Treatment of muscle-invasive and metastatic bladder cancer: Update of the EAU guidelines | Actas Urológicas Españolas (English Edition)

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"apellidos" => "Witjes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "g" "identificador" => "aff0035" ] ] ] ] "afiliaciones" => array:7 [ 0 => array:3 [ "entidad" => "Servicio de Urología, Universidad Eberhard-KarlsTuebingen, Tuebingen, Germany" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Radiología, The Churchill Hospital, Oxford, United Kingdom" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Médico y ACR-ITR/CEADDP y LBI-ACR Vienna-CTO, Kaiser Franz Josef Spital, Viena, Austria" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Urología y Oncología Urológica, Escuela de Medicina de Hannover (MHH), Hannover, Germany" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Urología, Clínica Hospitalaria, Universidad de Barcelona, Barcelona, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Urología, Hospital Universitario Karolinska, Estocolmo, Sweden" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Urología, Universidad Centro Médico Radboud Nijmegen, Nijmegen, Netherlands" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento del cáncer de vejiga con invasión muscular y metastásico: actualización de la Guía Clínica de la EAU" ] ] "textoCompleto" => "IntroductionThis is the first major update of the guidelines on muscle-invasive and metastatic bladder cancer (MiM-BC) published by the European Association of Urology (EAU) Guideline Panel in 2008. Most of the change has taken place in the surgical and medical treatment of the disease, and this overview therefore focuses on altered recommendations for the management of MiM-BC.The intention of these EAU guidelines, produced by a panel of international multidisciplinary experts in this field, is to support urologists in assessing evidence-based management of MiM-BC and incorporating guideline recommendations into their clinical practice. Comprehensive literature searches were designed for each section of the MiM-BC guideline with the help of an expert external consultant. Following detailed internal discussion, searches were carried out in the Cochrane Database of Systematic Reviews, the Cochrane Collaboration's Central Register of Controlled Clinical Trials, Medline, and Embase on the Dialog DataStar platform. The searches used the narrowest single terms available in the controlled vocabulary of the respective databases. Those terms were urinary bladder neoplasm in Medical Subject Headings (MeSH) for Medline and bladder cancer in Emtree for Embase.Results of all searches were scan-read by panel members. In many cases, there was a high “numbers needed to read” because of the sensitivity of the search. There is clearly a need for continuous reevaluation of the information presented in the current guideline by an expert panel. Even though the current guideline update contains information on the treatment of an individual patient according to a standardised approach, it must be emphasised that the recommendations based on the literature research cannot be binding because of either a nonstandardised approach or an unusual situation or desire in individual patients.In this article, we have grouped the various discussions and recommendations of treatment options of MiM-BC into localised bladder cancer (BCa) and metastatic BCa. The level of evidence (LE) and grade of recommendation (GR) provided in this guideline of treatment options follow the listings outlined in the full-text version (see <a href="http://www.uroweb.org/guidelines/online-guidelines/">http://www.uroweb.org/guidelines/online-guidelines/</a>).<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Localised invasive bladder cancerLocalised invasive BCa is defined as histologically verified T≥1 N0 M0 disease.Neoadjuvant chemotherapyNeoadjuvant chemotherapy is administered to patients with clinically operable, muscle-invasive (N0 M0), urothelial cancer (UC) of the urinary bladder before the planned definitive surgery (or radiation). Neoadjuvant chemotherapy has many advantages: (1) It is delivered at the earliest time-point, when the burden of micrometastatic disease is expected to be low; (2) there is a potential reflection of in vivo chemosensitivity; (3) the tolerability of chemotherapy is expected to be better before cystectomy rather than after it; and (4) hypothetically, patients with micrometastatic disease might respond to neoadjuvant therapy and reveal favourable pathologic status, as determined mainly by negative lymph node status and negative surgical margins.However, neoadjuvant chemotherapy also has potential disadvantages: (1) Patients without micrometastatic disease—approximately half of which are clinically N0 M0 patients—will receive unnecessary treatment; (2) staging errors may hypothetically lead to overtreatment; (3) the delay in cystectomy may compromise outcomes in patients who do not respond to chemotherapy<a class="elsevierStyleCrossRefs" href="#bib0010">2–4</a>; and (4) chemotherapy may have side-effects that affect the outcome of surgery and type of urinary diversion (UD).<a class="elsevierStyleCrossRef" href="#bib0025">5</a>In a randomised trial of cystectomy following neoadjuvant chemotherapy, the overall morbidity showed the same distribution of postoperative grade 3–4 complications in both trial arms. However, preoperative anaemia and neuropathy were more common in the chemotherapy-treated group.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> In the combined Nordic trials NCS1+NCS2 (n=620), neoadjuvant chemotherapy did not have any major adverse effect on the percentage of performable cystectomies.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>As a result of a 5–8% overall survival (OS) advantage in recently published studies and meta-analyses, neoadjuvant cisplatin-containing combination chemotherapy should be considered and discussed with the patient in cases of muscle-invasive, node-negative, and nonmetastatic (N0 M0) urinary bladder carcinoma, irrespective of definitive treatment<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> (LE: 1).In patients, a performance status (PS)≥2 and/or impaired renal function are contraindications for neoadjuvant chemotherapy (LE: 1). Generally, chemotherapy alone is not recommended as the primary therapy for localised, muscle-invasive, N0 M0, UC of the bladder<a class="elsevierStyleCrossRef" href="#bib0040">8</a> (LE: 1). A summary of the treatment recommendations can be found in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Preoperative radiation therapySeveral retrospective studies have looked at the effect of preoperative radiation therapy (RT) in patients with BCa, suggesting downstaging in 40–65% of patients, improved local control in 10–42% of patients, and improved survival in 11–12% of patients. Improved local control seemed highest in T3b tumours, and a pathologically confirmed, complete remission after RT appeared to be a positive prognostic factor for survival.Randomised studies have investigated preoperative RT.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Although the results from these trials suggested that there was an advantage in both downstaging and survival—especially in ≥pT3 tumours—as well as better results in pathologic complete responders and limited toxicity of neoadjuvant RT, all the studies had severe limitations, including no documentation of the effect on local recurrences in all the studies. Furthermore, a meta-analysis of the trials showed an odds ratio (OR) for the difference in 5-yr survival of 0.71 (95% confidence interval [CI], 0.48–1.06). However, the meta-analysis was potentially biased by results from the largest trial, in which patients were not given the planned treatment. When the results of the largest trial were excluded, the OR became 0.95 (95% CI, 0.57–1.55), indicating that improved survival with preoperative RT had not been proven.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Although a more recent study has reached similar conclusions, the results, unfortunately, suffer from the same limitations.<a class="elsevierStyleCrossRef" href="#bib0050">10</a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents a summary of the conclusions and a recommendation regarding preoperative therapy.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Cystectomy and urinary diversionTo date, there have been no randomised studies comparing removal of the entire urinary bladder and associated lymph nodes with bladder-preserving treatment strategies. However, efforts to evaluate multimodality treatment in a prospective, randomised fashion are being developed.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Radical cystectomy (RC) remains the preferred treatment option for patients with advanced, localised urothelial BCa<a class="elsevierStyleCrossRef" href="#bib0060">12</a> (LE: 2a).Standard surgical techniqueIn male patients, the literature over the past two decades has set the standard of surgical limits for curative RC, which involves complete removal of the bladder with all macroscopically visible and resectable bladder-perforating tumour extensions, removal of the adjacent distal ureters, and removal of the lymph nodes corresponding to the tumour-bearing bladder. Technical variations from this standard that may improve patients’ quality of life (QoL) include preservation of (1) anterior and membranous urethra, including the rhabdosphincter, to enable an orthotopic neobladder; (2) parts of the prostate and seminal vesicles for reasons of fertility, potency, and continence; and (3) intrapelvic autonomic and sensory nerves to enhance potency and continence. However, these variations must be carefully judged against the potential for increased oncologic risk<a class="elsevierStyleCrossRef" href="#bib0065">13</a> (LE: 3).Preservation of parts of the prostatic gland during resection carry risks as high as 23–54% of unsuspected adenocarcinomas, of which up to 29% may be clinically significant, leading to local recurrence or even metastasis.<a class="elsevierStyleCrossRefs" href="#bib0070">14–16</a> Because UC may be present in the prostate, in some series, only 26–33% of patients undergoing cystoprostatectomy were found to have neither prostate cancer nor prostatic UC.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> A recently developed technical variation that aimed to better preserve the surrounding autonomic nerves involves deliberately leaving out the seminal vesicles, with or without the prostatic capsule. The results for potency versus oncologic risk in small series of selected patients have been encouraging, but long-term confirmation is needed for using larger series.<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a>In female patients, standard anterior pelvic exenteration includes the bladder, entire urethra, adjacent vagina, uterus, distal ureters, and respective lymph nodes (LE: 3; GR: C). Unless the primary tumour is located at the bladder neck or in the urethra, it is possible to preserve a major part of the functioning female urethra and (provided a complete tumour resection is possible) its supplying autonomous nerves in case of a planned orthotopic neobladder<a class="elsevierStyleCrossRefs" href="#bib0065">13,20</a> (LE: 3). New data also question the necessity of removing the uterus or any portion of the vagina in favour of providing improved anatomic support for the neobladder and better preservation of surrounding autonomous nerves.In both sexes, the length of the distal ureteral segment to be removed with the bladder has not been specified. It depends on oncologic status (e.g., tumour extension or the presence of carcinoma in situ and the type of subsequent UD). In a recent study, a frozen section of the distal ureteral margins had a sensitivity of 74% and a specificity of 99.8%, resulting in an overall accuracy of 98.3%.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> With a serial sectioning strategy, most initially positive ureteral margins can be converted into negative final margins. These patients are at decreased risk of developing upper urinary tract recurrent disease.<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a>Current literature unanimously supports the simultaneous removal of pelvic lymph nodes together with the tumour-bearing bladder (LE: 3). Retrospective studies have shown that extended lymphadenectomy can improve survival in patients with muscle-invasive BCa. The true curative value of lymph node dissection (LND), however, is still unknown, and a standardised LND is yet to be defined.<a class="elsevierStyleCrossRefs" href="#bib0035">7,24</a>Several localisation studies with regards to lymphadenectomy<a class="elsevierStyleCrossRefs" href="#bib0120">24–27</a> have demonstrated both retrospectively and prospectively that lymph nodes in BCa patients are not found outside the pelvis if the pelvic lymph nodes are free of tumour<a class="elsevierStyleCrossRef" href="#bib0135">28</a> (LE: 3). Furthermore, both progression-free survival and OS may be correlated with the amount of lymph nodes removed during surgery.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a>Both laparoscopic RC and the robot-assisted procedure have been shown to be feasible.<a class="elsevierStyleCrossRef" href="#bib0140">29</a> However, the recommendation for minimally invasive techniques is still optional and reserved for surgeons skilled in this technique for reasons of selection bias, including the patient's general health status, tumour stage, or type of UD chosen as well as the generally much smaller, reported series compared to open cystectomy reports.<a class="elsevierStyleCrossRef" href="#bib0145">30</a>Laparoscopic intracorporeal construction of UD with or without robotic assistance has been tested in small series only.<a class="elsevierStyleCrossRefs" href="#bib0140">29,31</a> It is a challenging and lengthy procedure with the technical equipment currently available and must therefore be regarded as experimental. Laparoscopic cystectomy and pelvic lymphadenectomy (with or without robotic assistance), with extracorporeal construction of UD, is an option for surgical treatment (LE: 3).Urinary diversion after radical cystectomyFrom an anatomic standpoint, three alternative forms of UD outlet are presently used after cystectomy: abdominal, urethral, and rectosigmoid. In the case of an abdominal or rectosigmoid diversion, the ureters can be diverted either directly (ureterocutaneostomy or ureterorectosigmoidostomy) or by interposing an intestinal segment, such as stomach, ileum, colon, or appendix.<a class="elsevierStyleCrossRef" href="#bib0155">32</a> According to large series, the most common abdominal rerouting is ureteroileocutaneostomy or a Bricker ileal conduit.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>In a recent retrospective comparison with short or median follow-up of 16mo, the diversion-related complication rate was considerably lower for ureterocutaneostomy compared to an ileal or colon conduit.<a class="elsevierStyleCrossRef" href="#bib0160">33</a> Despite the limited comparative data available, it has to be taken into consideration that older data and clinical experience suggest stricturing at the skin level and ascending urinary tract infection more frequently as compared to ileal conduit. In a retrospective study comparing various forms of intestinal diversion, ileal conduits had fewer late complications than continent abdominal pouches or orthotopic neobladders.<a class="elsevierStyleCrossRef" href="#bib0165">34</a>Several studies have compared certain aspects of health-related QoL, including sexual function, urinary continence, and body image, in patient cohorts with different types of UD. However, more research is necessary in this field. It is not possible to evaluate QoL issues for a type of UD without taking into account other factors, such as preoperative tumour stage, patient age and expectations, functional situation, socioeconomic status, experience of the treating urologist, and possible surgical complications. Currently, it is not possible to recommend a particular type of UD, except to say that ureterocutaneostomy is surgically the least-burdensome type of diversion for the patient (LE: 3).Patients undergoing any type of UD have to be motivated to learn to cope with their diversion and to develop the manual dexterity required. Debilitating neurologic and psychiatric illnesses, limited life expectancy, impaired liver or renal function, and UC of the urethral margin or other surgical margins have been defined as contraindications to more complex forms of intestinal UD (LE: 2b). Relative contraindications specific to an orthotopic neobladder are high-dose preoperative RT, complex urethral stricture disease, and severe urethral sphincter-related incontinence<a class="elsevierStyleCrossRefs" href="#bib0170">35–38</a> (LE: 2b).There are no explicit data that age precludes any type of UD. However, because of an increasing number of underlying morbidities and reduced general health status, most patients older than 75yr of age receive an incontinent form of UD following cystectomy.<a class="elsevierStyleCrossRef" href="#bib0190">39</a>Standard RC in male patients with bladder neoplasms includes removal of the entire bladder, prostate, seminal vesicles, distal ureters (length of the segment undefined), and corresponding lymph nodes (extent undefined; LE: 2b). Currently, it is not possible to recommend a particular type of UD. However, most institutions prefer ileal orthotopic neobladders and ileal conduits based on clinical experience.<a class="elsevierStyleCrossRefs" href="#bib0060">12,36</a> In selected patients, ureterocutaneostomy is surgically the least-burdensome type of diversion (LE: 3; GR: C). Recommendations related to RC and UD are listed in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Oncologic outcome after surgeryRecurrence-free survival (RFS) and OS in male and female patients is reported as 66–68% and 58–66% at 5yr and 60–73% and 43–49% at 10yr, respectively.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> In node-positive patients, 10-yr disease-specific survival and OS rates were reduced to 27.7% and 20.9%, respectively.<a class="elsevierStyleCrossRef" href="#bib0195">40</a> These results (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>) have to date not been reached in stage-equivalent large studies with bladder-sparing treatment alternatives.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Nomograms on cancer-specific survival (CSS) following RC have been developed and externally validated, but their wider use cannot be recommended prior to further data.<a class="elsevierStyleCrossRefs" href="#bib0200">41,42</a> In a retrospective series of 768 male patients by Stein et al.,<a class="elsevierStyleCrossRef" href="#bib0180">37</a> the overall urethral recurrence rate was 6%, irrespective of UD. In a multivariate statistical analysis, prostatic involvement by the primary tumour and cutaneous UD was independently associated with an increased risk for the development of second primary tumours (LE: 2b). The calculated risk of second primary tumours was 5% and 9% for patients with an orthotopic and cutaneous UD, respectively. A difference for second primary tumours, depending on initial prostatic tumour involvement, was apparent for both superficial (12% vs 5%) and invasive UC (18% vs 5%).Cystectomy is associated with the greatest risk reduction in disease-related and non-disease-related death in patients older than 80yr of age.