Consensus document on the implications of standardization of BCG supply in the management of patients with non-muscle-invasive bladder cancer | Actas Urológicas Españolas (English Edition)

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Rodríguez Faba, J.M. Fernández Gómez, F. Guerrero-Ramos, M. Álvarez-Maestro, M.J. Ledo Cepero, M. Unda Urzaiz, L. Martínez-Piñeiro, J.M. Cózar Olmo, J. Palou Redorta, J.L. Álvarez-Ossorio" "autores" => array:10 [ 0 => array:4 [ "nombre" => "Ó." "apellidos" => "Rodríguez Faba" "email" => array:1 [ 0 => "orodriguez@fundacio-puigvert.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J.M." "apellidos" => "Fernández Gómez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "F." "apellidos" => "Guerrero-Ramos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "M." "apellidos" => "Álvarez-Maestro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "M.J." "apellidos" => "Ledo Cepero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] ] ] 5 => array:3 [ "nombre" => "M." "apellidos" => "Unda Urzaiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] ] ] 6 => array:3 [ "nombre" => "L." "apellidos" => "Martínez-Piñeiro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 7 => array:3 [ "nombre" => "J.M." "apellidos" => "Cózar Olmo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "g" "identificador" => "aff0035" ] ] ] 8 => array:3 [ "nombre" => "J. Palou" "apellidos" => "Redorta" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 9 => array:3 [ "nombre" => "J.L." "apellidos" => "Álvarez-Ossorio" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "h" "identificador" => "aff0040" ] ] ] ] "afiliaciones" => array:8 [ 0 => array:3 [ "entidad" => "Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Asturias, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Universitario 12 de Octubre, Madrid, ROC Clinic y Hospital Universitario HM Sanchinarro, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Hospital Universitario La Paz – IdiPAZ, Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Hospital Universitario Puerta del Mar, Cádiz, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Laboratorio Mixto de Investigación Traslacional en Cáncer de Próstata, CICbioGUNE-Basurto, IIS Biobizkaia, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Urología, Hospital Universitario Virgen de las Nieves, Granada, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Hospital Universitario Puerta del del Mar, Cádiz, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Documento de consenso sobre las implicaciones de la normalización del suministro del BCG en el manejo del paciente con tumor vesical no-músculo invasivo (TVNMI)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1209 "Ancho" => 1475 "Tamanyo" => 131286 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanism of action of new treatments for BCG failure." ] ] ] "textoCompleto" => "IntroductionThe origin of the BCG vaccine dates back to the years 1908−1921. Albert Calmette and Camille Guérin discovered the tuberculosis (TB) vaccine from a virulent strain of Mycobacterium bovis by gradually reducing its toxicity through consecutive sub-passages. The widespread use of the vaccine led to a drastic reduction in TB-related deaths worldwide. Later, it was proven to inhibit the growth of transplanted tumors in mice.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In 1969, BCG was combined with chemotherapy for the treatment of acute lymphoblastic leukemia showing beneficial effects,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> and in 1970 it was reported that intralesional BCG could inhibit the growth of malignant melanomas.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> However, the discovery and broad applicability of chemotherapy and radiotherapy led to the gradual abandonment of BCG for oncological treatments.In 1976, Morales<a class="elsevierStyleCrossRef" href="#bib0020">4</a> was the first to use BCG for the treatment of 9 patients with recurrent NMIBC. Since then, multiple clinical trials have shown the oncologic efficacy of BCG in this group of patients.Different strains were developed over the years as laboratories around the world mass-produced BCG for tuberculosis vaccines in their own countries. Likewise, when the use of BCG for the treatment of NMIBC was well established, manufacturers modified the vial concentration (one dose of BCG for bladder cancer is similar to over 4000 doses of BCG for vaccination), although few companies produce or have produced BCG for this indication as an adjuvant treatment in bladder cancer (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). In late 2012, an unforeseen incident caused the collapse of the Sanofi factory that produced BCG Connaught in Canada. In a routine inspection by the Food and Drug Administration (FDA), mold was found in the BCG production area due to previous natural flooding. The factory was forced to close, and production of the BCG vaccine was suspended as a result. At that time, the BCG Connaught produced and distributed by Sanofi was one of the main sources for BC treatment in North America and Europe. Later, Sanofi made the decision to halt production of BCG and confirmed their exit from the market in mid-2017. Furthermore, over the past five years, issues with BCG production in other companies have led to supply constraints from the main suppliers. Hence, the situation has become significantly more critical due to both the rising global demand for NMIBC treatment and the announced anticipated shortages caused by suppliers depleting their stocks. Even the increased production of BCG by Merck of more than one hundred percent was not enough to solve the enormous scarcity problem.