition, treatment with weekly docetaxel may be appropriate, due to the lower hematologic toxicity expected with this schedule of administration. To summarize, <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> describes the arguments for and against the early use of CT. Although the survival gain in absolute terms is modest, we must not forget what could be more important, as the fact that a greater benefit in palliation of the patients is observed: improvement of pain, decreased use of analgesia, and improvement in the parameters of quality of life, even when considering patients aged over 70 years.<a class="elsevierStyleCrossRef" href="#bib0095">19</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>It must be emphasized that most patients will receive treatment with CT over the course of the disease, so the patient will have to be referred to a medical oncologist to determine the best time to start this treatment. Furthermore, delaying a therapy that can prolong life and reduce pain could be ethically unacceptable.What is the role of the doubling time of the prostate specific antigen?Multiple published studies have highlighted the interest of the prostate specific antigen doubling time (PSA-DT) as a significant prognostic marker in different stages of the disease, including metastatic CRPC. Oudard assessed the usefulness of PSA-DT before the CT as a surrogate marker of survival in the CRPC in a retrospective study, which found that the median survival was significantly lower (16.5 months) if the PSA-DT was shorter than 45 days, compared to 26.4 months if the PSA-DT was longer than 45 days.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> In different studies, it is confirmed that the PSA response rate to the CT in the CRPC correlates with survival and is accepted as a measure of the potential benefit to the patient.<a class="elsevierStyleCrossRefs" href="#bib0100">20–22</a> Hussain reported the results of a retrospective study of 1015 patients in whom the PSA progression, defined by the PCWG 1 and 2, correlated with the survival in the HSPC and HRPC, and therefore, it was a potent predictor of survival, and the PSA progression is considered a good primary variable for the phase-II trials.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Therefore, today, we recommend the assessment of the PSA kinetics and it can help in making decisions, especially in those cases with no clear indication for CT, such as asymptomatic patients or with exclusive biochemical progression, since it reports the prognosis and the potential benefit of the early CT.What information do prognostic nomograms provide?Several nomograms have been published<a class="elsevierStyleCrossRefs" href="#bib0120">24–26</a> based on prognostic variables analyzed in patients treated with CT in the pre-docetaxel era, of which the Armstrong nomogram stands out, incorporating the PSA kinetics to predict survival at 1, 2, and 5 years in patients with CRPC treated with CT, and including new independent clinical factors, which makes it a useful tool for stratifying patients in trials.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> In clinical practice, they are not often used, since their usefulness is limited when deciding the best time to start treatment with CT.Which should be considered criteria for progression in castration-resistant prostate cancer?In order to assess the criteria for progression and disease assessment in patients with CRPC, a new consensus was published in 2008 (PCWG2), whose implementation is suggested (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). The modification of the old criteria with the new ones makes it possible to select to the maximum the patients to be included in clinical trials, and so we can assess the effectiveness of new treatments.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> One of the key concepts introduced by the PCWG2 is that it defines 5 groups of patients with very different prognosis and natural history of the different disease (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Despite clarifying certain criteria, most studies on CRPC use those of PCWG2 modified. These modifications generally introduce the following changes:<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030">1.They use the RECIST 1.1 criteria in which the size of the adenopathies smaller than 1.5cm is not taken into account.</li><li class="elsevierStyleListItem" id="lsti0035">2.They use the radiographic progression criteria, which are not covered by the PCWG2, published by the Memorial Sloan Kettering Cancer Center group and based on a study of retrospective characteristics in which 98 patients of whom 63 had measurable disease are analyzed.<a class="elsevierStyleCrossRef" href="#bib0135">27</a></li><li class="elsevierStyleListItem" id="lsti0040">3.In the last year there have been different drugs that have proven useful in the treatment of CRPC once it has progressed after docetaxel. Therefore, it is important to know what the prognostic factors of disease progression in this situation are. In this sense, a paper by Armstrong et al.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> has recently been published in which the statistically significant prognostic factors of progression after docetaxel (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>) are analyzed. With the selected variables of this model, we can generate a nomogram that estimates the survival after progression.<a class="elsevierStyleCrossRef" href="#bib0140">28</a><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></li></ul>Treatment of progression after docetaxel: chemotherapy versus hormone therapyOne of the reasons given for delaying the cytostatic treatment of the asymptomatic disease was the lack of therapeutic alternatives.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> This preconception should be reviewed with the arrival of new drugs effective in docetaxel progression: FDA approved cabazitaxel (June 2010), EMA approved cabazitaxel (March 2011), FDA approved abiraterone (April 2011), and EMA approved abiraterone (September 2011).Currently, cabazitaxel is considered the second-line treatment of choice, after having shown in the TROPIC<a class="elsevierStyleCrossRef" href="#bib0150">30</a> clinical trial 30% survival benefit compared to mitoxantrone (15.1 months versus 12.7 months, respectively) in patients with CRPC who had progressed during or after the treatment with docetaxel. Cabazitaxel demonstrated a survival benefit even in groups of patients with a poor prognosis. The secondary objectives of the study, progression-free survival, PSA response and response rate were also favorable to cabazitaxel. Other secondary objectives, such as pain reduction, were similar in both arms (9.2% cabazitaxel vs. 7.7% mitoxantrone), so the already demonstrated analgesic effect of mitoxantrone to cabazitaxel can be extrapolated.In hormone therapy, the arrival of abiraterone hormone has confirmed the assumption of the relative hormonone refractoriness of CRPC and the need to redefine hormone refractoriness and progression to docetaxel. Abiraterone has recently demonstrated an increase in overall survival in a phase-III study, in which it was compared to placebo plus steroids in patients with metastatic CRPC who had failed CT treatment with regimens including docetaxel.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> The patients who received abiraterone showed an increase in overall survival of 4.6 months (15.8 vs. 11.2 months), delay of progression-free survival, and a benefit in pain control over placebo. Its main drawback is that its inhibitory action causes a decrease in the serum cortisol levels, which in turn may cause increased ACTH and the subsequent risk of hypokalemia and hypertension, which can be avoided by the concomitant administration of prednisone.But chemotherapy or second-line hormone therapy?Pending the availability of predictive factors of response, the choice of one or another treatment should be based on the clinical features and the analysis of the toxicities observed in phase-III trials. With the development of new drugs that not only increase survival but also delay the complications of metastases, new expectations have been generated for both patients and specialists. It is clinical practice which will have to confirm these good results and the profiles of candidate patients for each of the treatments.In this sense, cabazitaxel is already presented as a reality and it is considered as the standard treatment of choice in metastatic CRPC after failure of docetaxel.Which new treatments are being studied?Between 2004 and 2010, the research focused on various combinations of docetaxel with other agents in order to increase this survival benefit. The results have been disappointing: combinations with calcitriol,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> bevacizumab,<a class="elsevierStyleCrossRef" href="#bib0160">32</a> G-VAX,<a class="elsevierStyleCrossRef" href="#bib0165">33</a> and oblimersen (Bcl-2 antisense oligonucleotide),<a class="elsevierStyleCrossRef" href="#bib0170">34</a> or zibotentan<a class="elsevierStyleCrossRef" href="#bib0175">35</a> have not shown increased survival compared to docetaxel alone.The years 2010 and 2011 can be considered exceptional for the research on CRPC with 4 phase-III studies with positive results, showing increased survival: the aforementioned cabazitaxel and abiraterone, and sipuleucel-T and alpharadin studies. On the other hand, we must emphasize other hormonal agents such as MDV3100 (Medivation®) and denosumab, which has proved to significantly decrease the incidence of bone events compared to zoledronic acid.Sipuleucel-T is an autologous cellular immunotherapy that in a phase-III study has demonstrated a 22% reduction in mortality, compared to placebo (25.8 months versus 21.7 months, respectively), in patients with asymptomatic or minimally symptomatic CRPC that had not been previously treated with docetaxel.