<a class="elsevierStyleCrossRef" href="#bib0220">45</a> The largest, retrospective, single-institution study on cystectomy to date demonstrated that patients older than 80yr of age did have an increased postoperative morbidity but not increased mortality<a class="elsevierStyleCrossRef" href="#bib0220">45</a> (LE: 3).Remnant disease may be inevitable in patients with locally advanced pelvic cancer and urinary bladder involvement. However, in these cases, palliative RC and UD—with or without using intestinal segments—is performed only for the relief of symptoms such as pain, recurrent bleeding, urgency, and fistula formation. The morbidity associated with surgery and QoL should be weighed against other options (LE: 3).<a class="elsevierStyleCrossRefs" href="#bib0220">45–47</a><a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> lists the recommendations regarding oncologic outcome after surgery.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Outcome of radical surgeryMost surgical complications are associated with UD, of which a great portion is related to the use of intestinal segments.<a class="elsevierStyleCrossRefs" href="#bib0170">35,38</a> Variables such as patient factors, surgeon's skills, hospital volume, and type of UD all influence the rate, type, and severity of surgical complications (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<a class="elsevierStyleCrossRefs" href="#bib0220">45–49</a>When reporting surgical complications in cystectomy, regardless of the technique used, a standardised and reproducible classification of surgical complications should be applied. Complications of several urologic procedures, including open<a class="elsevierStyleCrossRef" href="#bib0245">50</a> and laparoscopic cystectomy,<a class="elsevierStyleCrossRef" href="#bib0250">51</a> have recently been reported using the modified, five-grade Clavien system, which has been tested in >6300 surgical procedures.<a class="elsevierStyleCrossRef" href="#bib0255">52</a> Alternatively, complications have been reported with the Common Terminology Criteria for Adverse Events.<a class="elsevierStyleCrossRef" href="#bib0260">53</a> Early and late complications following surgery are defined as those that occur within 90d and after 90d, respectively.<a class="elsevierStyleCrossRefs" href="#bib0245">50,54</a> In the most recent reports on cystectomy, an adverse event of any grade was seen in 54–58% of patients.<a class="elsevierStyleCrossRefs" href="#bib0245">50,53,55</a>Bladder-sparing treatments for localised diseaseDefinitive external-beam radiation therapyThe target field usually comprises the bladder only, with a safety margin of 1.5–2cm. The target dose for curative RT for BCa is 60–66Gy. Modern RT techniques result in major, late gastrointestinal or genitourinary morbidity in <5% of patients. Overall 5-yr survival rates range between 30% and 60%, with a CSS rate of 20–50%.<a class="elsevierStyleCrossRefs" href="#bib0275">56–58</a> Prognostic factors for RT were addressed in a recent Italian single-institution series of 459 irradiated patients, including approximately 30% of unfit T1 patients, with an average of 4.4-yr follow-up. Significant factors were age, T category (for all end points), and tumour dose (only for failure-free survival) in a multivariate survival analysis.<a class="elsevierStyleCrossRef" href="#bib0290">59</a> Based on available trials, a Cochrane analysis has demonstrated that RC has an OS benefit compared with RT.<a class="elsevierStyleCrossRef" href="#bib0295">60</a> However, external-beam RT (EBRT) can be an alternative in patients unfit for radical surgery, with a cystoscopically assessed, complete remission rate at 3mo of 78% and a 3-yr local control rate of 56%<a class="elsevierStyleCrossRef" href="#bib0300">61</a> (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>). A recent single-institution report investigating the 90-d early complication rate of RC after full-dose RT found a higher complication rate according to the Clavien reporting system in 148 irradiated patients versus 2480 nonirradiated patients.<a class="elsevierStyleCrossRef" href="#bib0305">62</a><elsevierMultimedia ident="tbl0030"></elsevierMultimedia>ChemotherapyChemotherapy alone rarely produces durable complete responses (CR) of the primary tumour. In general, a clinical CR rate of up to 56%, as reported in some series, must be weighed against a staging error of >60%.<a class="elsevierStyleCrossRefs" href="#bib0025">5,8</a> Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> though it may be confounded by patient selection. Several groups have reported the effect of chemotherapy on resectable tumours (neoadjuvant approach) as well as nonresectable primary tumours.<a class="elsevierStyleCrossRefs" href="#bib0020">4,63,64</a> Two to three cycles of methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC) or gemcitabine and cisplatin (GC) achieved not only downstaging of the primary tumour but also pathologic CRs of bladder primary tumours in 12–50% of patients after M-VAC and in 12–22% of patients after GC in phase 2 and phase 3 trials.<a class="elsevierStyleCrossRefs" href="#bib0020">4,63,65</a>Contemporary series with GC followed by RC reported inferior pT0 rates, which may have been related to a low dose density and inappropriate delay of surgery.<a class="elsevierStyleCrossRef" href="#bib0325">66</a> As for bladder preservation, a response is evaluated by cystoscopy and computed tomography imaging only, followed by close surveillance. This approach is prone to an imminent staging error, which can put the patient at risk for local recurrence and/or consecutive metastatic disease. For highly selected patients, a bladder-conserving strategy with transurethral resection of the bladder and systemic cisplatin-based chemotherapy—preferably with M-VAC—may allow long-term survival with an intact bladder.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> However, this approach cannot be recommended for routine use.Metastatic bladder cancerAdvanced BCa is a chemosensitive tumour. Response rates differ with respect to patient-related factors and pretreatment disease. Prognostic factors for response and survival have been established.<a class="elsevierStyleCrossRefs" href="#bib0330">67–71</a> A major prognostic factor is the suitability of patients for treatment with a cisplatin-based combination chemotherapy. Cisplatin remains the most effective single agent for treatment of UC.Factors preventing patients from receiving cisplatin at any dose include age; obstructing disease; chronic upper tract inflammation; or metabolic changes subsequent to bowel interposition after cystectomy, general health status, and/or poor renal function. Patients are categorised into “fit” or “unfit” for the purpose of receiving cisplatin-containing combination chemotherapy<a class="elsevierStyleCrossRef" href="#bib0355">72</a> (<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>).<elsevierMultimedia ident="tbl0035"></elsevierMultimedia>Standard first-line chemotherapy for “fit” patientsThe use of M-VAC and GC both result in prolonged survival of up to 14.8 and 13.8mo, respectively, also with long-term follow-up.<a class="elsevierStyleCrossRefs" href="#bib0360">73–76</a> The lower toxicity of GC, however, has resulted in GC increasingly becoming a new standard regimen.<a class="elsevierStyleCrossRef" href="#bib0370">75</a>Although all disease sites have been shown to respond to cisplatin-based combination chemotherapy, most studies have reported the response in lymph nodes. A response rate of 66% and 77% with M-VAC and high-dose (HD)-M-VAC, respectively, has been reported in retroperitoneal lymph nodes versus 29% and 33% at extranodal sites.<a class="elsevierStyleCrossRefs" href="#bib0380">77,78</a>The sites of disease also affect long-term survival. In lymph node-only disease, 20.9% of patients were alive at 5yr compared to only 6.8% of patients with visceral metastases.<a class="elsevierStyleCrossRef" href="#bib0375">76</a> To date, further intensification of treatment using new triplets, dose-dense schedules, or adding targeted therapies has not proven superior to GC or M-VAC and is still being investigated.<a class="elsevierStyleCrossRefs" href="#bib0390">79,80</a> The recommendation for first-line treatment for fit patients remains cisplatin-containing combination chemotherapy with GC or M-VAC, preferably with granulocyte-stimulating colony factor (GSCF) or HD-M-VAC with GCSF (<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>).Chemotherapy in patients ineligible (“unfit”) for cisplatinUp to 50% of patients are ineligible for cisplatin-containing chemotherapy, either because of a poor PS and/or impaired renal function or because of comorbidity preventing high-volume hydration. The first randomised phase 2/3 trial in this setting was conducted by the European Organisation for Research and Treatment of Cancer and compared methotrexate, carboplatin, and vinblastine (M-CAVI) and carboplatin and gemcitabine (Carbo/Gem) in patients unfit for cisplatin. Both regimens were active. Severe acute toxicity (SAT) was 13.6% in patients given Carbo/Gem versus 23% on M-CAVI, while the overall response rate was 42% on Carbo/Gem and 30% on M-CAVI. Further analysis showed that combination chemotherapy provides limited benefit in patients with PS 2 and impaired renal function.<a class="elsevierStyleCrossRef" href="#bib0400">81</a> The overall response rate and SAT were both 26% for the former group and 20% and 24%, respectively, for the latter group.<a class="elsevierStyleCrossRef" href="#bib0400">81</a> Recent phase 3 data have confirmed these results.Second-line chemotherapySecond-line chemotherapy data are highly variable in this setting. Vinflunine is a novel, third-generation vinca alkaloid that has shown objective response rates of 18% and disease control in 67% of trial subjects.<a class="elsevierStyleCrossRef" href="#bib0405">82</a> A phase 3 trial of vinflunine plus best supportive care (BSC) randomised against BSC alone in patients progressing after first-line treatment with platinum-containing combination chemotherapy for metastatic disease was recently published.<a class="elsevierStyleCrossRef" href="#bib0410">83</a> The results showed modest activity (overall response rate: 8.6%), a clinical benefit with a favourable safety profile, and—most importantly—a survival benefit in favour of vinflunine that was statistically significant in the eligible patient population (not in the intention-to-treat population). For second-line treatment in this clinical setting, this trial reached the highest level of evidence reported to date. Currently, vinflunine is the only approved second-line treatment; any other treatment should take place in the context of clinical trials (<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>).BiomarkersStatistically, relatively modest disease control rates but (sporadically) remarkable responses in some patients with urothelial BCa have led to investigation of biomarkers for assessment of prognosis after surgery and as an indication for chemotherapy or for its monitoring. Most of the biomarkers were associated with tumour angiogenesis. To date, small studies—usually retrospective—have investigated microvessel density, altered p53 tumour expression,<a class="elsevierStyleCrossRef" href="#bib0415">84</a> serum vascular endothelial growth factor,<a class="elsevierStyleCrossRef" href="#bib0420">85</a> urinary and tissue basic fibroblast growth factor (bFGF),<a class="elsevierStyleCrossRef" href="#bib0425">86</a> urinary (wild type and mutant) and tissue FGF receptor-3,<a class="elsevierStyleCrossRef" href="#bib0430">87</a> and—more recently—thrombospondin-1,<a class="elsevierStyleCrossRef" href="#bib0435">88</a> the detection of circulating tumour cells,<a class="elsevierStyleCrossRef" href="#bib0440">89</a> and multi-drug-resistance gene expression.<a class="elsevierStyleCrossRef" href="#bib0445">90</a> Although a few biomarkers have shown potential, none has sufficient evidence to support its routine clinical use (LE: 3; <a class="elsevierStyleCrossRef" href="#tbl0040">Table 8</a>).<elsevierMultimedia ident="tbl0040"></elsevierMultimedia>BisphosphonatesThe prevalence of metastatic bone disease (MBD) in patients with advanced/metastatic UC has been reported as 30–40%.<a class="elsevierStyleCrossRef" href="#bib0345">70</a> Skeletal complications resulting from MBD have a detrimental effect on pain and QoL and are also associated with increased mortality. Bisphosphonates reduce and delay skeletal-related events (SRE) from bone metastases by inhibiting bone absorption. Bisphosphonate treatment should therefore be considered for all patients with MBD, irrespective of cancer type<a class="elsevierStyleCrossRef" href="#bib0450">91</a> (<a class="elsevierStyleCrossRef" href="#tbl0045">Table 9</a>).<elsevierMultimedia ident="tbl0045"></elsevierMultimedia>To date, only one published randomised, placebo-controlled phase 3 trial has confirmed the beneficial effect of zoledronic acid in treating bone metastases from UC. UC patients treated with zoledronic acid experienced a decrease in SREs and an improvement in their QoL and 1-yr OS. Zoledronic acid is the only bisphosphonate that has been studied<a class="elsevierStyleCrossRefs" href="#bib0455">92,93</a> and approved for the treatment of MBD in all tumour types (LE: 2). Bisphosphonate treatment should be accompanied by calcium and vitamin D supplementation. Dosing regimens should follow respective regulatory recommendations and should be adjusted according to preexisting medical conditions.Author contributionsArnulf Stenzl had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Stenzl.Acquisition of data: Stenzl, Cowan, Ribal, Kuczyk, Merseburger, De Santis, Sherif, Witjes.Analysis and interpretation of data: Stenzl, Cowan, Ribal, Kuczyk, Merseburger, De Santis, Sherif, Witjes.Drafting of the manuscript: Stenzl.Critical revision of the manuscript for important intellectual content: Stenzl, Cowan, Ribal, Kuczyk, Merseburger, De Santis, Sherif, Witjes.Statistical analysis: Stenzl.Obtaining funding: None.Administrative, technical, or material support: None.Supervision: Stenzl.Other (specify): None.Financial disclosuresI certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Prof Dr Stenzl is a consultant for GE Healthcare and Novartis; has received company speaker honoraria from AMGEN and Novartis; and has participated in trials for MEDAC, Photocure, Immatics, Novartis, Johnson & Johnson, and Amgen; and has received research grants from Immatics. Prof Dr Witjes is a consultant for Endo Pharm (2010), Astellas (2010), Spectrum Pharmaceuticals (2009), Sanofi Pasteur (2010), GE Healthcare (2010), and Telormedix (2009); has received a company speaker honorarium from GE Healthcare; and has participated in trials with MEL Amsterdam, Telormedix, and Photocure Oslo. Dr De Santis is a company consultant for GlaxoSmithKline, AMGEN, Bayer, Novartis, and Pierre-Fabre; has received company speaker honoraria from Pfizer, Eli Lilly, Sanofi Aventis, Novartis, and Roche; and has received fellowships and travel grants from Bayer, Novartis, Pfizer, AMGEN, and Sanofi Aventis. Prof Dr Kuczyk holds equity interests in Bayer Healthcare, Astellas, Storz, Pfizer, and Wyeth; is a company consultant for Bayer Healthcare, Pfizer, Astra Zeneca, Astellas, and Storz; has received company speaker honoraria from Bayer, Pfizer, MEDAC, Astellas, Bayer Healthcare, and Astellas; has participated in trials with Astra Zeneca, Pfizer, Bayer Healthcare, Astellas, and Ipsen; and has received research grants from Wyeth. Prof Dr Merseburger is a company consultant for Ipsen Pharma and Bayer; has received company speaker honoraria from Ipsen Pharma, Wyeth, Astellas,Novartis, Pfizer, and SEP; has participated in trials with Astra Zeneca,Bayer, Pfizer, TEVA, and Novartis; and has received research grants fromWyeth. Dr Sherif has received speaker honoraria from Orion Pharma and MEDAC AB.Funding/support and role of the sponsor: None." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres101986" "titulo" => array:6 [ 0 => "Abstract" 1 => "Context" 2 => "Objective" 3 => "Evidence acquisition" 4 => "Evidence synthesis" 5 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec89152" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres101987" "titulo" => array:6 [ 0 => "Resumen" 1 => "Contexto" 2 => "Objetivo" 3 => "Adquisición de evidencia" 4 => "Síntesis de evidencia" 5 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec89153" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Localised invasive bladder cancer" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Neoadjuvant chemotherapy" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Preoperative radiation therapy" ] 2 => array:3 [ "identificador" => "sec0025" "titulo" => "Cystectomy and urinary diversion" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Standard surgical technique" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Urinary diversion after radical cystectomy" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Oncologic outcome after surgery" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Outcome of radical surgery" ] ] ] 3 => array:3 [ "identificador" => "sec0050" "titulo" => "Bladder-sparing treatments for localised disease" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Definitive external-beam radiation therapy" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Chemotherapy" ] ] ] ] ] 6 => array:3 [ "identificador" => "sec0065" "titulo" => "Metastatic bladder cancer" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Standard first-line chemotherapy for “fit” patients" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Chemotherapy in patients ineligible (“unfit”) for cisplatin" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Second-line chemotherapy" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Biomarkers" ] 4 => array:2 [ "identificador" => "sec0090" "titulo" => "Bisphosphonates" ] ] ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Author contributions" ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Financial disclosures" ] 9 => array:2 [ "identificador" => "xack35405" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-11-16" "fechaAceptado" => "2011-11-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec89152" "palabras" => array:8 [ 0 => "Bladder cancer" 1 => "Muscle-invasive" 2 => "Chemotherapy" 3 => "Radiation therapy" 4 => "Cystectomy" 5 => "EAU guidelines" 6 => "Multidisciplinary management" 7 => "Quality of life" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec89153" "palabras" => array:8 [ 0 => "Cáncer de vejiga" 1 => "Músculo-invasivo" 2 => "Quimioterapia" 3 => "Radioterapia" 4 => "Cistectomía" 5 => "Guía Clínica de la EAU" 6 => "Manejo multidisciplinario" 7 => "Calidad de vida" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ContextNew data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC. ObjectiveTo review the new EAU guidelines for MiM-BC with a specific focus on treatment. Evidence acquisitionNew literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. Evidence synthesisCurrent data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available. ConclusionsIn the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ContextoHan surgido nuevos datos sobre el tratamiento del cáncer de vejiga con invasión muscular y metastásico (CVIMM) que han llevado a una actualización de la Guía Clínica de la Asociación Europea de Urología (European Association of Urology, EAU) del CVIMM. ObjetivoRevisar la nueva Guía Clínica de la EAU sobre el CVIMM con un enfoque específico en el tratamiento. Adquisición de evidenciaLa literatura nueva publicada desde la última actualización de la Guía Clínica de la EAU en 2008 se obtuvo de Medline, la Base de Datos Cochrane de Revisiones Sistemáticas y listas de referencia en publicaciones y artículos de revisión y se examinó exhaustivamente por un grupo de urólogos, oncólogos, y un radiólogo designado por la Oficina de Guías Clínicas de la EAU. También se tuvieron en cuenta recomendaciones previas basadas en la literatura anterior sobre este tema. Se añadieron los niveles de evidencia (NE) y grados de recomendación (GR) basándose en un sistema modificado del Centro de Medicina Basada en la Evidencia de Oxford. Síntesis de evidenciaLos datos actuales demuestran que la quimioterapia neoadyuvante junto con la cistectomía radical (CR) es recomendable en ciertas constelaciones de CVIMM. La CR sigue siendo el tratamiento básico de elección en enfermedad invasiva localizada para ambos sexos. Se ha intentado definir el grado de cirugía en condiciones estándar en ambos sexos. Se debería ofrecer un sustituto vesical ortotópico a pacientes tanto masculinos como femeninos sin contraindicaciones tales como ausencia de tumor al nivel de la disección uretral. En contraste con la quimioterapia neoadyuvante, actualmente se recomienda el uso de quimioterapia adyuvante únicamente en ensayos clínicos. La terapia preservadora de la vejiga multimodalidad en la enfermedad localizada se observa actualmente sólo como una alternativa en pacientes seleccionados, bien informados y acatadores para los que la cistectomía no se plantea por razones médicas o personales. En la enfermedad metastásica, el tratamiento de primera línea para los pacientes en condiciones suficientes para soportar el cisplatino sigue siendo la poliquimioterapia con cisplatino. Con la llegada de vinflunina, la quimioterapia de segunda línea se ha vuelto disponible. ConclusionesEn el tratamiento del cáncer de vejiga (CV) invasivo localizado, el tratamiento estándar sigue siendo la extirpación quirúrgica radical de la vejiga dentro de los límites estándar, incluyendo los ganglios linfáticos regionales aún sin especificar. Sin embargo, la adición de la quimioterapia adyuvante debe ser considerada para ciertos grupos de pacientes específicos. Se ha aprobado y se recomienda un nuevo medicamento para la quimioterapia de segunda línea (vinflunina) en la enfermedad metastásica." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Stenzl A, et al. Tratamiento del cáncer de vejiga con invasión muscular y metastásico: actualización de la Guía Clínica de la EAU. Actas Urol Esp. 2012;36:449–60." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "La traducción de este artículo se ha llevado a cabo con el permiso de la Asociación Europea de Urología." ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "GR=grade of recommendation; BCa=bladder cancer; PS=performance status; UC=urothelial carcinoma." "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">Recommendations \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">GR \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">Neoadjuvant cisplatin-containing combination chemotherapy should be offered in muscle-invasive BCa, irrespective of further treatment. \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">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">Neoadjuvant chemotherapy is not recommended in patients with a PS≥2 and/or impaired renal function. \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">B \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">For localised, muscle-invasive, N0 M0 UC of the bladder, chemotherapy alone is not recommended as the primary therapy. \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">A \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184364.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations for neoadjuvant chemotherapy." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "LE=level of evidence; RT=radiation therapy; GR=grade of recommendation; BCa=bladder cancer; RC=radical cystectomy." "tablatextoimagen" => array:2 [ 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">Conclusions \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">LE \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">Preoperative RT can lead to downstaging. \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">2 \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">Toxicity is not significantly increased. \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">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184366.png" ] ] 1 => 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">Recommendation \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">GR \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">Preoperative RT for operable muscle-invasive BCa followed by RC does not increase survival and therefore is not recommended. \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">B \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184369.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Preoperative radiotherapy: conclusions and recommendations." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "LE=level of evidence; RC=radical cystectomy; UD=urinary diversion; GR=grade of recommendation; BCa=bladder cancer." "tablatextoimagen" => array:2 [ 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">Conclusions \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">LE \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">Male patients: standard curative RC is defined as the complete removal of the urinary bladder and all visible tumour, adjacent distal ureters, and lymph nodes corresponding to the tumour-bearing bladder. \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">3 \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">Male patients: preservation of the entire or anterior urethra, rhabdosphincter, prostate, seminal vesicles, and intrapelvic autonomic and sensory nerves are all technical variations to the above standard. \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">3 \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">Female patients: standard anterior pelvic exenteration includes removal of the entire urethra, adjacent vagina, uterus, distal ureters, and respective lymph nodes. \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">3 \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">Ureterocutaneostomy is the least burdensome type of UD for patients with compromised general health. \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">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184363.png" ] ] 1 => 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">Recommendations \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">GR \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">In T2–T4a N0 M0 and high-risk non-muscle-invasive BCa, RC remains the recommended treatment. \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">A<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">In female patients, tumour permitting, preserve a major part of a functioning urethra and its supplying autonomous nerves in the case of a planned orthotopic neobladder. \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">C \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">Simultaneous removal of pelvic lymph nodes is recommended as an integral part of RC and anterior pelvic exenteration. \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">B \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">Laparoscopic cystectomy and pelvic lymphadenectomy, with or without robotic assistance, in conjunction with extracorporeal UD is an option for surgical treatment. \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">C \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">Treatment is recommended at centres experienced in cystectomy, major types of diversion techniques, and postoperative care.<a class="elsevierStyleCrossRefs" href="#bib0220">45,49</a> \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">C \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">In the absence of any interfering psychological or physical abnormality or disease, an orthotopic bladder substitute should be offered to male and female patients lacking any oncologic contraindications. \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">C \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184374.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Upgraded following panel consensus." ] ] ] "descripcion" => array:1 [ "en" => "Conclusions and recommendations for radical cystectomy and urinary diversion." ] ] 3 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "RFS=recurrence-free survival." "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">Reference \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. of patients</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">Median follow-up, mo \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">RFS \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Recurrence</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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">Male \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">Female \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">5yr, % \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">10yr, % \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">Local only, % \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">Distant only, % \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">Stein<a class="elsevierStyleCrossRef" href="#bib0210">43</a> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1054 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">122 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \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">Madersbacher<a class="elsevierStyleCrossRef" href="#bib0215">44</a> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">507 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 \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">Hautmann<a class="elsevierStyleCrossRef" href="#bib0185">38</a> \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">788 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184373.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Largest single-institution studies looking at recurrence-free survival rates after cystectomy.<a class="elsevierStyleCrossRefs" href="#bib0185">38,43,44</a>" ] ] 4 => array:7 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "GR=grade of recommendation; RC=radical cystectomy; BCa=bladder cancer; QoL=quality of life; UD=urinary diversion." "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">Recommendation \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">GR \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oncologic outcome</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">For patients with inoperable locally advanced tumours (T4b), primary RC is a palliative option and not recommended as a curative treatment. \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">C \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">In patients with invasive BCa >80yr of age, cystectomy is an option. \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">C \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">For palliative cystectomy, surgery-related morbidity and QoL should be weighed against other options. \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">C \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Surgical outcome</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">Surgical complications of cystectomy and UD should be reported in a uniform grading system. Currently, the best-adapted graded system for cystectomy is the Clavien grading system. \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">B \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">Comorbidity, age, previous treatment for BCa or other pelvic diseases, surgeon and hospital volume of cystectomy, and type of UD influence surgical outcome. \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">B \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184367.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendations regarding outcome after surgery." ] ] 5 => array:7 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "EBRT=external-beam radiation therapy; RC=radical cystectomy; GR=grade of recommendation; BCa=bladder cancer." "tablatextoimagen" => array:2 [ 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 " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Definitive EBRT</td></tr><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">Conclusion \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">LE \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">Previously irradiated patients undergoing RC later on have a higher risk of early complications. \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">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184371.png" ] ] 1 => 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">Recommendations \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">GR \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Definitive EBRT</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">EBRT as a primary approach is only recommended when the patient is unfit for cystectomy. \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">C \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chemotherapy</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">Chemotherapy alone is not recommended as the primary therapy for localised BCa. \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">A \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184365.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Bladder-sparing treatments for localised disease." ] ] 6 => array:7 [ "identificador" => "tbl0035" "etiqueta" => "Table 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "GR=grade of recommendation; GC=gemcitabine and cisplatin; M-VAC=methotrexate, vinblastine, adriamycin, and cisplatin; PS=performance status; Carbo/Gem=carboplatin and gemcitabine; LE=level of evidence." "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">Recommendation \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">GR \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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Standard first-line chemotherapy for “fit” patients</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">First-line treatment for cisplatin-eligible patients (“fit”) is cisplatin-containing combination chemotherapy with GC or M-VAC. \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">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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chemotherapy in patients ineligible (“unfit”) for cisplatin</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">For cisplatin-ineligible patients (“unfit”) with either a PS 2 or impaired renal function or with 0–1 poor Bajorin prognostic factors, first-line treatment is carboplatin-containing combination chemotherapy, preferably with Carbo/Gem. \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">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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\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 " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Second-line chemotherapy</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">In patients progressing after platinum-based combination chemotherapy for metastatic disease, a trial of vinflunine should be offered, which has the highest LE to date, or clinical trials of other treatments. \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">A<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 => "xTab184372.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Grade A recommendation is weakened by a problem of statistical significance." ] ] ] "descripcion" => array:1 [ "en" => "Chemotherapy in metastatic bladder cancer." ] ] 7 => array:7 [ "identificador" => "tbl0040" "etiqueta" => "Table 8" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "GR=grade of recommendation; BCa=bladder cancer." "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">Recommendation \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">GR \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">Currently, no biomarkers can be recommended in daily clinical practice because they have no impact on predicting outcome, treatment decisions, or monitoring therapy in invasive BCa. \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">A<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184370.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Upgraded following panel consensus." ] ] ] "descripcion" => array:1 [ "en" => "Recommendation on the use of biomarkers." ] ] 8 => array:7 [ "identificador" => "tbl0045" "etiqueta" => "Table 9" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "GR=grade of recommendation." "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">Recommendation \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">GR \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">Patients with metastatic bone disease should receive bisphosphonate treatment. \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">A \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab184368.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Recommendation on supportive therapy." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:93 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Oxford Centre for Evidence-based Medicine – levels of evidence (March 2009). Centre for Evidence-based Medicine. Available from: <a class="elsevierStyleInterRef" href="http://www.cebm.net/index.aspx%3Fo=1025">http://www.cebm.net/index.aspx?o=1025</a> [updated March 2009]." ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Can patient selection for bladder preservation be based on response to chemotherapy?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.11232" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "2003" "volumen" => "97" "paginaInicial" => "1644" "paginaFinal" => "1652" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.ju.0000039620.76907.0d" "Revista" => array:6 [ "tituloSerie" => "J Urol" "fecha" => "2003" "volumen" => "169" "paginaInicial" => "110" "paginaFinal" => "115" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 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=> array:2 [ "titulo" => "Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "Advanced Bladder Cancer (ABC) Meta-analysis Collaboration" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.eururo.2005.04.005" "Revista" => array:7 [ "tituloSerie" => "Eur Urol" "fecha" => "2005" "volumen" => "48" "paginaInicial" => "189" "paginaFinal" => "201" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0140673612614287" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => 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Treatment of muscle-invasive and metastatic bladder cancer: Update of the EAU guidelines