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>This shortage has had a clinical impact. First, patients might have received fewer doses than those recommended, with the consequent impact on earlier recurrence.<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a> They might have also received instillations of different strains depending on their availability in each region, and last, they might have received a reduced length of the maintenance therapy recommended by clinical guidelines.Moreover, there was an increased number of patients who had to be treated by cystectomy. Ourfali et al. estimated the clinical impact of BCG shortages between 2013 and 2016 and found a significantly higher 2-year recurrence rate for patients in the intermediate- and high-risk group treated in this period compared to a control group. In addition, they found an increased cost due to decreased BCG production, estimated at approximately €783 per patient.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>The decreased availability of BCG stocks is having a particularly detrimental effect in countries where only one specific BCG strain has been approved. In USA and Canada, OncoTICE from Merck is the only strain available. Importing BCG from other countries is a reasonable option, but regulatory issues hinder a rapid supply. In some cases, clinical trials must be conducted to introduce new strains. The SWOG Cancer Research Network is conducting a randomized control trial, S1602, that compares the Tokyo and TICE strains. This trial aims to approve the use of other therapeutic options.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>In this context, the Spanish Association of Urology (AEU) through its Research Institute (IDI-URO) is conducting a prospective clinical trial<a class="elsevierStyleCrossRef" href="#bib0045">9</a> ENCORE-01 (<a href="ctgov:NCT03982797">NCT03982797</a>) in patients with high-risk NMIBC with or without associated CIS or CIS without associated papillary tumor. The trial uses the MOREAU RJ strain developed by BIOFABRI (Porriño-Pontevedra) after an audit that corroborated the quality of the manufacturing and the stability of the batches.Throughout all these years of BCG shortage, international urological societies have developed and adapted recommendations to address the problem, although each strategy depends specifically on the availability of BCG in each particular country. In Spain, the AEU advised the Spanish Agency of Medicines and Medical Products (AEMPS) to publish recommendations on the use of BCG. These were followed by all hospitals and Hospital Pharmacy Services in Spain, along with alternatives available at the time.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Finally, after multiple incidents with the supply of the drug since 2012, the Spanish Ministry of Health announced the complete reestablishment of the supply of BCG RIVM strain without any limitations in October 2023.MethodologyA group of 10 urologists with expertise in bladder cancer and members of the AEU gathered together. The thematic framework was elaborated and developed jointly.A literature search was carried out including the first publications on BCG up to the present (clinical trials, published papers or with results reported at congresses, adequately designed retrospective studies, prospective studies and meta-analysis) in the databases of the Cochrane Library, Medline (Pubmed), with the combination of the keywords in the title or abstract "BCG and NMIBC", "BCG strains" and "BCG dose" "clinical trials BCG" "non-muscle invasive bladder cancer". The clinical guidelines of the EAU, AUA, NCCN, ASCO, ESMO were also reviewed. The document sections were based on the selected publications, in relation to the effectiveness of BCG, previous procurement issues, toxicity and treatment recommendations in the context of restoration of supplies.Efficacy of BCGMechanism of actionBCG immunotherapy results in a massive local immune response characterized by induced cytokine expression in urine and bladder tissue, and an influx of monocytes, granulocytes and mononuclear cells into the bladder wall.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> After instillation into the bladder, BCG attaches to the urothelium through fibronectin and after being kept in contact with the wall for the appropriate time, with monocytes and granulocytes present, these phagocytose the bacilli and activate the production of a considerable variety of cytokines inside the cell. These include tumor necrosis factor alpha (TNF-a), granulocyte colony-stimulating factor, interferon gamma (IFN-g), interleukins (IL)-1, IL-2, IL-5, IL-6, IL8, IL-10, IL-12 and IL18, as well as the development of membrane antigens such as HLA-DR, CD25 and intracellular adhesion molecule 1. Production of membrane antigens within monocytes also occurs in the urothelium and the urothelium expresses major histocompatibility complex class II (MHC-II).The presence of membrane antigens in monocytes activates CD4 helper cells and these produce IL-2 and IFN-g, which in turn activate effector or natural killer (NK) cells. Once these cells are activated, CD8+/CD16dim and CD56+ cell subpopulations lyse the tumor via perforin production.