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> In the clinical trial, no effect on the progression-free time was shown. It is approved in the U.S. for the treatment of CRPC, but not in Europe.Alpharadin (Radium 232), particle emitter radioisotope drug craving for areas with bone neoformation, such as prostate cancer metastases,<a class="elsevierStyleCrossRef" href="#bib0185">37</a> induces a primary lesion not repairable in the DNA of the adjacent tumor cells. In the phase-II trial in symptomatic metastatic castration-resistant patients, it showed 40% increase in overall survival. A phase-III study (ALSYMPCA) has achieved its primary objective to increase survival by 44%, with a median overall survival of 14 months compared to the 11.2 months in the placebo group.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>The MDV3100 (Medivation®) is a hormonal agent that acts as an inhibitor of the androgen receptor blocking its passage to the core and its activation. After a phase I/II trial which obtained 56% of responses in terms of declines in the PSA and 22% of radiological responses,<a class="elsevierStyleCrossRef" href="#bib0195">39</a> data of the phase-III trial regarding its postdocetaxel effectiveness (AFFIRM) have been published to confirm its effectiveness, data that have forced to close the study prematurely and that will lead to its approval (median overall survival of 18.4 months for patients treated with MDV 3100 vs 13.6 months in patients treated with placebo).<a class="elsevierStyleCrossRef" href="#bib0200">40</a>In July 2011, denosumab was approved by the EMA for the prevention of skeletal-related events (SREs: pathologic fracture, bone radiotherapy, spinal cord compression, and bone surgery) in adults with bone metastases from solid tumors. Denosumab is a human monoclonal antibody against the ligand of the receptor activator of nuclear factor kB (RANKL) that has shown better results than zoledronic acid in a phase-III study in patients with CRPC for the prevention of SREs.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>An essential precondition: the multidisciplinary approach of castration-resistant prostate cancerCurrently, due to the acquired complexity of the management of patients with CRPC, it is necessary to incorporate multidisciplinary opinions to the process associated with the establishment of their care plan. Only in this way we can ensure that the right diagnostic, therapeutic, and rehabilitation decisions are made, optimizing the results of cancer treatment. The Clinical Practice Guideline of the EUA on CRPC explicitly recommends that the treatment of these patients is addressed by multidisciplinary teams.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Its implementation should be a priority in the health care of patients with CRPC.Given that the vision of the problem can only be addressed by a multidisciplinary team of professionals, we suggest the need to create a Multidisciplinary Committee at each center which will treat these patients, since only then continuous and comprehensive care of the entire process of this disease can be ensured. These committees would ideally be integrated by professionals from different disciplines: urology, medical oncology, and radiation oncology, nuclear medicine, radiodiagnosis, pathological anatomy, without forgetting the support of units of pain and palliative, psychological care, as well as primary care and nursing professionals. In order to assist in the creation and improvement of these multidisciplinary committees, the AEU, SOGUG, and SEOR published in 2012 a practical manual on the organization and functioning of the multidisciplinary uro-oncology committees.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>ConclusionsThis document is the result of the work by a multidisciplinary group of experts, supported by the relevant scientific societies of the specialties that have worked on it, and in which the basis for the proper management of the patient with CRPC are trying to be established.For the definition of CRPC, we exclusively consider the patients undergoing castration with a total serum testosterone below 30ng/dl plus 3 consecutive increases of PSA, or a clinical progression without PSA elevation, while the HRPC is defined by the lack of response of a CRPC to any hormonal maneuver, including second-line, such as the withdrawal of the AA which is essential before any therapeutic decision, as well as adding an AA when the patient was initially treated with hormonal monotherapy. In patients with biochemical relapse after the previous maneuvers, successive hormonal maneuvers could be provided. In asymptomatic patients in whom the second hormonal maneuvers fail, CT should be considered.Most patients will receive treatment with CT with docetaxel at some point over the course of the disease. Today we recommend evaluating the PSA kinetics and it can help in those cases with no clear indication of the beginning of treatment with CT, such as asymptomatic patients or with exclusive biochemical progression, as it reports the prognosis and the potential benefit of early CT. Delaying a therapy that can prolong life and achieve adequate symptom control might be ethically unacceptable, and if it is finally decided to treat the patient with docetaxel, after failure thereof, cabazitaxel is presented as a valid option in patients that maintain their tolerability to these treatments, and it is considered the standard treatment of choice in metastatic CRPC. Furthermore, the therapeutic horizon of PCa opens dramatically with the advent of new drugs such as abiraterone, sipuleucel T, alpharadin, MDV3100, etc., which will possibly continue changing positively the course of this disease.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>As we have observed throughout the article, the management of the patients with CRPC is really complex, so the EUA explicitly recommends, in its Clinical Practice Guidelines, that the treatment of these patients is addressed by multidisciplinary teams, therefore, we aim to create a Multidisciplinary Committee at each center to ensure continuous and comprehensive care of the whole process of this disease.Conflict of interestThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:2 [ "identificador" => "xres102016" "titulo" => array:6 [ 0 => "Abstract" 1 => "Context" 2 => "Objective" 3 => "Evidence Acquisition" 4 => "Evidence Synthesis" 5 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec89183" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres102017" "titulo" => array:6 [ 0 => "Resumen" 1 => "Contexto" 2 => "Objetivo" 3 => "Adquisición de la Evidencia" 4 => "Síntesis de la Evidencia" 5 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec89182" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Proposed definition of castration-resistant prostate cancer and hormone-refractory prostate cancer" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Which and how many should be the second-line hormonal maneuvers?" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Which are the first-line recommendations and the prognostic tools in castration-resistant prostate cancer?" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "At what point should treatment with docetaxel begin?" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "What is the role of the doubling time of the prostate specific antigen?" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "What information do prognostic nomograms provide?" ] ] ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Which should be considered criteria for progression in castration-resistant prostate cancer?" ] 9 => array:3 [ "identificador" => "sec0045" "titulo" => "Treatment of progression after docetaxel: chemotherapy versus hormone therapy" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "But chemotherapy or second-line hormone therapy?" ] ] ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Which new treatments are being studied?" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "An essential precondition: the multidisciplinary approach of castration-resistant prostate cancer" ] 12 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusions" ] 13 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interest" ] 14 => array:2 [ "identificador" => "xack35411" "titulo" => "Acknowledgement" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-05-22" "fechaAceptado" => "2012-06-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec89183" "palabras" => array:6 [ 0 => "Prostate cancer" 1 => "CRPC" 2 => "HRPC" 3 => "Controversies" 4 => "Docetaxel" 5 => "Cabazitaxel" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec89182" "palabras" => array:6 [ 0 => "Cáncer de próstata" 1 => "CPRC" 2 => "CPHR" 3 => "Controversias" 4 => "Docetaxel" 5 => "Cabazitaxel" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus. ObjectiveTo develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety. Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (oncologist and urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease. Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG). ConclusionsWith the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ContextoEn el manejo integral del cáncer de próstata avanzado resistente a la castración siguen existiendo incertidumbres y controversias a pesar de la existencia de numerosas guías de práctica clínica basadas en la evidencia, internacionalmente consensuadas. ObjetivoElaborar un documento en el que se revise el manejo de controversias en el cáncer de próstata avanzado resistente a la castración con recomendaciones desde su definición hasta el manejo de maniobras hormonales y el tratamiento de primera y segunda línea con nuevos fármacos como cabacitaxel y abiraterona, así como el abordaje multidisciplinar de la patología con el objetivo de buscar la alternativa más eficiente, el mejor momento de actuar y la mayor seguridad. Adquisición de la EvidenciaSe realizaron 2 reuniones de un grupo de expertos multidisciplinares implicados en el manejo de esta enfermedad (urólogos y oncólogos) donde se pusieron en común el análisis bibliográfico de artículos originales y se consensuó este documento de recomendaciones sobre el cáncer de próstata resistente a la castración, revisando e intentando dar respuesta a las actuales controversias de la enfermedad. Síntesis de la EvidenciaEste documento está avalado por las principales Sociedades Científicas y grupos de trabajo implicados en el manejo actual de los tumores genitourinarios: la Asociación Española de Urología (AEU), el Grupo de Urología Oncológica (GUO) y el Grupo Español de Oncología Genitourinaria (SOGUG). ConclusionesCon la adaptación e implementación de este Documento de Recomendaciones a la práctica clínica se dispone, por primera vez, de una verdadera hoja de ruta de calidad, eficiencia y seguridad del manejo de los pacientes con cáncer de próstata avanzado resistente a la castración." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Cózar JM, et al. Recomendaciones sobre el manejo de controversias en cáncer de próstata avanzado resistente a la castración. Actas Urol Esp. 2012;36:569–77." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Consider only patients undergoing castration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">And total serum testosterone below 30ng/dl<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">And 3 consecutive PSA increases, in minimum intervals of one week, resulting in 2 increases of at least 50% above the PSA nadir, with a PSA greater than 2ng/ml \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Or clinical progression without PSA elevation. Two or more new lesions on bone scan or RECIST 1.1 criteria for soft tissue lesions \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184418.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "If serum testosterone is confirmed >30ng/dl, consider inadequate castration and assess other forms of castration (the EAU guidelines considers 50ng/dl). EAU: European Association of Urology; PSA: Prostate-Specific Antigen; RECIST: Response Evaluation Criteria in Solid Tumors." ] ] ] "descripcion" => array:1 [ "en" => "Proposed definition of castration-resistant prostate cancer." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patient with CRPC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">And failure to answer all and any hormonal-base maneuvers<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184417.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Lack of response will be assessed as biochemical progression (3 consecutive increases of prostate specific antigen (PSA) at minimum intervals of one week, resulting in 2 increases of at least 50% on the previous PSA to every hormonal maneuver) or clinical progression without elevated PSA (2 or more new lesions on bone scan or Response Evaluation Criteria in Solid Tumors 1.1 for soft tissue lesions). CRPC: castration-resistant prostate cancer." ] ] ] "descripcion" => array:1 [ "en" => "Proposed definition of hormone refractory prostate cancer." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "CRPC: castration-resistant prostate cancer; FDA: Food and Drug Administration; CT: chemotherapy." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arguments for \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arguments against \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The benefit demonstrated in other solid tumors, both of efficiency and pain reductionThe low rate of androgen-independent clones at the beginning of the disease that favors a priori greater efficiency of the CT. From 2010 with the FDA approval of the use of cabazitaxel in CRPC<a class="elsevierStyleCrossRef" href="#bib0090">18</a>, we have second lines of treatment after failure of docetaxel that have shown a clear clinical benefit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The possibility of rapid induction of resistances by their early useThere is no difference in hazard ratio of death according to prescribing treatment in symptomatic versus asymptomatic patients (same end result)Deterioration in the quality of life of patients by the adverse effects of the toxicity of the CT \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184416.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Arguments for and against the early use of chemotherapy." ] ] 3 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "CRPC: castration-resistant prostate cancer; PCWG: Prostate Specific Antigen Working Group; PET: positron emission tomography; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; MRI: magnetic resonance imaging; CT: computed tomography." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Variable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PCWG2 criteria \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Assess PSA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Obtain the sequence of elevation of the values at weekly intervals at leastInitial minimum value 2.0ng/mlAssess the pre-treatment PSA doubling time if there are 3 or more separated values every 4 weeks or more \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Target lesions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">The presence of lymph node or visceral lesions is enough to enter a study, regardless of the PSANo measurable lesions are required for the inclusionUse RECIST criteria to assess the soft-tissue lesions (lymph node or visceral) as a target or no targetOnly the lymph nodes ≥2cm diameter to assess its change in sizeRegister the presence of lymph node and/or visceral disease separately \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary location of the tumor in the prostate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Register the previous therapeutic treatment of the primary tumorPerform pelvic imaging scans (CT, MRI, PET/CT, endorectal MRI, transrectal ultrasound) to document the presence or absence of disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progression is considered when there are 2 or more new lesionsConfirm the ambiguous results with other imaging tests (CT o MRI) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other locations of the diasease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Patients with epidural lesions treated without epidural progression are eligible if another criteria for inclusion is met \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184420.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Criteria for progression and assessment of the disease in CRPC." ] ] 4 => array:7 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "PSA: prostate-specific antigen." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Subtype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Pattern of proliferation \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Local tumor progression without metastatic disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased PSA in patient at testosterone suppression but without metastatic involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nodal spread but without evidence of bone or visceral involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bone involvement with or without lymph node involvement but absence of visceral metastases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Visceral metastases \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184419.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical subtypes based on the patterns of prostate cancer proliferation." ] ] 5 => array:7 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "PSA: prostate-specific antigen; CT: chemotherapy." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PreCT variables \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PostCT variables \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Progression in the first line of CT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">General condition of Karnofsky \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of factors of progression (PSA, pain) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alkaline phosphatase level \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of cycles of 3 weeks of the first line of CT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of metastatic sites \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presence of hepatic metastases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemoglobin values \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PSA value \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Period of time from diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184421.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Prognostic factors before and after the use of the CT." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:43 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. 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Recommendations on the management of controversies in advanced castrate-resistant prostate cancer