Tratamiento del cáncer de vejiga con invasión muscular y metastásico: actualización de la Guía Clínica de la EAU

A. Stenzla,

Corresponding author

Urologie@med.uni-tuebingen.de

Corresponding author.

, N.C. Cowanb, M. De Santisc, M.A. Kuczykd, A.S. Merseburgerd, M.J. Ribale, A. Sheriff, J.A. Witjesg

a Servicio de Urología, Universidad Eberhard-KarlsTuebingen, Tuebingen, Germany

b Servicio de Radiología, The Churchill Hospital, Oxford, United Kingdom

c Servicio de Médico y ACR-ITR/CEADDP y LBI-ACR Vienna-CTO, Kaiser Franz Josef Spital, Viena, Austria

d Servicio de Urología y Oncología Urológica, Escuela de Medicina de Hannover (MHH), Hannover, Germany

e Servicio de Urología, Clínica Hospitalaria, Universidad de Barcelona, Barcelona, Spain

f Servicio de Urología, Hospital Universitario Karolinska, Estocolmo, Sweden

g Servicio de Urología, Universidad Centro Médico Radboud Nijmegen, Nijmegen, Netherlands

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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">This is the first major update of the guidelines on muscle-invasive and metastatic bladder cancer &#40;MiM-BC&#41; published by the European Association of Urology &#40;EAU&#41; Guideline Panel in 2008&#46; Most of the change has taken place in the surgical and medical treatment of the disease&#44; and this overview therefore focuses on altered recommendations for the management of MiM-BC&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The intention of these EAU guidelines&#44; produced by a panel of international multidisciplinary experts in this field&#44; is to support urologists in assessing evidence-based management of MiM-BC and incorporating guideline recommendations into their clinical practice&#46; Comprehensive literature searches were designed for each section of the MiM-BC guideline with the help of an expert external consultant&#46; Following detailed internal discussion&#44; searches were carried out in the Cochrane Database of Systematic Reviews&#44; the Cochrane Collaboration&#39;s Central Register of Controlled Clinical Trials&#44; Medline&#44; and Embase on the Dialog DataStar platform&#46; The searches used the narrowest single terms available in the controlled vocabulary of the respective databases&#46; Those terms were <span class="elsevierStyleItalic">urinary bladder neoplasm</span> in Medical Subject Headings &#40;MeSH&#41; for Medline and <span class="elsevierStyleItalic">bladder cancer</span> in Emtree for Embase&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Results of all searches were scan-read by panel members&#46; In many cases&#44; there was a high &#8220;numbers needed to read&#8221; because of the sensitivity of the search&#46; There is clearly a need for continuous reevaluation of the information presented in the current guideline by an expert panel&#46; Even though the current guideline update contains information on the treatment of an individual patient according to a standardised approach&#44; it must be emphasised that the recommendations based on the literature research cannot be binding because of either a nonstandardised approach or an unusual situation or desire in individual patients&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this article&#44; we have grouped the various discussions and recommendations of treatment options of MiM-BC into localised bladder cancer &#40;BCa&#41; and metastatic BCa&#46; The level of evidence &#40;LE&#41; and grade of recommendation &#40;GR&#41; provided in this guideline of treatment options follow the listings outlined in the full-text version &#40;see <a href="http://www.uroweb.org/guidelines/online-guidelines/">http&#58;&#47;&#47;www&#46;uroweb&#46;org&#47;guidelines&#47;online-guidelines&#47;</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Localised invasive bladder cancer</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Localised invasive BCa</span> is defined as histologically verified T<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1 N0 M0 disease&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Neoadjuvant chemotherapy</span><p id="par0030" class="elsevierStylePara elsevierViewall">Neoadjuvant chemotherapy is administered to patients with clinically operable&#44; muscle-invasive &#40;N0 M0&#41;&#44; urothelial cancer &#40;UC&#41; of the urinary bladder before the planned definitive surgery &#40;or radiation&#41;&#46; Neoadjuvant chemotherapy has many advantages&#58; &#40;1&#41; It is delivered at the earliest time-point&#44; when the burden of micrometastatic disease is expected to be low&#59; &#40;2&#41; there is a potential reflection of in vivo chemosensitivity&#59; &#40;3&#41; the tolerability of chemotherapy is expected to be better before cystectomy rather than after it&#59; and &#40;4&#41; hypothetically&#44; patients with micrometastatic disease might respond to neoadjuvant therapy and reveal favourable pathologic status&#44; as determined mainly by negative lymph node status and negative surgical margins&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">However&#44; neoadjuvant chemotherapy also has potential disadvantages&#58; &#40;1&#41; Patients without micrometastatic disease&#8212;approximately half of which are clinically N0 M0 patients&#8212;will receive unnecessary treatment&#59; &#40;2&#41; staging errors may hypothetically lead to overtreatment&#59; &#40;3&#41; the delay in cystectomy may compromise outcomes in patients who do not respond to chemotherapy<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;4</span></a>&#59; and &#40;4&#41; chemotherapy may have side-effects that affect the outcome of surgery and type of urinary diversion &#40;UD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In a randomised trial of cystectomy following neoadjuvant chemotherapy&#44; the overall morbidity showed the same distribution of postoperative grade 3&#8211;4 complications in both trial arms&#46; However&#44; preoperative anaemia and neuropathy were more common in the chemotherapy-treated group&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In the combined Nordic trials NCS1<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>NCS2 &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>620&#41;&#44; neoadjuvant chemotherapy did not have any major adverse effect on the percentage of performable cystectomies&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">As a result of a 5&#8211;8&#37; overall survival &#40;OS&#41; advantage in recently published studies and meta-analyses&#44; neoadjuvant cisplatin-containing combination chemotherapy should be considered and discussed with the patient in cases of muscle-invasive&#44; node-negative&#44; and nonmetastatic &#40;N0 M0&#41; urinary bladder carcinoma&#44; irrespective of definitive treatment<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> &#40;LE&#58; 1&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In patients&#44; a performance status &#40;PS&#41;<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2 and&#47;or impaired renal function are contraindications for neoadjuvant chemotherapy &#40;LE&#58; 1&#41;&#46; Generally&#44; chemotherapy alone is not recommended as the primary therapy for localised&#44; muscle-invasive&#44; N0 M0&#44; UC of the bladder<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> &#40;LE&#58; 1&#41;&#46; A summary of the treatment recommendations can be found in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Preoperative radiation therapy</span><p id="par0055" class="elsevierStylePara elsevierViewall">Several retrospective studies have looked at the effect of preoperative radiation therapy &#40;RT&#41; in patients with BCa&#44; suggesting downstaging in 40&#8211;65&#37; of patients&#44; improved local control in 10&#8211;42&#37; of patients&#44; and improved survival in 11&#8211;12&#37; of patients&#46; Improved local control seemed highest in T3b tumours&#44; and a pathologically confirmed&#44; complete remission after RT appeared to be a positive prognostic factor for survival&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Randomised studies have investigated preoperative RT&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Although the results from these trials suggested that there was an advantage in both downstaging and survival&#8212;especially in &#8805;pT3 tumours&#8212;as well as better results in pathologic complete responders and limited toxicity of neoadjuvant RT&#44; all the studies had severe limitations&#44; including no documentation of the effect on local recurrences in all the studies&#46; Furthermore&#44; a meta-analysis of the trials showed an odds ratio &#40;OR&#41; for the difference in 5-yr survival of 0&#46;71 &#40;95&#37; confidence interval &#91;CI&#93;&#44; 0&#46;48&#8211;1&#46;06&#41;&#46; However&#44; the meta-analysis was potentially biased by results from the largest trial&#44; in which patients were not given the planned treatment&#46; When the results of the largest trial were excluded&#44; the OR became 0&#46;95 &#40;95&#37; CI&#44; 0&#46;57&#8211;1&#46;55&#41;&#44; indicating that improved survival with preoperative RT had not been proven&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Although a more recent study has reached similar conclusions&#44; the results&#44; unfortunately&#44; suffer from the same limitations&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents a summary of the conclusions and a recommendation regarding preoperative therapy&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Cystectomy and urinary diversion</span><p id="par0070" class="elsevierStylePara elsevierViewall">To date&#44; there have been no randomised studies comparing removal of the entire urinary bladder and associated lymph nodes with bladder-preserving treatment strategies&#46; However&#44; efforts to evaluate multimodality treatment in a prospective&#44; randomised fashion are being developed&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Radical cystectomy &#40;RC&#41; remains the preferred treatment option for patients with advanced&#44; localised urothelial BCa<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> &#40;LE&#58; 2a&#41;&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Standard surgical technique</span><p id="par0075" class="elsevierStylePara elsevierViewall">In male patients&#44; the literature over the past two decades has set the standard of surgical limits for curative RC&#44; which involves complete removal of the bladder with all macroscopically visible and resectable bladder-perforating tumour extensions&#44; removal of the adjacent distal ureters&#44; and removal of the lymph nodes corresponding to the tumour-bearing bladder&#46; Technical variations from this standard that may improve patients&#8217; quality of life &#40;QoL&#41; include preservation of &#40;1&#41; anterior and membranous urethra&#44; including the rhabdosphincter&#44; to enable an orthotopic neobladder&#59; &#40;2&#41; parts of the prostate and seminal vesicles for reasons of fertility&#44; potency&#44; and continence&#59; and &#40;3&#41; intrapelvic autonomic and sensory nerves to enhance potency and continence&#46; However&#44; these variations must be carefully judged against the potential for increased oncologic risk<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> &#40;LE&#58; 3&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Preservation of parts of the prostatic gland during resection carry risks as high as 23&#8211;54&#37; of unsuspected adenocarcinomas&#44; of which up to 29&#37; may be clinically significant&#44; leading to local recurrence or even metastasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a> Because UC may be present in the prostate&#44; in some series&#44; only 26&#8211;33&#37; of patients undergoing cystoprostatectomy were found to have neither prostate cancer nor prostatic UC&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> A recently developed technical variation that aimed to better preserve the surrounding autonomic nerves involves deliberately leaving out the seminal vesicles&#44; with or without the prostatic capsule&#46; The results for potency versus oncologic risk in small series of selected patients have been encouraging&#44; but long-term confirmation is needed for using larger series&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In female patients&#44; standard anterior pelvic exenteration includes the bladder&#44; entire urethra&#44; adjacent vagina&#44; uterus&#44; distal ureters&#44; and respective lymph nodes &#40;LE&#58; 3&#59; GR&#58; C&#41;&#46; Unless the primary tumour is located at the bladder neck or in the urethra&#44; it is possible to preserve a major part of the functioning female urethra and &#40;provided a complete tumour resection is possible&#41; its supplying autonomous nerves in case of a planned orthotopic neobladder<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;20</span></a> &#40;LE&#58; 3&#41;&#46; New data also question the necessity of removing the uterus or any portion of the vagina in favour of providing improved anatomic support for the neobladder and better preservation of surrounding autonomous nerves&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In both sexes&#44; the length of the distal ureteral segment to be removed with the bladder has not been specified&#46; It depends on oncologic status &#40;e&#46;g&#46;&#44; tumour extension or the presence of carcinoma in situ and the type of subsequent UD&#41;&#46; In a recent study&#44; a frozen section of the distal ureteral margins had a sensitivity of 74&#37; and a specificity of 99&#46;8&#37;&#44; resulting in an overall accuracy of 98&#46;3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> With a serial sectioning strategy&#44; most initially positive ureteral margins can be converted into negative final margins&#46; These patients are at decreased risk of developing upper urinary tract recurrent disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Current literature unanimously supports the simultaneous removal of pelvic lymph nodes together with the tumour-bearing bladder &#40;LE&#58; 3&#41;&#46; Retrospective studies have shown that extended lymphadenectomy can improve survival in patients with muscle-invasive BCa&#46; The true curative value of lymph node dissection &#40;LND&#41;&#44; however&#44; is still unknown&#44; and a standardised LND is yet to be defined&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;24</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Several localisation studies with regards to lymphadenectomy<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#8211;27</span></a> have demonstrated both retrospectively and prospectively that lymph nodes in BCa patients are not found outside the pelvis if the pelvic lymph nodes are free of tumour<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">28</span></a> &#40;LE&#58; 3&#41;&#46; Furthermore&#44; both progression-free survival and OS may be correlated with the amount of lymph nodes removed during surgery&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Both laparoscopic RC and the robot-assisted procedure have been shown to be feasible&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">29</span></a> However&#44; the recommendation for minimally invasive techniques is still optional and reserved for surgeons skilled in this technique for reasons of selection bias&#44; including the patient&#39;s general health status&#44; tumour stage&#44; or type of UD chosen as well as the generally much smaller&#44; reported series compared to open cystectomy reports&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">30</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Laparoscopic intracorporeal construction of UD with or without robotic assistance has been tested in small series only&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">29&#44;31</span></a> It is a challenging and lengthy procedure with the technical equipment currently available and must therefore be regarded as experimental&#46; Laparoscopic cystectomy and pelvic lymphadenectomy &#40;with or without robotic assistance&#41;&#44; with extracorporeal construction of UD&#44; is an option for surgical treatment &#40;LE&#58; 3&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Urinary diversion after radical cystectomy</span><p id="par0115" class="elsevierStylePara elsevierViewall">From an anatomic standpoint&#44; three alternative forms of UD outlet are presently used after cystectomy&#58; abdominal&#44; urethral&#44; and rectosigmoid&#46; In the case of an abdominal or rectosigmoid diversion&#44; the ureters can be diverted either directly &#40;ureterocutaneostomy or ureterorectosigmoidostomy&#41; or by interposing an intestinal segment&#44; such as stomach&#44; ileum&#44; colon&#44; or appendix&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">32</span></a> According to large series&#44; the most common abdominal rerouting is ureteroileocutaneostomy or a Bricker ileal conduit&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In a recent retrospective comparison with short or median follow-up of 16<span class="elsevierStyleHsp" style=""></span>mo&#44; the diversion-related complication rate was considerably lower for ureterocutaneostomy compared to