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>BCG does not induce a tumor-specific immune response. In this regard, the lack of precise knowledge of the mechanism of action complicates the understanding of the mechanisms by which BCG failure occurs.It is important to note that these changes in the patients' bladder may be present for more than one year after the first contact with the bacillus, but usually diminish after three to six months, thus providing a rational basis for maintenance therapy.<a class="elsevierStyleCrossRef" href="#bib0060">12</a><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>; Adapted from Audisio et al.<a class="elsevierStyleCrossRef" href="#bib0065">13</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Strain differences and their impact on clinical outcomeThere are several strains of BCG currently available. The original strain was Pasteur, obtained by Calmette and Guerin in 1921. Although the EAU (European Association of Urology) Guidelines do not recommend any specific strain, there are studies that have compared the clinical differences in terms of efficacy between some of them. Rentsch et al. in 2014 demonstrated that treatment with BCG Connaught prevented recurrences more efficiently than TICE BCG.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Similarly, Wegt et al. published the inferiority of TICE compared to RIVM in reducing the risk of recurrence.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Witjes et al. also compared the efficacy of Connaught and TICE in a population of 2099 patients and their results did not demonstrate a significant difference between the two strains in terms of time to progression and overall survival.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> A meta-analysis published in 2017 identified up to 10 different strains currently in use but did not confirm the superiority of any strain over another.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>In 2017, the Spanish BCG Strain Registry Group published an observational, prospective, multicenter registry including 433 patients. The study evaluated disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS) and adverse events in 12 months of follow-up. TICE, Russian, Tokyo, Connaught and RIVM strains were studied. The results demonstrated that there were no significant differences in any of the parameters evaluated.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Therefore, any of them can be used in both induction and maintenance courses.Efficacy according to treatment duration and doseThe first intravesical BCG dose was empirically determined to be 120mg (Frappier strain) based on the observation that it was well tolerated by intradermal scarification.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Several studies have been conducted to determine whether a lower dose of BCG can guarantee the same efficacy and less toxicity. Either 80, 81, or 120mg was used as a standard dose in most studies, and the low dose was defined as a half or one/two-third of the standard dose in the most studies.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>An induction course is required in order to provoke an immune response in the bladder. The treatment should be initiated two to four weeks after TUR and can be applied until the sixth week if necessary. The six-week weekly application schedule was chosen arbitrarily, and most patients develop an adequate immune response with six instillations.In this regard, Grimm et al. reported that reducing the total number of instillations from 15 (standard) to 9 significantly increases recurrences.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>According to data published by the EORTC, the comparison between full-dose and 1/3 dose of TICE reported that the efficacy of a 1/3 dose for 1year is lower than that of a full dose for 3 years in patients with intermediate- or high-risk NMIBC.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> There was no difference in toxicity between the 1/3 dose and the full dose. The CUETO group published a similar study in 2005. In this work, a lower efficacy of 1/3 dose compared to full dose BCG Connaught strain could not be confirmed (progression rate of 26% and 24.7%, respectively). The population of this study included 90 T1G3 and subgroup analysis by stage did not differ significantly. Moreover, the 1/3 dose was associated with significantly lower toxicity.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Furthermore, this review confirmed that 27mg BCG represents the minimum effective dose. Many different maintenance schedules have been proposed in recent years, ranging from a total of 10 instillations given in 18–27 weeks over 3 years.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> However, there is still no consensus on the optimal duration of maintenance courses. The most commonly used maintenance schedule is that proposed by Lamm and the Southwest Oncology Group (SWOG): a six-week weekly induction instillation followed by a course of a three-week weekly instillation at three and six months, with subsequent three-week weekly instillation every six months for up to three years. Globally, it has been established that the benefit of 2 additional years of BCG maintenance needs to be accurately assessed as it may increase toxicity and costs.