Recomendaciones sobre el manejo de controversias en cáncer de próstata avanzado resistente a la castración

J.M. Cózara,

Corresponding author

cozarjm@yahoo.es

Corresponding author.

, E. Solsonab, J. Morotec, B. Miñanad, J.P. Marotoe, A. González del Albaf, M.Á. Climentg, J. Carlesh, A. Alcarazi, D. Castellanoj

a Servicio de Urología, Hospital Universitario Virgen de las Nieves, Granada, Spain

b Servicio de Urología, Instituto Valenciano de Oncología (IVO), Valencia, Spain

c Servicio de Urología, Hospital Universitario Vall d’Hebron, Barcelona, Spain

d Servicio de Urología, Hospital Morales Meseguer, Murcia, Spain

e Servicio de Oncología, Hospital Sant Pau, Barcelona, Spain

f Servicio de Oncología, Hospital Universitario Son Espases, Palma de Mallorca, Spain

g Servicio de Oncología, Instituto Valenciano de Oncología (IVO), Valencia, Spain

h Servicio de Oncología, Instituto de Oncología de la Vall d¿Hebron, Barcelona, Spain

i Servicio de Urología, IDIBAPS, Hospital Clínic, Barcelona, Spain

j Servicio de Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain

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        "titulo" => "Recomendaciones sobre el manejo de controversias en c&#225;ncer de pr&#243;stata avanzado resistente a la castraci&#243;n"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Numerous clinical guidelines based on evidence show the diagnostic&#8211;therapeutic decision algorithms at the different stages of prostate cancer &#40;PCa&#41;&#44; with broad consensus on them&#46; However&#44; there remain some uncertainties with regard to the management of the advanced disease in the castration-resistant phase&#44; which starts with the complexity of its definition and variability in its interpretation&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">For these reasons&#44; a group of experts made the decision to write this document of recommendations on the current management of castration-resistant prostate cancer &#40;CRPC&#41;&#44; with the aim to find the most efficient alternative&#44; the best moment to act&#44; and the greatest safety&#46; This document is endorsed by the leading scientific societies and working groups involved in the current management of genitourinary tumors &#40;the Spanish Association of Urology &#91;AEU&#93;&#44; the Uro-Oncology Group &#91;GUO&#93;&#44; and the Spanish Group of Genitourinary Oncology &#91;SOGUG&#93;&#41;&#46; With the adaptation and implementation of this document of recommendations into clinical practice&#44; we have&#44; for the first time&#44; a true roadmap of quality&#44; efficiency&#44; and safety of the management of patients with CRPC&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Proposed definition of castration-resistant prostate cancer and hormone-refractory prostate cancer</span><p id="par0015" class="elsevierStylePara elsevierViewall">The term hormone-refractory PCa &#40;HRPC&#41; has been used for many years to define the stage in which a patient with PCa undergoing androgen deprivation experiences a progression&#59; however&#44; recently&#44; the term CRPC has been used more often&#46; In the context of the HRPC-CRPC&#44; there is a great heterogeneity of patients according to their clinical situation&#44; PSA level&#44; and presence or absence of metastatic spread&#46; In this broad spectrum of patients&#44; the estimated mean survival ranges from 4 years for patients with asymptomatic elevated PSA to 9&#8211;16 months of a symptomatic patient with extensive metastatic disease&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The definition of resistance to castration involves biochemical and&#47;or clinical progression &#40;PSA&#41; in a patient properly castrated&#46; Therefore&#44; the CRPC includes 2 essential conditions assessed by the panel of experts&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Proper castration &#40;in response to the serum testosterone level&#41;&#58; although castration levels of testosterone with values between 20 and 50<span class="elsevierStyleHsp" style=""></span>ng&#47;dl<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> are assessed&#44; the experts consider that&#44; according to the scientific evidence available today&#44; an appropriate level would be 30<span class="elsevierStyleHsp" style=""></span>ng&#47;dl&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">A progression&#58; in relation to the criteria of progression&#44; the EAU guidelines consider the criteria established by the Prostate-Specific Antigen Working Group &#40;PCWG2&#41;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> when a biochemical progression is detected&#46; In the case that there may be clinical progressions without PSA elevation&#44; the progression of bone lesions is considered&#44; 2 or more on bone scan or soft-tissue injuries according to Response Evaluation Criteria in Solid Tumors &#40;RECIST 1&#46;1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However&#44; it is important to know that about 80&#37; of these patients do not have bidimensional measurable disease&#44; and possibly the only prognostic factor is different when there are only metastatic bone lesions or soft-tissue involvement&#46;</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall">In view of these data&#44; the definition of castration suggested is the one shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">So much for the consideration of CRPC&#59; it would be from this moment when second-line hormonal maneuvers that will define whether PCa is still hormone sensitive &#40;HSPC&#41; can be started or if instead it can be regarded as as HRPC&#46; The EAU guidelines consider that for the definition of CRPC&#44; an antiandrogen &#40;AA&#41; deprivation of at least 4 weeks or performing a second hormonal manipulation and PSA progression are required&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The EAU guidelines also specify that in order to consider castration resistance at least one second-line hormonal maneuver is required&#46; It is known that the lack of response to a second-line hormonal maneuver does not imply a lack of response to other hormonal maneuvers and it has been confirmed that&#44; even after failure of chemotherapy &#40;CT&#41;&#44; the HRPC may still respond to hormone-based treatments such as androgen synthesis inhibitors through the CYP17 inhibitor pathway&#44; like abiraterone&#44; or the new anti-androgen receptor drugs&#44; such as MDV3100&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">It is therefore suggested that the definition of HRPC &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; incorporates the concept of non-response to any hormonal maneuver&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Which and how many should be the second-line hormonal maneuvers&#63;</span><p id="par0050" class="elsevierStylePara elsevierViewall">There are several second-line hormonal maneuvers following failure of androgen deprivation used as first-line therapy&#44; according to the patient profile&#58; withdrawal&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> addition&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> or change<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> of the AA&#44; adding high doses of bicalutamide&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> ketoconazole&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> corticosteroids&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> or estrogens&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The maneuvers described are sometimes used interchangeably as second or third hormonal lines&#46; In a recent study in this regard there is a greater response rate to second and third hormonal lines after the withdrawal of the AA when there is response to previous maneuvers and even more if a steroidal AA is replaced by a non-steroidal one&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Evaluating the scientific evidence on these second hormonal maneuvers it is suggested that&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">1&#46;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Removal of AA is an essential maneuver before any therapeutic decision&#44; as well as adding an AA when the patient was initially treated with hormone monotherapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">2&#46;</span><p id="par0065" class="elsevierStylePara elsevierViewall">In patients with biochemical progression after the previous maneuvers&#44; successive hormonal maneuvers could be provided&#44; particularly where one response to the previous maneuvers would have been observed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">3&#46;</span><p id="par0070" class="elsevierStylePara elsevierViewall">In asymptomatic patients in whom the second hormonal maneuvers fail&#44; CT should be considered&#44; although factors such as PSA kinetics can more accurately refine the candidate patient for CT&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Which are the first-line recommendations and the prognostic tools in castration-resistant prostate cancer&#63;</span><p id="par0075" class="elsevierStylePara elsevierViewall">PCa has traditionally been regarded as resistant to CT&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> but the initial studies in the 90s<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> that introduced mitoxantrone with low doses of corticosteroids as initial standard palliative treatment &#40;TAX 327<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and SWOG<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#41; made the treatment with tri-weekly docetaxel plus prednisone the new standard first-line treatment for patients with CRPC&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">At what point should treatment with docetaxel begin&#63;</span><p id="par0080" class="elsevierStylePara elsevierViewall">In clinical practice&#44; the spectrum of patients who will benefit from treatment with CT is very varied&#46; The recommendations should be individualized&#46; CT must be offered within a multidisciplinary team and its potential benefits versus its side effects must be discussed individually with each patient&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In patients with symptoms or objective progression of visceral and&#47;or lymph node metastases&#44; treatment with CT should not be delayed&#46; In the asymptomatic patients&#44; who have as the only criterion of progression elevated PSA levels&#44; the second-line hormonal treatment could provide a similar benefit to the CT&#44; leaving the benefit of the treatment with CT for a more advanced situation&#46; However&#44; the risk of progression of patients should be assessed&#46; Those patients at greatest risk of a rapid progression should be selected as candidates for CT&#46; In those patients in whom an hematologic toxicity greater than normality is predicted&#44; or with initial deterioration of the general condition&#44; treatment with weekly docetaxel may be appropriate&#44; due to the lower hematologic toxicity expected with this schedule of administration&#46; To summarize&#44; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> describes the arguments for and against the early use of CT&#46; Although the survival gain in absolute terms is modest&#44; we must not forget what could be more important&#44; as the fact that a greater benefit in palliation of the patients is observed&#58; improvement of pain&#44; decreased use of analgesia&#44; and improvement in the parameters of quality of life&#44; even when considering patients aged over 70 years&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">It must be emphasized that most patients will receive treatment with CT over the course of the disease&#44; so the