an ileal or colon conduit&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">33</span></a> Despite the limited comparative data available&#44; it has to be taken into consideration that older data and clinical experience suggest stricturing at the skin level and ascending urinary tract infection more frequently as compared to ileal conduit&#46; In a retrospective study comparing various forms of intestinal diversion&#44; ileal conduits had fewer late complications than continent abdominal pouches or orthotopic neobladders&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">34</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Several studies have compared certain aspects of health-related QoL&#44; including sexual function&#44; urinary continence&#44; and body image&#44; in patient cohorts with different types of UD&#46; However&#44; more research is necessary in this field&#46; It is not possible to evaluate QoL issues for a type of UD without taking into account other factors&#44; such as preoperative tumour stage&#44; patient age and expectations&#44; functional situation&#44; socioeconomic status&#44; experience of the treating urologist&#44; and possible surgical complications&#46; Currently&#44; it is not possible to recommend a particular type of UD&#44; except to say that ureterocutaneostomy is surgically the least-burdensome type of diversion for the patient &#40;LE&#58; 3&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Patients undergoing any type of UD have to be motivated to learn to cope with their diversion and to develop the manual dexterity required&#46; Debilitating neurologic and psychiatric illnesses&#44; limited life expectancy&#44; impaired liver or renal function&#44; and UC of the urethral margin or other surgical margins have been defined as contraindications to more complex forms of intestinal UD &#40;LE&#58; 2b&#41;&#46; Relative contraindications specific to an orthotopic neobladder are high-dose preoperative RT&#44; complex urethral stricture disease&#44; and severe urethral sphincter-related incontinence<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">35&#8211;38</span></a> &#40;LE&#58; 2b&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">There are no explicit data that age precludes any type of UD&#46; However&#44; because of an increasing number of underlying morbidities and reduced general health status&#44; most patients older than 75<span class="elsevierStyleHsp" style=""></span>yr of age receive an incontinent form of UD following cystectomy&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">39</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Standard RC in male patients with bladder neoplasms includes removal of the entire bladder&#44; prostate&#44; seminal vesicles&#44; distal ureters &#40;length of the segment undefined&#41;&#44; and corresponding lymph nodes &#40;extent undefined&#59; LE&#58; 2b&#41;&#46; Currently&#44; it is not possible to recommend a particular type of UD&#46; However&#44; most institutions prefer ileal orthotopic neobladders and ileal conduits based on clinical experience&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;36</span></a> In selected patients&#44; ureterocutaneostomy is surgically the least-burdensome type of diversion &#40;LE&#58; 3&#59; GR&#58; C&#41;&#46; Recommendations related to RC and UD are listed in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Oncologic outcome after surgery</span><p id="par0145" class="elsevierStylePara elsevierViewall">Recurrence-free survival &#40;RFS&#41; and OS in male and female patients is reported as 66&#8211;68&#37; and 58&#8211;66&#37; at 5<span class="elsevierStyleHsp" style=""></span>yr and 60&#8211;73&#37; and 43&#8211;49&#37; at 10<span class="elsevierStyleHsp" style=""></span>yr&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In node-positive patients&#44; 10-yr disease-specific survival and OS rates were reduced to 27&#46;7&#37; and 20&#46;9&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">40</span></a> These results &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41; have to date not been reached in stage-equivalent large studies with bladder-sparing treatment alternatives&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Nomograms on cancer-specific survival &#40;CSS&#41; following RC have been developed and externally validated&#44; but their wider use cannot be recommended prior to further data&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">41&#44;42</span></a> In a retrospective series of 768 male patients by Stein et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">37</span></a> the overall urethral recurrence rate was 6&#37;&#44; irrespective of UD&#46; In a multivariate statistical analysis&#44; prostatic involvement by the primary tumour and cutaneous UD was independently associated with an increased risk for the development of second primary tumours &#40;LE&#58; 2b&#41;&#46; The calculated risk of second primary tumours was 5&#37; and 9&#37; for patients with an orthotopic and cutaneous UD&#44; respectively&#46; A difference for second primary tumours&#44; depending on initial prostatic tumour involvement&#44; was apparent for both superficial &#40;12&#37; vs 5&#37;&#41; and invasive UC &#40;18&#37; vs 5&#37;&#41;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Cystectomy is associated with the greatest risk reduction in disease-related and non-disease-related death in patients older than 80<span class="elsevierStyleHsp" style=""></span>yr of age&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">45</span></a> The largest&#44; retrospective&#44; single-institution study on cystectomy to date demonstrated that patients older than 80<span class="elsevierStyleHsp" style=""></span>yr of age did have an increased postoperative morbidity but not increased mortality<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">45</span></a> &#40;LE&#58; 3&#41;&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Remnant disease may be inevitable in patients with locally advanced pelvic cancer and urinary bladder involvement&#46; However&#44; in these cases&#44; palliative RC and UD&#8212;with or without using intestinal segments&#8212;is performed only for the relief of symptoms such as pain&#44; recurrent bleeding&#44; urgency&#44; and fistula formation&#46; The morbidity associated with surgery and QoL should be weighed against other options &#40;LE&#58; 3&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">45&#8211;47</span></a><a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> lists the recommendations regarding oncologic outcome after surgery&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Outcome of radical surgery</span><p id="par0165" class="elsevierStylePara elsevierViewall">Most surgical complications are associated with UD&#44; of which a great portion is related to the use of intestinal segments&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">35&#44;38</span></a> Variables such as patient factors&#44; surgeon&#39;s skills&#44; hospital volume&#44; and type of UD all influence the rate&#44; type&#44; and severity of surgical complications &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">45&#8211;49</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">When reporting surgical complications in cystectomy&#44; regardless of the technique used&#44; a standardised and reproducible classification of surgical complications should be applied&#46; Complications of several urologic procedures&#44; including open<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">50</span></a> and laparoscopic cystectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">51</span></a> have recently been reported using the modified&#44; five-grade Clavien system&#44; which has been tested in &#62;6300 surgical procedures&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">52</span></a> Alternatively&#44; complications have been reported with the Common Terminology Criteria for Adverse Events&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">53</span></a> Early and late complications following surgery are defined as those that occur within 90<span class="elsevierStyleHsp" style=""></span>d and after 90<span class="elsevierStyleHsp" style=""></span>d&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">50&#44;54</span></a> In the most recent reports on cystectomy&#44; an adverse event of any grade was seen in 54&#8211;58&#37; of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">50&#44;53&#44;55</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bladder-sparing treatments for localised disease</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Definitive external-beam radiation therapy</span><p id="par0175" class="elsevierStylePara elsevierViewall">The target field usually comprises the bladder only&#44; with a safety margin of 1&#46;5&#8211;2<span class="elsevierStyleHsp" style=""></span>cm&#46; The target dose for curative RT for BCa is 60&#8211;66<span class="elsevierStyleHsp" style=""></span>Gy&#46; Modern RT techniques result in major&#44; late gastrointestinal or genitourinary morbidity in &#60;5&#37; of patients&#46; Overall 5-yr survival rates range between 30&#37; and 60&#37;&#44; with a CSS rate of 20&#8211;50&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">56&#8211;58</span></a> Prognostic factors for RT were addressed in a recent Italian single-institution series of 459 irradiated patients&#44; including approximately 30&#37; of unfit T1 patients&#44; with an average of 4&#46;4-yr follow-up&#46; Significant factors were age&#44; T category &#40;for all end points&#41;&#44; and tumour dose &#40;only for failure-free survival&#41; in a multivariate survival analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">59</span></a> Based on available trials&#44; a Cochrane analysis has demonstrated that RC has an OS benefit compared with RT&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">60</span></a> However&#44; external-beam RT &#40;EBRT&#41; can be an alternative in patients unfit for radical surgery&#44; with a cystoscopically assessed&#44; complete remission rate at 3<span class="elsevierStyleHsp" style=""></span>mo of 78&#37; and a 3-yr local control rate of 56&#37;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">61</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46; A recent single-institution report investigating the 90-d early complication rate of RC after full-dose RT found a higher complication rate according to the Clavien reporting system in 148 irradiated patients versus 2480 nonirradiated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">62</span></a></p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Chemotherapy</span><p id="par0180" class="elsevierStylePara elsevierViewall">Chemotherapy alone rarely produces durable complete responses &#40;CR&#41; of the primary tumour&#46; In general&#44; a clinical CR rate of up to 56&#37;&#44; as reported in some series&#44; must be weighed against a staging error of &#62;60&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8</span></a> Response to chemotherapy is a prognostic factor for treatment outcome and eventual survival&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> though it may be confounded by patient selection&#46; Several groups have reported the effect of chemotherapy on resectable tumours &#40;neoadjuvant approach&#41; as well as nonresectable primary tumours&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;63&#44;64</span></a> Two to three cycles of methotrexate&#44; vinblastine&#44; adriamycin&#44; and cisplatin &#40;M-VAC&#41; or gemcitabine and cisplatin &#40;GC&#41; achieved not only downstaging of the primary tumour but also pathologic CRs of bladder primary tumours in 12&#8211;50&#37; of patients after M-VAC and in 12&#8211;22&#37; of patients after GC in phase 2 and phase 3 trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;63&#44;65</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Contemporary series with GC followed by RC reported inferior pT0 rates&#44; which may have been related to a low dose density and inappropriate delay of surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">66</span></a> As for bladder preservation&#44; a response is evaluated by cystoscopy and computed tomography imaging only&#44; followed by close surveillance&#46; This approach is prone to an imminent staging error&#44; which can put the patient at risk for local recurrence and&#47;or consecutive metastatic disease&#46; For highly selected patients&#44; a bladder-conserving strategy with transurethral resection of the bladder and systemic cisplatin-based chemotherapy&#8212;preferably with M-VAC&#8212;may allow long-term survival with an intact bladder&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> However&#44; this approach cannot be recommended for routine use&#46;</p></span></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Metastatic bladder cancer</span><p id="par0190" class="elsevierStylePara elsevierViewall">Advanced BCa is a chemosensitive tumour&#46; Response rates differ with respect to patient-related factors and pretreatment disease&#46; Prognostic factors for response and survival have been established&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">67&#8211;71</span></a> A major prognostic factor is the suitability of patients for treatment with a cisplatin-based combination chemotherapy&#46; Cisplatin remains the most effective single agent for treatment of UC&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Factors preventing patients from receiving cisplatin at any dose include age&#59; obstructing disease&#59; chronic upper tract inflammation&#59; or metabolic changes subsequent to bowel interposition after cystectomy&#44; general health status&#44; and&#47;or poor renal function&#46; Patients are categorised into &#8220;fit&#8221; or &#8220;unfit&#8221; for the purpose of receiving cisplatin-containing combination chemotherapy<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">72</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Standard first-line chemotherapy for &#8220;fit&#8221; patients</span><p id="par0200" class="elsevierStylePara elsevierViewall">The use of M-VAC and GC both result in prolonged survival of up to 14&#46;8 and 13&#46;8<span class="elsevierStyleHsp" style=""></span>mo&#44; respectively&#44; also with long-term follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">73&#8211;76</span></a> The lower toxicity of GC&#44; however&#44; has resulted in GC increasingly becoming a new standard regimen&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">75</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Although all disease sites have been shown to respond to cisplatin-based combination chemotherapy&#44; most studies have reported the response in lymph nodes&#46; A response rate of 66&#37; and 77&#37; with M-VAC and high-dose &#40;HD&#41;-M-VAC&#44; respectively&#44; has been reported in retroperitoneal lymph nodes versus 29&#37; and 33&#37; at extranodal sites&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">77&#44;78</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The sites of disease also affect long-term survival&#46; In lymph node-only disease&#44; 20&#46;9&#37; of patients were alive at 5<span class="elsevierStyleHsp" style=""></span>yr compared to only 6&#46;8&#37; of patients with visceral metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">76</span></a> To date&#44; further intensification of treatment using new triplets&#44; dose-dense schedules&#44; or adding targeted therapies has not proven superior to GC or M-VAC and is still being investigated&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">79&#44;80</span></a> The recommendation for first-line treatment for fit patients remains cisplatin-containing combination chemotherapy with GC or M-VAC&#44; preferably with granulocyte-stimulating colony factor &#40;GSCF&#41; or HD-M-VAC with GCSF &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Chemotherapy in patients ineligible &#40;&#8220;unfit&#8221;&#41; for cisplatin</span><p id="par0215" class="elsevierStylePara elsevierViewall">Up to 50&#37; of patients are ineligible for cisplatin-containing chemotherapy&#44; either because of a poor PS and&#47;or impaired renal function or because of comorbidity preventing high-volume hydration&#46; The first randomised phase 2&#47;3 trial in this setting was conducted by the European Organisation for Research and Treatment of Cancer and compared methotrexate&#44; carboplatin&#44; and vinblastine &#40;M-CAVI&#41; and carboplatin and gemcitabine &#40;Carbo&#47;Gem&#41; in patients unfit for cisplatin&#46; Both regimens were active&#46; Severe acute toxicity &#40;SAT&#41; was 13&#46;6&#37; in patients given Carbo&#47;Gem versus 23&#37; on M-CAVI&#44; while the overall response rate was 42&#37; on Carbo&#47;Gem and 30&#37; on M-CAVI&#46; Further analysis showed that combination chemotherapy provides limited benefit in patients with PS 2 and impaired renal function&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">81</span></a> The overall response rate and SAT were both 26&#37; for the former group and 20&#37; and 24&#37;&#44; respectively&#44; for the latter