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Alternatives to BCG in case of supply shortageGiven the circumstances previously outlined, various scientific societies, such as the EUA, promptly published documents with recommendations for treating patients with NMIBC who had a BCG indication.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> As a preliminary comment, we must stress the importance of performing a second TUR in patients with an indication given its prognostic and oncologic value. Considering the association between TUR quality and oncologic outcomes, it must be performed with the utmost care, aiming to achieve the highest quality.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>The following are the recommendations made by different expert committees:Intravesical chemotherapy and radical cystectomyAlthough adjuvant treatment with Mitomycin C (MMC) does not seem to be clearly recommended in high-risk tumors, it could provide some benefit in cases of BCG shortage and could be an advisable action in cases of supply shortage.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>Other agents evaluated or under study are:<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0120">-Intravesical gemcitabine, with definitive results pending in BCG naïve NNMIBC (Sunrise-3 trial) based on the incorporation of TAR-200, a 21-day intravesical gemcitabine delivery system combined with systemic administration of cetrelimab (anti-PD1 antibody) in one arm of the trial. Encouraging preliminary results have also been reported (Sunrise-1) in BCG unresponsive (82.8% overall complete response in the group of CIS patients).<a class="elsevierStyleCrossRef" href="#bib0130">26</a></li><li class="elsevierStyleListItem" id="lsti0125">-Intravesical combination therapy of gemcitabine with Docetaxel (Gem/Doce) weekly for 6 weeks, followed by monthly maintenance for one year. It presents similar recurrence rates to BCG for any/high-grade recurrences.<a class="elsevierStyleCrossRef" href="#bib0135">27</a></li><li class="elsevierStyleListItem" id="lsti0130">-The BRIDGE prospective phase 3 clinical trial of Gem/Doce versus BCG instillations in high-risk NMIBC is underway.<a class="elsevierStyleCrossRef" href="#bib0140">28</a></li><li class="elsevierStyleListItem" id="lsti0135">-Combination therapy of BCG with interferon alpha.<a class="elsevierStyleCrossRef" href="#bib0145">29</a></li></ul>In patients with very high risk NMIBC according to EAU criteria, it is advisable to offer immediate radical cystectomy.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>BCG: strains, prioritization, treatment duration and dose reductionThere are several studies in the literature that compare different BCG strains, with results that are not always consistent. However, according to the most recent evidence, it is generally accepted that there are no significant differences in the efficacy between strains.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> There are even data in the literature combining Connaught for induction and OncoTICE for maintenance.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> This shows that if the same BCG strain is not available for the entire treatment of one patient, different strains can be used, depending on stock availability.On the other hand, regarding the prioritization of the BCG available, it should be reserved for high-risk patients, using intravesical chemotherapy for patients with intermediate-risk tumors; even for patients with allergy or relapse after MMC, another alternative to BCG would be the use of other chemotherapy drugs such as gemcitabine.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Regarding the duration of treatment, it is recommended to reduce it from 3 years to 1year in high-risk patients, with a reduced dose in the second and third year in patients with CIS, based on data from previous studies, and assuming a slight increase in recurrence rates.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>The data available in the literature when consensus documents were issued by expert committees established that the administration of reduced doses of BCG (one-third of the full dose) had no impact on progression rates compared to full doses, although there was an increased risk of recurrence.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> A recent systematic review and meta-analysis demonstrated that recurrence rates are comparable provided that a maintenance schedule is administered despite using a reduced dose.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> Consequently, another recommendation is to administer reduced doses of BCG, so that one vial can be used to treat three patients, although with certain limitations in terms of logistics and dose preparation.Device-assisted intravesical chemotherapyIn those extreme situations of absolute lack of BCG for patients with high-risk tumors, and in those cases in which immediate radical cystectomy is not considered, the use of device-assisted intravesical chemotherapy is recommended. Patients should be referred to centers equipped with this technology in case it is not available. This recommendation is based on the results of previous studies that showed promising response rates with this therapeutic alternative.