patient will have to be referred to a medical oncologist to determine the best time to start this treatment&#46; Furthermore&#44; delaying a therapy that can prolong life and reduce pain could be ethically unacceptable&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What is the role of the doubling time of the prostate specific antigen&#63;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Multiple published studies have highlighted the interest of the prostate specific antigen doubling time &#40;PSA-DT&#41; as a significant prognostic marker in different stages of the disease&#44; including metastatic CRPC&#46; Oudard assessed the usefulness of PSA-DT before the CT as a surrogate marker of survival in the CRPC in a retrospective study&#44; which found that the median survival was significantly lower &#40;16&#46;5 months&#41; if the PSA-DT was shorter than 45 days&#44; compared to 26&#46;4 months if the PSA-DT was longer than 45 days&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In different studies&#44; it is confirmed that the PSA response rate to the CT in the CRPC correlates with survival and is accepted as a measure of the potential benefit to the patient&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#8211;22</span></a> Hussain reported the results of a retrospective study of 1015 patients in whom the PSA progression&#44; defined by the PCWG 1 and 2&#44; correlated with the survival in the HSPC and HRPC&#44; and therefore&#44; it was a potent predictor of survival&#44; and the PSA progression is considered a good primary variable for the phase-II trials&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Therefore&#44; today&#44; we recommend the assessment of the PSA kinetics and it can help in making decisions&#44; especially in those cases with no clear indication for CT&#44; such as asymptomatic patients or with exclusive biochemical progression&#44; since it reports the prognosis and the potential benefit of the early CT&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What information do prognostic nomograms provide&#63;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Several nomograms have been published<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;26</span></a> based on prognostic variables analyzed in patients treated with CT in the pre-docetaxel era&#44; of which the Armstrong nomogram stands out&#44; incorporating the PSA kinetics to predict survival at 1&#44; 2&#44; and 5 years in patients with CRPC treated with CT&#44; and including new independent clinical factors&#44; which makes it a useful tool for stratifying patients in trials&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In clinical practice&#44; they are not often used&#44; since their usefulness is limited when deciding the best time to start treatment with CT&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Which should be considered criteria for progression in castration-resistant prostate cancer&#63;</span><p id="par0110" class="elsevierStylePara elsevierViewall">In order to assess the criteria for progression and disease assessment in patients with CRPC&#44; a new consensus was published in 2008 &#40;PCWG2&#41;&#44; whose implementation is suggested &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; The modification of the old criteria with the new ones makes it possible to select to the maximum the patients to be included in clinical trials&#44; and so we can assess the effectiveness of new treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> One of the key concepts introduced by the PCWG2 is that it defines 5 groups of patients with very different prognosis and natural history of the different disease &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Despite clarifying certain criteria&#44; most studies on CRPC use those of PCWG2 modified&#46; These modifications generally introduce the following changes&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">1&#46;</span><p id="par0120" class="elsevierStylePara elsevierViewall">They use the RECIST 1&#46;1 criteria in which the size of the adenopathies smaller than 1&#46;5<span class="elsevierStyleHsp" style=""></span>cm is not taken into account&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">2&#46;</span><p id="par0125" class="elsevierStylePara elsevierViewall">They use the radiographic progression criteria&#44; which are not covered by the PCWG2&#44; published by the <span class="elsevierStyleItalic">Memorial Sloan Kettering Cancer Center</span> group and based on a study of retrospective characteristics in which 98 patients of whom 63 had measurable disease are analyzed&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">3&#46;</span><p id="par0130" class="elsevierStylePara elsevierViewall">In the last year there have been different drugs that have proven useful in the treatment of CRPC once it has progressed after docetaxel&#46; Therefore&#44; it is important to know what the prognostic factors of disease progression in this situation are&#46; In this sense&#44; a paper by Armstrong et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> has recently been published in which the statistically significant prognostic factors of progression after docetaxel &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41; are analyzed&#46; With the selected variables of this model&#44; we can generate a nomogram that estimates the survival after progression&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment of progression after docetaxel&#58; chemotherapy versus hormone therapy</span><p id="par0135" class="elsevierStylePara elsevierViewall">One of the reasons given for delaying the cytostatic treatment of the asymptomatic disease was the lack of therapeutic alternatives&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> This preconception should be reviewed with the arrival of new drugs effective in docetaxel progression&#58; FDA approved cabazitaxel &#40;June 2010&#41;&#44; EMA approved cabazitaxel &#40;March 2011&#41;&#44; FDA approved abiraterone &#40;April 2011&#41;&#44; and EMA approved abiraterone &#40;September 2011&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Currently&#44; cabazitaxel is considered the second-line treatment of choice&#44; after having shown in the TROPIC<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> clinical trial 30&#37; survival benefit compared to mitoxantrone &#40;15&#46;1 months versus 12&#46;7 months&#44; respectively&#41; in patients with CRPC who had progressed during or after the treatment with docetaxel&#46; Cabazitaxel demonstrated a survival benefit even in groups of patients with a poor prognosis&#46; The secondary objectives of the study&#44; progression-free survival&#44; PSA response and response rate were also favorable to cabazitaxel&#46; Other secondary objectives&#44; such as pain reduction&#44; were similar in both arms &#40;9&#46;2&#37; cabazitaxel vs&#46; 7&#46;7&#37; mitoxantrone&#41;&#44; so the already demonstrated analgesic effect of mitoxantrone to cabazitaxel can be extrapolated&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In hormone therapy&#44; the arrival of abiraterone hormone has confirmed the assumption of the relative hormonone refractoriness of CRPC and the need to redefine hormone refractoriness and progression to docetaxel&#46; Abiraterone has recently demonstrated an increase in overall survival in a phase-III study&#44; in which it was compared to placebo plus steroids in patients with metastatic CRPC who had failed CT treatment with regimens including docetaxel&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The patients who received abiraterone showed an increase in overall survival of 4&#46;6 months &#40;15&#46;8 vs&#46; 11&#46;2 months&#41;&#44; delay of progression-free survival&#44; and a benefit in pain control over placebo&#46; Its main drawback is that its inhibitory action causes a decrease in the serum cortisol levels&#44; which in turn may cause increased ACTH and the subsequent risk of hypokalemia and hypertension&#44; which can be avoided by the concomitant administration of prednisone&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">But chemotherapy or second-line hormone therapy&#63;</span><p id="par0150" class="elsevierStylePara elsevierViewall">Pending the availability of predictive factors of response&#44; the choice of one or another treatment should be based on the clinical features and the analysis of the toxicities observed in phase-III trials&#46; With the development of new drugs that not only increase survival but also delay the complications of metastases&#44; new expectations have been generated for both patients and specialists&#46; It is clinical practice which will have to confirm these good results and the profiles of candidate patients for each of the treatments&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In this sense&#44; cabazitaxel is already presented as a reality and it is considered as the standard treatment of choice in metastatic CRPC after failure of docetaxel&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Which new treatments are being studied&#63;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Between 2004 and 2010&#44; the research focused on various combinations of docetaxel with other agents in order to increase this survival benefit&#46; The results have been disappointing&#58; combinations with calcitriol&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> bevacizumab&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> G-VAX&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> and oblimersen &#40;Bcl-2 antisense oligonucleotide&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> or zibotentan<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> have not shown increased survival compared to docetaxel alone&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The years 2010 and 2011 can be considered exceptional for the research on CRPC with 4 phase-III studies with positive results&#44; showing increased survival&#58; the aforementioned cabazitaxel and abiraterone&#44; and sipuleucel-T and alpharadin studies&#46; On the other hand&#44; we must emphasize other hormonal agents such as MDV3100 &#40;Medivation<span class="elsevierStyleSup">&#174;</span>&#41; and denosumab&#44; which has proved to significantly decrease the incidence of bone events compared to zoledronic acid&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Sipuleucel-T is an autologous cellular immunotherapy that in a phase-III study has demonstrated a 22&#37; reduction in mortality&#44; compared to placebo &#40;25&#46;8 months versus 21&#46;7 months&#44; respectively&#41;&#44; in patients with asymptomatic or minimally symptomatic CRPC that had not been previously treated with docetaxel&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In the clinical trial&#44; no effect on the progression-free time was shown&#46; It is approved in the U&#46;S&#46; for the treatment of CRPC&#44; but not in Europe&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Alpharadin &#40;Radium 232&#41;&#44; particle emitter radioisotope drug craving for areas with bone neoformation&#44; such as prostate cancer metastases&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> induces a primary lesion not repairable in the DNA of the adjacent tumor cells&#46; In the phase-II trial in symptomatic metastatic castration-resistant patients&#44; it showed 40&#37; increase in overall survival&#46; A phase-III study &#40;ALSYMPCA&#41; has achieved its primary objective to increase survival by 44&#37;&#44; with a median overall survival of 14 months compared to the 11&#46;2 months in the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The MDV3100 &#40;Medivation<span class="elsevierStyleSup">&#174;</span>&#41; is a hormonal agent that acts as an