group&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">81</span></a> Recent phase 3 data have confirmed these results&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Second-line chemotherapy</span><p id="par0220" class="elsevierStylePara elsevierViewall">Second-line chemotherapy data are highly variable in this setting&#46; Vinflunine is a novel&#44; third-generation vinca alkaloid that has shown objective response rates of 18&#37; and disease control in 67&#37; of trial subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">82</span></a> A phase 3 trial of vinflunine plus best supportive care &#40;BSC&#41; randomised against BSC alone in patients progressing after first-line treatment with platinum-containing combination chemotherapy for metastatic disease was recently published&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">83</span></a> The results showed modest activity &#40;overall response rate&#58; 8&#46;6&#37;&#41;&#44; a clinical benefit with a favourable safety profile&#44; and&#8212;most importantly&#8212;a survival benefit in favour of vinflunine that was statistically significant in the eligible patient population &#40;not in the intention-to-treat population&#41;&#46; For second-line treatment in this clinical setting&#44; this trial reached the highest level of evidence reported to date&#46; Currently&#44; vinflunine is the only approved second-line treatment&#59; any other treatment should take place in the context of clinical trials &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Biomarkers</span><p id="par0225" class="elsevierStylePara elsevierViewall">Statistically&#44; relatively modest disease control rates but &#40;sporadically&#41; remarkable responses in some patients with urothelial BCa have led to investigation of biomarkers for assessment of prognosis after surgery and as an indication for chemotherapy or for its monitoring&#46; Most of the biomarkers were associated with tumour angiogenesis&#46; To date&#44; small studies&#8212;usually retrospective&#8212;have investigated microvessel density&#44; altered p53 tumour expression&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">84</span></a> serum vascular endothelial growth factor&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">85</span></a> urinary and tissue basic fibroblast growth factor &#40;bFGF&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">86</span></a> urinary &#40;wild type and mutant&#41; and tissue FGF receptor-3&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">87</span></a> and&#8212;more recently&#8212;thrombospondin-1&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">88</span></a> the detection of circulating tumour cells&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">89</span></a> and multi-drug-resistance gene expression&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">90</span></a> Although a few biomarkers have shown potential&#44; none has sufficient evidence to support its routine clinical use &#40;LE&#58; 3&#59; <a class="elsevierStyleCrossRef" href="#tbl0040">Table 8</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bisphosphonates</span><p id="par0230" class="elsevierStylePara elsevierViewall">The prevalence of metastatic bone disease &#40;MBD&#41; in patients with advanced&#47;metastatic UC has been reported as 30&#8211;40&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">70</span></a> Skeletal complications resulting from MBD have a detrimental effect on pain and QoL and are also associated with increased mortality&#46; Bisphosphonates reduce and delay skeletal-related events &#40;SRE&#41; from bone metastases by inhibiting bone absorption&#46; Bisphosphonate treatment should therefore be considered for all patients with MBD&#44; irrespective of cancer type<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">91</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0045">Table 9</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0045"></elsevierMultimedia><p id="par0235" class="elsevierStylePara elsevierViewall">To date&#44; only one published randomised&#44; placebo-controlled phase 3 trial has confirmed the beneficial effect of zoledronic acid in treating bone metastases from UC&#46; UC patients treated with zoledronic acid experienced a decrease in SREs and an improvement in their QoL and 1-yr OS&#46; Zoledronic acid is the only bisphosphonate that has been studied<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">92&#44;93</span></a> and approved for the treatment of MBD in all tumour types &#40;LE&#58; 2&#41;&#46; Bisphosphonate treatment should be accompanied by calcium and vitamin D supplementation&#46; Dosing regimens should follow respective regulatory recommendations and should be adjusted according to preexisting medical conditions&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Author contributions</span><p id="par0240" class="elsevierStylePara elsevierViewall">Arnulf Stenzl had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Study concept and design&#58; Stenzl&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Acquisition of data&#58; Stenzl&#44; Cowan&#44; Ribal&#44; Kuczyk&#44; Merseburger&#44; De Santis&#44; Sherif&#44; Witjes&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Analysis and interpretation of data&#58; Stenzl&#44; Cowan&#44; Ribal&#44; Kuczyk&#44; Merseburger&#44; De Santis&#44; Sherif&#44; Witjes&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Drafting of the manuscript&#58; Stenzl&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Critical revision of the manuscript for important intellectual content&#58; Stenzl&#44; Cowan&#44; Ribal&#44; Kuczyk&#44; Merseburger&#44; De Santis&#44; Sherif&#44; Witjes&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Statistical analysis&#58; Stenzl&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Obtaining funding&#58; None&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Administrative&#44; technical&#44; or material support&#58; None&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Supervision&#58; Stenzl&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Other &#40;specify&#41;&#58; None&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Financial disclosures</span><p id="par0295" class="elsevierStylePara elsevierViewall">I certify that all conflicts of interest&#44; including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript &#40;e&#46;g&#46;&#44; employment&#47;affiliation&#44; grants or funding&#44; consultancies&#44; honoraria&#44; stock ownership or options&#44; expert testimony&#44; royalties&#44; or patents filed&#44; received&#44; or pending&#41;&#44; are the following&#58; Prof Dr Stenzl is a consultant for GE Healthcare and Novartis&#59; has received company speaker honoraria from AMGEN and Novartis&#59; and has participated in trials for MEDAC&#44; Photocure&#44; Immatics&#44; Novartis&#44; Johnson &#38; Johnson&#44; and Amgen&#59; and has received research grants from Immatics&#46; Prof Dr Witjes is a consultant for Endo Pharm &#40;2010&#41;&#44; Astellas &#40;2010&#41;&#44; Spectrum Pharmaceuticals &#40;2009&#41;&#44; Sanofi Pasteur &#40;2010&#41;&#44; GE Healthcare &#40;2010&#41;&#44; and Telormedix &#40;2009&#41;&#59; has received a company speaker honorarium from GE Healthcare&#59; and has participated in trials with MEL Amsterdam&#44; Telormedix&#44; and Photocure Oslo&#46; Dr De Santis is a company consultant for GlaxoSmithKline&#44; AMGEN&#44; Bayer&#44; Novartis&#44; and Pierre-Fabre&#59; has received company speaker honoraria from Pfizer&#44; Eli Lilly&#44; Sanofi Aventis&#44; Novartis&#44; and Roche&#59; and has received fellowships and travel grants from Bayer&#44; Novartis&#44; Pfizer&#44; AMGEN&#44; and Sanofi Aventis&#46; Prof Dr Kuczyk holds equity interests in Bayer Healthcare&#44; Astellas&#44; Storz&#44; Pfizer&#44; and Wyeth&#59; is a company consultant for Bayer Healthcare&#44; Pfizer&#44; Astra Zeneca&#44; Astellas&#44; and Storz&#59; has received company speaker honoraria from Bayer&#44; Pfizer&#44; MEDAC&#44; Astellas&#44; Bayer Healthcare&#44; and Astellas&#59; has participated in trials with Astra Zeneca&#44; Pfizer&#44; Bayer Healthcare&#44; Astellas&#44; and Ipsen&#59; and has received research grants from Wyeth&#46; Prof Dr Merseburger is a company consultant for Ipsen Pharma and Bayer&#59; has received company speaker honoraria from Ipsen Pharma&#44; Wyeth&#44; Astellas&#44;Novartis&#44; Pfizer&#44; and SEP&#59; has participated in trials with Astra Zeneca&#44;Bayer&#44; Pfizer&#44; TEVA&#44; and Novartis&#59; and has received research grants fromWyeth&#46; Dr Sherif has received speaker honoraria from Orion Pharma and MEDAC AB&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Funding&#47;support and role of the sponsor&#58; None&#46;</p></span></span>"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Context</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">New data regarding treatment of muscle-invasive and metastatic bladder cancer &#40;MiM-BC&#41; has emerged and led to an update of the European Association of Urology &#40;EAU&#41; guidelines for MiM-BC&#46;</p> <span class="elsevierStyleSectionTitle">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To review the new EAU guidelines for MiM-BC with a specific focus on treatment&#46;</p> <span class="elsevierStyleSectionTitle">Evidence acquisition</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">New literature published since the last update of the EAU guidelines in 2008 was obtained from Medline&#44; the Cochrane Database of Systematic Reviews&#44; and reference lists in publications and review articles and comprehensively screened by a group of urologists&#44; oncologists&#44; and a radiologist appointed by the EAU Guidelines Office&#46; Previous recommendations based on the older literature on this subject were also taken into account&#46; Levels of evidence &#40;LEs&#41; and grades of recommendations &#40;GRs&#41; were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence&#46;</p> <span class="elsevierStyleSectionTitle">Evidence synthesis</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy &#40;RC&#41; is recommended in certain constellations of MiM-BC&#46; RC remains the basic treatment of choice in localised invasive disease for both sexes&#46; An attempt has been made to define the extent of surgery under standard conditions in both sexes&#46; An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications&#44; such as no tumour at the level of urethral dissection&#46; In contrast to neoadjuvant chemotherapy&#44; current advice recommends the use of adjuvant chemotherapy only within clinical trials&#46; Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected&#44; well-informed&#44; and compliant patients for whom cystectomy is not considered for medical or personal reasons&#46; In metastatic disease&#44; the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy&#46; With the advent of vinflunine&#44; second-line chemotherapy has become available&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">In the treatment of localised invasive bladder cancer &#40;BCa&#41;&#44; the standard treatment remains radical surgical removal of the bladder within standard limits&#44; including as-yet-unspecified regional lymph nodes&#46; However&#44; the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups&#46; A new drug for second-line chemotherapy &#40;vinflunine&#41; in metastatic disease has been approved and is recommended&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle">Contexto</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Han surgido nuevos datos sobre el tratamiento del c&#225;ncer de vejiga con invasi&#243;n muscular y metast&#225;sico &#40;CVIMM&#41; que han llevado a una actualizaci&#243;n de la Gu&#237;a Cl&#237;nica de la Asociaci&#243;n Europea de Urolog&#237;a &#40;European Association of Urology&#44; EAU&#41; del CVIMM&#46;</p> <span class="elsevierStyleSectionTitle">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Revisar la nueva Gu&#237;a Cl&#237;nica de la EAU sobre el CVIMM con un enfoque espec&#237;fico en el tratamiento&#46;</p> <span class="elsevierStyleSectionTitle">Adquisici&#243;n de evidencia</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La literatura nueva publicada desde la &#250;ltima actualizaci&#243;n de la Gu&#237;a Cl&#237;nica de la EAU en 2008 se obtuvo de Medline&#44; la Base de Datos Cochrane de Revisiones Sistem&#225;ticas y listas de referencia en publicaciones y art&#237;culos de revisi&#243;n y se examin&#243; exhaustivamente por un grupo de ur&#243;logos&#44; onc&#243;logos&#44; y un radi&#243;logo designado por la Oficina de Gu&#237;as Cl&#237;nicas de la EAU&#46; Tambi&#233;n se tuvieron en cuenta recomendaciones previas basadas en la literatura anterior sobre este tema&#46; Se a&#241;adieron los niveles de evidencia &#40;NE&#41; y grados de recomendaci&#243;n &#40;GR&#41; bas&#225;ndose en un sistema modificado del Centro de Medicina Basada en la Evidencia de Oxford&#46;</p> <span class="elsevierStyleSectionTitle">S&#237;ntesis de evidencia</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los datos actuales demuestran que la quimioterapia neoadyuvante junto con la cistectom&#237;a radical &#40;CR&#41; es recomendable en ciertas constelaciones de CVIMM&#46; La CR sigue siendo el tratamiento b&#225;sico de elecci&#243;n en enfermedad invasiva localizada para ambos sexos&#46; Se ha intentado definir el grado de cirug&#237;a en condiciones est&#225;ndar en ambos sexos&#46; Se deber&#237;a ofrecer un sustituto vesical ortot&#243;pico a pacientes tanto masculinos como femeninos sin contraindicaciones tales como ausencia de tumor al nivel de la disecci&#243;n uretral&#46; En contraste con la quimioterapia neoadyuvante&#44; actualmente se recomienda el uso de quimioterapia adyuvante &#250;nicamente en ensayos cl&#237;nicos&#46; La terapia preservadora de la vejiga multimodalidad en la enfermedad localizada se observa actualmente s&#243;lo como una alternativa en pacientes seleccionados&#44; bien informados y acatadores para los que la cistectom&#237;a no se plantea por razones m&#233;dicas o personales&#46; En la enfermedad metast&#225;sica&#44; el tratamiento de primera l&#237;nea para los pacientes en condiciones suficientes para soportar el cisplatino sigue siendo la poliquimioterapia con cisplatino&#46; Con la llegada de vinflunina&#44; la quimioterapia de segunda l&#237;nea se ha vuelto disponible&#46;</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">En el tratamiento del c&#225;ncer de vejiga &#40;CV&#41; invasivo localizado&#44; el tratamiento est&#225;ndar sigue siendo la extirpaci&#243;n quir&#250;rgica radical de la vejiga dentro de los l&#237;mites est&#225;ndar&#44; incluyendo los ganglios linf&#225;ticos regionales a&#250;n sin especificar&#46; Sin embargo&#44; la adici&#243;n de la quimioterapia adyuvante debe ser considerada para ciertos grupos de pacientes espec&#237;ficos&#46; Se ha aprobado y se recomienda un nuevo medicamento para la quimioterapia de segunda l&#237;nea &#40;vinflunina&#41; en la enfermedad metast&#225;sica&#46;</p>"
      ]
    ]
    "NotaPie" => array:2 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Stenzl A&#44; et al&#46; Tratamiento del c&#225;ncer de vejiga con invasi&#243;n muscular y metast&#225;sico&#58; actualizaci&#243;n de la Gu&#237;a Cl&#237;nica de la EAU&#46; Actas Urol Esp&#46; 2012&#59;36&#58;449&#8211;60&#46;</p>"
      ]
      1 => array:2 [
        "etiqueta" => "&#9734;&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">La traducci&#243;n de este art&#237;culo se ha llevado a cabo con el permiso de la Asociaci&#243;n Europea de Urolog&#237;a&#46;</p>"
      ]
    ]
    "multimedia" => array:9 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#59; BCa<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>bladder cancer&#59; PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>performance status&#59; UC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>urothelial carcinoma&#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">Recommendations&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">GR&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">Neoadjuvant cisplatin-containing combination chemotherapy should be offered in muscle-invasive BCa&#44; irrespective of further treatment&#46;&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">A&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">Neoadjuvant chemotherapy is not recommended in patients with a PS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>2 and&#47;or impaired renal function&#46;&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">B&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">For localised&#44; muscle-invasive&#44; N0 M0 UC of the bladder&#44; chemotherapy alone is not recommended as the primary therapy&#46;&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">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184364.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Recommendations for neoadjuvant chemotherapy&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">LE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>level of evidence&#59; RT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>radiation therapy&#59; GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#59; BCa<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>bladder cancer&#59; RC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>radical cystectomy&#46;</p>"
          "tablatextoimagen" => array:2 [
            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">Conclusions&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">LE&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">Preoperative RT can lead to downstaging&#46;&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">2&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">Toxicity is not significantly increased&#46;&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184366.png"
              ]
            ]
            1 => 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">Recommendation&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">GR&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">Preoperative RT for operable muscle-invasive BCa followed by RC does not increase survival and therefore is not recommended&#46;&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">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184369.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Preoperative radiotherapy&#58; conclusions and recommendations&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">LE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>level of evidence&#59; RC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>radical cystectomy&#59; UD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>urinary diversion&#59; GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#59; BCa<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>bladder cancer&#46;</p>"
          "tablatextoimagen" => array:2 [
            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">Conclusions&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">LE&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">Male patients&#58; standard curative RC is defined as the complete removal of the urinary bladder and all visible tumour&#44; adjacent distal ureters&#44; and lymph nodes corresponding to the tumour-bearing bladder&#46;&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">3&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">Male patients&#58; preservation of the entire or anterior urethra&#44; rhabdosphincter&#44; prostate&#44; seminal vesicles&#44; and intrapelvic autonomic and sensory nerves are all technical variations to the above standard&#46;&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">3&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">Female patients&#58; standard anterior pelvic exenteration includes removal of the entire urethra&#44; adjacent vagina&#44; uterus&#44; distal ureters&#44; and respective lymph nodes&#46;&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">3&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">Ureterocutaneostomy is the least burdensome type of UD for patients with compromised general health&#46;&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184363.png"
              ]
            ]
            1 => 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">Recommendations&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">GR&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">In T2&#8211;T4a N0 M0 and high-risk non-muscle-invasive BCa&#44; RC remains the recommended treatment&#46;&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">A<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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">In female patients&#44; tumour permitting&#44; preserve a major part of a functioning urethra and its supplying autonomous nerves in the case of a planned orthotopic neobladder&#46;&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">C&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">Simultaneous removal of pelvic lymph nodes is recommended as an integral part of RC and anterior pelvic exenteration&#46;&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">B&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">Laparoscopic cystectomy and pelvic lymphadenectomy&#44; with or without robotic assistance&#44; in conjunction with extracorporeal UD is an option for surgical treatment&#46;&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">C&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">Treatment is recommended at centres experienced in cystectomy&#44; major types of diversion techniques&#44; and postoperative care&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">45&#44;49</span></a>&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">C&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">In the absence of any interfering psychological or physical abnormality or disease&#44; an orthotopic bladder substitute should be offered to male and female patients lacking any oncologic contraindications&#46;&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">C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab184374.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara">Upgraded following panel consensus&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Conclusions and recommendations for radical cystectomy and urinary diversion&#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">RFS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>recurrence-free survival&#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">Reference&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">No&#46; of patients</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">Median follow-up&#44; mo&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">RFS&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Recurrence</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&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">Male&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">Female&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">5<span class="elsevierStyleHsp" style=""></span>yr&#44; &#37;&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">10<span class="elsevierStyleHsp" style=""></span>yr&#44; &#37;&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">Local only&#44; &#37;&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">Distant only&#44; &#37;&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">Stein<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">43</span></a>&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1054&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">122&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&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">Madersbacher<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">44</span></a>&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">507&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35&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">Hautmann<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">38</span></a>&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">788&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">65&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab184373.png"
              ]
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Largest single-institution studies looking at recurrence-free survival rates after cystectomy&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">38&#44;43&#44;44</span></a></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">GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#59; RC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>radical cystectomy&#59; BCa<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>bladder cancer&#59; QoL<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>quality of life&#59; UD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>urinary diversion&#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">Recommendation&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">GR&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Oncologic outcome</span></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"><span class="elsevierStyleHsp" style=""></span>For patients with inoperable locally advanced tumours &#40;T4b&#41;&#44; primary RC is a palliative option and not recommended as a curative treatment&#46;&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">C&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"><span class="elsevierStyleHsp" style=""></span>In patients with invasive BCa &#62;80<span class="elsevierStyleHsp" style=""></span>yr of age&#44; cystectomy is an option&#46;&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">C&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"><span class="elsevierStyleHsp" style=""></span>For palliative cystectomy&#44; surgery-related morbidity and QoL should be weighed against other options&#46;&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">C&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Surgical outcome</span></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"><span class="elsevierStyleHsp" style=""></span>Surgical complications of cystectomy and UD should be reported in a uniform grading system&#46; Currently&#44; the best-adapted graded system for cystectomy is the Clavien grading system&#46;&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">B&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"><span class="elsevierStyleHsp" style=""></span>Comorbidity&#44; age&#44; previous treatment for BCa or other pelvic diseases&#44; surgeon and hospital volume of cystectomy&#44; and type of UD influence surgical outcome&#46;&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">B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Recommendations regarding outcome after surgery&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">EBRT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>external-beam radiation therapy&#59; RC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>radical cystectomy&#59; GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#59; BCa<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>bladder cancer&#46;</p>"
          "tablatextoimagen" => array:2 [
            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  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Definitive EBRT</td></tr><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">Conclusion&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">LE&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">Previously irradiated patients undergoing RC later on have a higher risk of early complications&#46;&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">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              ]
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            1 => array:2 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><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">Recommendations&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">GR&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
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Definitive EBRT</span></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"><span class="elsevierStyleHsp" style=""></span>EBRT as a primary approach is only recommended when the patient is unfit for cystectomy&#46;&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">C&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Chemotherapy</span></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"><span class="elsevierStyleHsp" style=""></span>Chemotherapy alone is not recommended as the primary therapy for localised BCa&#46;&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">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#59; GC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>gemcitabine and cisplatin&#59; M-VAC<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>methotrexate&#44; vinblastine&#44; adriamycin&#44; and cisplatin&#59; PS<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>performance status&#59; Carbo&#47;Gem<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>carboplatin and gemcitabine&#59; LE<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>level of evidence&#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">Recommendation&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">GR&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Standard first-line chemotherapy for &#8220;fit&#8221; patients</span></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"><span class="elsevierStyleHsp" style=""></span>First-line treatment for cisplatin-eligible patients &#40;&#8220;fit&#8221;&#41; is cisplatin-containing combination chemotherapy with GC or M-VAC&#46;&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">A&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Chemotherapy in patients ineligible &#40;&#8220;unfit&#8221;&#41; for cisplatin</span></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"><span class="elsevierStyleHsp" style=""></span>For cisplatin-ineligible patients &#40;&#8220;unfit&#8221;&#41; with either a PS 2 or impaired renal function or with 0&#8211;1 poor Bajorin prognostic factors&#44; first-line treatment is carboplatin-containing combination chemotherapy&#44; preferably with Carbo&#47;Gem&#46;&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">A&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Second-line chemotherapy</span></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"><span class="elsevierStyleHsp" style=""></span>In patients progressing after platinum-based combination chemotherapy for metastatic disease&#44; a trial of vinflunine should be offered&#44; which has the highest LE to date&#44; or clinical trials of other treatments&#46;&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">A<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Chemotherapy in metastatic bladder cancer&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><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">Recommendation&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">GR&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">Currently&#44; no biomarkers can be recommended in daily clinical practice because they have no impact on predicting outcome&#44; treatment decisions&#44; or monitoring therapy in invasive BCa&#46;&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">A<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Recommendation on the use of biomarkers&#46;</p>"
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        "etiqueta" => "Table 9"
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        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">GR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>grade of recommendation&#46;</p>"
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                  \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">Recommendation&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">GR&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">Patients with metastatic bone disease should receive bisphosphonate treatment&#46;&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">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:93 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Oxford Centre for Evidence-based Medicine &#8211; levels of evidence &#40;March 2009&#41;&#46; Centre for Evidence-based Medicine&#46; Available from&#58; <a class="elsevierStyleInterRef" href="http://www.cebm.net/index.aspx%3Fo=1025">http&#58;&#47;&#47;www&#46;cebm&#46;net&#47;index&#46;aspx&#63;o&#61;1025</a> &#91;updated March 2009&#93;&#46;"
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Can patient selection for bladder preservation be based on response to chemotherapy&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/cncr.11232"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer"
                        "fecha" => "2003"
                        "volumen" => "97"
                        "paginaInicial" => "1644"
                        "paginaFinal" => "1652"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/01.ju.0000039620.76907.0d"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Urol"
                        "fecha" => "2003"
                        "volumen" => "169"
                        "paginaInicial" => "110"
                        "paginaFinal" => "115"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Contemporary concepts of radical cystectomy and the treatment of bladder cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/01.ju.0000042054.84500.10"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Urol"
                        "fecha" => "2003"
                        "volumen" => "169"
                        "paginaInicial" => "116"
                        "paginaFinal" => "117"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa022148"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2003"
                        "volumen" => "349"
                        "paginaInicial" => "859"
                        "paginaFinal" => "866"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer&#58; a combined analysis of two Nordic studies"
                      "autores" => array:1 [
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Article information