inhibitor of the androgen receptor blocking its passage to the core and its activation&#46; After a phase I&#47;II trial which obtained 56&#37; of responses in terms of declines in the PSA and 22&#37; of radiological responses&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> data of the phase-III trial regarding its postdocetaxel effectiveness &#40;AFFIRM&#41; have been published to confirm its effectiveness&#44; data that have forced to close the study prematurely and that will lead to its approval &#40;median overall survival of 18&#46;4 months for patients treated with MDV 3100 vs 13&#46;6 months in patients treated with placebo&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">In July 2011&#44; denosumab was approved by the EMA for the prevention of skeletal-related events &#40;SREs&#58; pathologic fracture&#44; bone radiotherapy&#44; spinal cord compression&#44; and bone surgery&#41; in adults with bone metastases from solid tumors&#46; Denosumab is a human monoclonal antibody against the ligand of the receptor activator of nuclear factor kB &#40;RANKL&#41; that has shown better results than zoledronic acid in a phase-III study in patients with CRPC for the prevention of SREs&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">An essential precondition&#58; the multidisciplinary approach of castration-resistant prostate cancer</span><p id="par0190" class="elsevierStylePara elsevierViewall">Currently&#44; due to the acquired complexity of the management of patients with CRPC&#44; it is necessary to incorporate multidisciplinary opinions to the process associated with the establishment of their care plan&#46; Only in this way we can ensure that the right diagnostic&#44; therapeutic&#44; and rehabilitation decisions are made&#44; optimizing the results of cancer treatment&#46; The Clinical Practice Guideline of the EUA on CRPC explicitly recommends that the treatment of these patients is addressed by multidisciplinary teams&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Its implementation should be a priority in the health care of patients with CRPC&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Given that the vision of the problem can only be addressed by a multidisciplinary team of professionals&#44; we suggest the need to create a Multidisciplinary Committee at each center which will treat these patients&#44; since only then continuous and comprehensive care of the entire process of this disease can be ensured&#46; These committees would ideally be integrated by professionals from different disciplines&#58; urology&#44; medical oncology&#44; and radiation oncology&#44; nuclear medicine&#44; radiodiagnosis&#44; pathological anatomy&#44; without forgetting the support of units of pain and palliative&#44; psychological care&#44; as well as primary care and nursing professionals&#46; In order to assist in the creation and improvement of these multidisciplinary committees&#44; the AEU&#44; SOGUG&#44; and SEOR published in 2012 a practical manual on the organization and functioning of the multidisciplinary uro-oncology committees&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">This document is the result of the work by a multidisciplinary group of experts&#44; supported by the relevant scientific societies of the specialties that have worked on it&#44; and in which the basis for the proper management of the patient with CRPC are trying to be established&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">For the definition of CRPC&#44; we exclusively consider the patients undergoing castration with a total serum testosterone below 30<span class="elsevierStyleHsp" style=""></span>ng&#47;dl plus 3 consecutive increases of PSA&#44; or a clinical progression without PSA elevation&#44; while the HRPC is defined by the lack of response of a CRPC to any hormonal maneuver&#44; including second-line&#44; such as the withdrawal of the AA which is essential before any therapeutic decision&#44; as well as adding an AA when the patient was initially treated with hormonal monotherapy&#46; In patients with biochemical relapse after the previous maneuvers&#44; successive hormonal maneuvers could be provided&#46; In asymptomatic patients in whom the second hormonal maneuvers fail&#44; CT should be considered&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Most patients will receive treatment with CT with docetaxel at some point over the course of the disease&#46; Today we recommend evaluating the PSA kinetics and it can help in those cases with no clear indication of the beginning of treatment with CT&#44; such as asymptomatic patients or with exclusive biochemical progression&#44; as it reports the prognosis and the potential benefit of early CT&#46; Delaying a therapy that can prolong life and achieve adequate symptom control might be ethically unacceptable&#44; and if it is finally decided to treat the patient with docetaxel&#44; after failure thereof&#44; cabazitaxel is presented as a valid option in patients that maintain their tolerability to these treatments&#44; and it is considered the standard treatment of choice in metastatic CRPC&#46; Furthermore&#44; the therapeutic horizon of PCa opens dramatically with the advent of new drugs such as abiraterone&#44; sipuleucel T&#44; alpharadin&#44; MDV3100&#44; etc&#46;&#44; which will possibly continue changing positively the course of this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">As we have observed throughout the article&#44; the management of the patients with CRPC is really complex&#44; so the EUA explicitly recommends&#44; in its Clinical Practice Guidelines&#44; that the treatment of these patients is addressed by multidisciplinary teams&#44; therefore&#44; we aim to create a Multidisciplinary Committee at each center to ensure continuous and comprehensive care of the whole process of this disease&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0220" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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          "identificador" => "xres102016"
          "titulo" => array:6 [
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          "titulo" => "Introduction"
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          "titulo" => "Proposed definition of castration-resistant prostate cancer and hormone-refractory prostate cancer"
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          "titulo" => "Which and how many should be the second-line hormonal maneuvers&#63;"
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          "titulo" => "Which are the first-line recommendations and the prognostic tools in castration-resistant prostate cancer&#63;"
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              "identificador" => "sec0025"
              "titulo" => "At what point should treatment with docetaxel begin&#63;"
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              "identificador" => "sec0030"
              "titulo" => "What is the role of the doubling time of the prostate specific antigen&#63;"
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              "titulo" => "What information do prognostic nomograms provide&#63;"
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          "identificador" => "sec0040"
          "titulo" => "Which should be considered criteria for progression in castration-resistant prostate cancer&#63;"
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          "identificador" => "sec0045"
          "titulo" => "Treatment of progression after docetaxel&#58; chemotherapy versus hormone therapy"
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              "identificador" => "sec0050"
              "titulo" => "But chemotherapy or second-line hormone therapy&#63;"
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          "titulo" => "Which new treatments are being studied&#63;"
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          "titulo" => "An essential precondition&#58; the multidisciplinary approach of castration-resistant prostate cancer"
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          "titulo" => "Conclusions"
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          "titulo" => "Conflict of interest"
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    "fechaRecibido" => "2012-05-22"
    "fechaAceptado" => "2012-06-30"
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          "clase" => "keyword"
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            0 => "Prostate cancer"
            1 => "CRPC"
            2 => "HRPC"
            3 => "Controversies"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Context</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Controversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus&#46;</p> <span class="elsevierStyleSectionTitle">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer&#44; with recommendations from the definition&#44; to the management in hormonal maneuvers&#44; first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient&#44; best time to act and safety&#46;</p> <span class="elsevierStyleSectionTitle">Evidence Acquisition</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Two meetings of a multidisciplinary group of experts involved in the management of this disease &#40;oncologist and urologist&#41; where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer&#44; reviewing and attempting to address the current controversies of the disease&#46;</p> <span class="elsevierStyleSectionTitle">Evidence Synthesis</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours&#58; the Spanish Association of Urology &#40;AEU&#41; with the Uro-Oncoloy Group &#40;GUO&#41; and the Spanish Oncology of Genitourinary Group &#40;SOGUG&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time&#44; a real road map for quality&#44; efficiency and safety in the management of patients with CRPC&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Contexto</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En el manejo integral del c&#225;ncer de pr&#243;stata avanzado resistente a la castraci&#243;n siguen existiendo incertidumbres y controversias a pesar de la existencia de numerosas gu&#237;as de pr&#225;ctica cl&#237;nica basadas en la evidencia&#44; internacionalmente consensuadas&#46;</p> <span class="elsevierStyleSectionTitle">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Elaborar un documento en el que se revise el manejo de controversias en el c&#225;ncer de pr&#243;stata avanzado resistente a la castraci&#243;n con recomendaciones desde su definici&#243;n hasta el manejo de maniobras hormonales y el tratamiento de primera y segunda l&#237;nea con nuevos f&#225;rmacos como cabacitaxel y abiraterona&#44; as&#237; como el abordaje multidisciplinar de la patolog&#237;a con el objetivo de buscar la alternativa m&#225;s eficiente&#44; el mejor momento de actuar y la mayor seguridad&#46;</p> <span class="elsevierStyleSectionTitle">Adquisici&#243;n de la Evidencia</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se realizaron 2 reuniones de un grupo de expertos multidisciplinares implicados en el manejo de esta enfermedad &#40;ur&#243;logos y onc&#243;logos&#41; donde se pusieron en com&#250;n el an&#225;lisis bibliogr&#225;fico de art&#237;culos originales y se consensu&#243; este documento de recomendaciones sobre el c&#225;ncer de pr&#243;stata resistente a la castraci&#243;n&#44; revisando e intentando dar respuesta a las actuales controversias de la enfermedad&#46;</p> <span class="elsevierStyleSectionTitle">S&#237;ntesis de la Evidencia</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Este documento est&#225; avalado por las principales Sociedades Cient&#237;ficas y grupos de trabajo implicados en el manejo actual de los tumores genitourinarios&#58; la Asociaci&#243;n Espa&#241;ola de Urolog&#237;a &#40;AEU&#41;&#44; el Grupo de Urolog&#237;a Oncol&#243;gica &#40;GUO&#41; y el Grupo Espa&#241;ol de Oncolog&#237;a Genitourinaria &#40;SOGUG&#41;&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Con la adaptaci&#243;n e implementaci&#243;n de este Documento de Recomendaciones a la pr&#225;ctica cl&#237;nica se dispone&#44; por primera vez&#44; de una verdadera hoja de ruta de calidad&#44; eficiencia y seguridad del manejo de los pacientes con c&#225;ncer de pr&#243;stata avanzado resistente a la castraci&#243;n&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; C&#243;zar JM&#44; et al&#46; Recomendaciones sobre el manejo de controversias en c&#225;ncer de pr&#243;stata avanzado resistente a la castraci&#243;n&#46; Actas Urol Esp&#46; 2012&#59;36&#58;569&#8211;77&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t">Consider only patients undergoing castration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">And total serum testosterone below 30<span class="elsevierStyleHsp" style=""></span>ng&#47;dl<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">And 3 consecutive PSA increases&#44; in minimum intervals of one week&#44; resulting in 2 increases of at least 50&#37; above the PSA nadir&#44; with a PSA greater than 2<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Or clinical progression without PSA elevation&#46; Two or more new lesions on bone scan or RECIST 1&#46;1 criteria for soft tissue lesions&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara">If serum testosterone is confirmed &#62;30<span class="elsevierStyleHsp" style=""></span>ng&#47;dl&#44; consider inadequate castration and assess other forms of castration &#40;the EAU guidelines considers 50<span class="elsevierStyleHsp" style=""></span>ng&#47;dl&#41;&#46;</p> <p class="elsevierStyleNotepara">EAU&#58; European Association of Urology&#59; PSA&#58; Prostate-Specific Antigen&#59; RECIST&#58; Response Evaluation Criteria in Solid Tumors&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Proposed definition of castration-resistant prostate cancer&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Patient with CRPC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">And failure to answer all and any hormonal-base maneuvers<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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              "nota" => "<p class="elsevierStyleNotepara">Lack of response will be assessed as biochemical progression &#40;3 consecutive increases of prostate specific antigen &#40;PSA&#41; at minimum intervals of one week&#44; resulting in 2 increases of at least 50&#37; on the previous PSA to every hormonal maneuver&#41; or clinical progression without elevated PSA &#40;2 or more new lesions on bone scan or Response Evaluation Criteria in Solid Tumors 1&#46;1 for soft tissue lesions&#41;&#46;</p> <p class="elsevierStyleNotepara">CRPC&#58; castration-resistant prostate cancer&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Proposed definition of hormone refractory prostate cancer&#46;</p>"
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                  \t\t\t\t">Arguments for&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arguments against&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The benefit demonstrated in other solid tumors&#44; both of efficiency and pain reductionThe low rate of androgen-independent clones at the beginning of the disease that favors a priori greater efficiency of the CT&#46; From 2010 with the FDA approval of the use of cabazitaxel in CRPC<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#44; we have second lines of treatment after failure of docetaxel that have shown a clear clinical benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The possibility of rapid induction of resistances by their early useThere is no difference in hazard ratio of death according to prescribing treatment in symptomatic versus asymptomatic patients &#40;same end result&#41;Deterioration in the quality of life of patients by the adverse effects of the toxicity of the CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184416.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Arguments for and against the early use of chemotherapy&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">CRPC&#58; castration-resistant prostate cancer&#59; PCWG&#58; Prostate Specific Antigen Working Group&#59; PET&#58; positron emission tomography&#59; PSA&#58; prostate-specific antigen&#59; RECIST&#58; Response Evaluation Criteria in Solid Tumors&#59; MRI&#58; magnetic resonance imaging&#59; CT&#58; computed tomography&#46;</p>"
          "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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">PCWG2 criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Assess PSA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Obtain the sequence of elevation of the values at weekly intervals at leastInitial minimum value 2&#46;0<span class="elsevierStyleHsp" style=""></span>ng&#47;mlAssess the pre-treatment PSA doubling time if there are 3 or more separated values every 4 weeks or more&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Target lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The presence of lymph node or visceral lesions is enough to enter a study&#44; regardless of the PSANo measurable lesions are required for the inclusionUse RECIST criteria to assess the soft-tissue lesions &#40;lymph node or visceral&#41; as a target or no targetOnly the lymph nodes &#8805;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>cm diameter to assess its change in sizeRegister the presence of lymph node and&#47;or visceral disease separately&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary location of the tumor in the prostate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Register the previous therapeutic treatment of the primary tumorPerform pelvic imaging scans &#40;CT&#44; MRI&#44; PET&#47;CT&#44; endorectal MRI&#44; transrectal ultrasound&#41; to document the presence or absence of disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progression is considered when there are 2 or more new lesionsConfirm the ambiguous results with other imaging tests &#40;CT o MRI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other locations of the diasease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Patients with epidural lesions treated without epidural progression are eligible if another criteria for inclusion is met&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184420.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Criteria for progression and assessment of the disease in CRPC&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">PSA&#58; prostate-specific antigen&#46;</p>"
          "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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Subtype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Pattern of proliferation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Local tumor progression without metastatic disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased PSA in patient at testosterone suppression but without metastatic involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nodal spread but without evidence of bone or visceral involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone involvement with or without lymph node involvement but absence of visceral metastases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Visceral metastases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184419.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Clinical subtypes based on the patterns of prostate cancer proliferation&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">PSA&#58; prostate-specific antigen&#59; CT&#58; chemotherapy&#46;</p>"
          "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"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">PreCT variables&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">PostCT variables&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progression in the first line of CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">General condition of Karnofsky&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of factors of progression &#40;PSA&#44; pain&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alkaline phosphatase level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of cycles of 3 weeks of the first line of CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of metastatic sites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of hepatic metastases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemoglobin values&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PSA value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Period of time from diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184421.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Prognostic factors before and after the use of the CT&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:43 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Morote"
                            1 => "A&#46; Orsola"
                            2 => "J&#46; Planas"
                            3 => "E&#46; Trilla"
                            4 => "C&#46;X&#46; Ravent&#243;s"
                            5 => "L&#46; Cecchini"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.juro.2007.05.129"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Urol"
                        "fecha" => "2007"
                        "volumen" => "178"
                        "paginaInicial" => "1290"
                        "paginaFinal" => "1295"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17698136"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gu&#237;a de la EAU sobre el c&#225;ncer de pr&#243;stata&#46; Parte II&#58; Tratamiento del c&#225;ncer de pr&#243;stata avanzado&#44; recidivante y resistente a la castraci&#243;n"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Mottet"
                            1 => "J&#46; Bellmunt"
                            2 => "M&#46; Bolla"
                            3 => "S&#46; Joniau"
                            4 => "M&#46; Mason"
                            5 => "V&#46; Matveev"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.acuro.2011.03.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Actas Urol Esp"
                        "fecha" => "2011"
                        "volumen" => "35"
                        "paginaInicial" => "565"
                        "paginaFinal" => "579"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21757258"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer&#58; Recommendations from the PSA Working Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;J&#46; Bubley"
                            1 => "M&#46; Carducci"
                            2 => "W&#46; Dahut"
                            3 => "N&#46; Dawson"
                            4 => "D&#46; Daliani"
                            5 => "M&#46; Eisenberger"
                          ]
                        ]
                      ]
                    ]
                  ]
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                      "titulo" => "C&#225;ncer de pr&#243;stata resistente a castraci&#243;n&#58; &#191;hacia d&#243;nde vamos&#63;"
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        "texto" => "<p id="par0225" class="elsevierStylePara elsevierViewall">We thank Sanofi for the logistical support for the organization of the meetings&#44; assuming they have no influence on the content development&#46;</p>"
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Article information