ISSN: 21735786
Original language: English

DOI:10.1016/j.acuroe.2011.11.007

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Year/Month	Html	Pdf	Total

2023 March	1	0	1
2018 February	9	1	10
2018 January	10	1	11
2017 December	11	4	15
2017 November	10	2	12
2017 October	12	6	18
2017 September	9	2	11
2017 August	10	2	12
2017 July	14	6	20
2017 June	22	7	29
2017 May	26	6	32
2017 April	23	7	30
2017 March	8	23	31
2017 February	8	0	8
2017 January	6	2	8
2016 December	30	7	37
2016 November	21	7	28
2016 October	40	13	53
2016 September	17	6	23
2016 August	16	4	20
2016 July	18	4	22
2016 June	9	3	12
2016 May	21	12	33
2016 April	23	13	36
2016 March	29	17	46
2016 February	27	16	43
2016 January	18	18	36
2015 December	18	13	31
2015 November	10	15	25
2015 October	13	11	24
2015 September	25	5	30
2015 August	17	5	22
2015 July	12	3	15
2015 June	9	2	11
2015 May	30	11	41
2015 April	30	5	35
2015 March	23	7	30
2015 February	24	2	26
2015 January	37	5	42
2014 December	35	15	50
2014 November	26	3	29
2014 October	51	10	61
2014 September	45	11	56
2014 July	2	0	2
2014 June	3	0	3
2014 May	4	1	5
2014 January	4	2	6
2013 December	5	3	8
2013 November	10	5	15
2013 October	16	8	24
2013 September	12	12	24
2013 July	0	1	1

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