ISSN: 21735786
Original language: English

DOI:10.1016/j.acuroe.2012.06.001

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Year/Month	Html	Pdf	Total

2023 March	2	3	5
2018 February	15	1	16
2018 January	11	1	12
2017 December	15	3	18
2017 November	11	2	13
2017 October	22	2	24
2017 September	17	2	19
2017 August	15	1	16
2017 July	17	14	31
2017 June	17	16	33
2017 May	17	2	19
2017 April	14	5	19
2017 March	16	14	30
2017 February	17	6	23
2017 January	11	0	11
2016 December	20	4	24
2016 November	27	7	34
2016 October	28	7	35
2016 September	22	4	26
2016 August	26	3	29
2016 July	23	3	26
2016 June	16	9	25
2016 May	28	21	49
2016 April	32	10	42
2016 March	24	12	36
2016 February	25	17	42
2016 January	19	18	37
2015 December	23	12	35
2015 November	13	12	25
2015 October	17	14	31
2015 September	18	4	22
2015 August	12	10	22
2015 July	8	1	9
2015 June	3	0	3
2015 May	14	7	21
2015 April	21	7	28
2015 March	33	8	41
2015 February	19	4	23
2015 January	22	2	24
2014 December	44	12	56
2014 November	0	1	1
2014 August	1	0	1
2014 July	1	0	1
2014 June	1	0	1
2014 May	4	1	5
2014 February	1	0	1
2014 January	6	1	7
2013 December	15	2	17
2013 November	14	5	19
2013 October	13	4	17
2013 September	10	3	13
2013 July	3	2	5
2013 June	3	0	3

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