<a class="elsevierStyleCrossRefs" href="#bib0170">34,35</a>Regarding the use of devices for the administration of chemotherapy in high-risk tumors, the strongest evidence up to the date when the stockouts began was a randomized clinical trial that used sequential BCG and electromotive mitomycin versus BCG alone. This study reports more favorable results for sequential treatment, with longer recurrence-free survival (69 vs 21 months), lower recurrence rate (41.9% vs 57.9%), lower progression rate (9.1% vs 21.9%), and lower overall (21.5% vs 32.4%) and cancer-specific (5.6% vs 16.2%) mortality rates.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>As a consequence of the shortages, and in search for the best alternative for these patients, evidence was generated showing the results of treatments other than BCG. Accordingly, the HIVEC-HR phase II randomized clinical trial was designed to compare BCG versus MMC with recirculating hyperthermia (HIVEC) in patients with high-risk tumors. The main objective of this trial was to determine the non-inferiority of HIVEC in terms of recurrence-free survival.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> In their per-protocol analysis, recurrence-free survival at 2 years showed no significant difference between the two groups (86.5% HIVEC vs 71.8% BCG, p=0.064), and progression-free survival at 24 months was found to be better for patients who received HIVEC (95.7% vs 71.8%, p=0.043). Although the results were not published until some years after the first stock-out, this study generates the first evidence based on a randomized trial in favor of the use of HIVEC in high-risk tumors in certain situations, such as BCG stock-out or BCG intolerance.Novel therapies for BCG failureOne of the most common scenarios evaluated in current studies is BCG-failure in high-grade non-muscle invasive disease.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> In this context, two treatments have been approved by the FDA for patients with CIS (with or without associated papillary tumor) unresponsive to BCG, systemic immunotherapy (pembrolizumab) with 3-month complete response rates of 41%.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Other novel therapies include intravesical viral delivery systems. Two promising viral delivery systems include Nadofaragene-Firadenovac (Adstiladrin®) with 3-month complete response rates of 53.4%,<a class="elsevierStyleCrossRef" href="#bib0200">40</a> and which has FDA approval and CG0070 (oncolytic adenovirus) with 6-month overall complete response rates of 47%.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>Furthermore, the BOND-003 (Intravesical Cretostimogene-Grenadenorepvec) Phase 3 trial has reported a 3-month complete response rate of 68.2% in SUO 2023.Subsequently, other drugs have reported preliminary results that exceed those of pembrolizumab and Nadofaragene-Firadenovec. Thus, the combination of BCG and N-803 (an IL-15 superagonist) reported a complete response rate of 71%, and the use of intravesical TAR-200 reaches 76.7%.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>In general, most trials based on this stage of disease present an additional cohort of papillary-only disease, without CIS. The objective in these patients, rather than assessment of complete response rate, and due to the fact that these are adjuvant treatments, is focused on high-grade recurrence-free survival. Being a theoretically less aggressive entity than CIS, the results of these cohorts are even more encouraging. There are still no approvals by regulatory agencies in this population. In addition to the results reported in these accessory cohorts of papillary disease from studies initially designed for patients with CIS, the recently reported results with erdafitinib are noteworthy. The only randomized study to date randomly allocated patients to receive oral erdafitinib versus investigator's choice of mitomycin C or gemcitabine (patients with BCG-unresponsive high-grade papillary tumor), after molecular screening for alterations or fusions for FGFR genes; the median high-grade recurrence-free survival was not achieved for erdafitinib and was 11.6 months for the chemotherapy group, with a Hazard Ratio of 0.28 (p=0.0008). However, a grade 3 or higher toxicity rate in the erdafitinib group of 38.8% limits the use of this treatment, among other problems, such as the recruitment of 73 patients when 240 were initially expected.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> To avoid the toxicity derived from systemic administration, it is possible to administer the drug intravesically using the TAR-210 device in the same patient population. Cohort 1 of the ErdaRIS clinical trial evaluates TAR-210 in a single arm in this patient population, preliminarily achieving 82% of patients free of high-grade disease with an excellent toxicity profile (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Updated guidelines for NMIBC treatment with BCGNMIBC is a heterogeneous disease that is often difficult to treat, given the number of clinicopathologic factors that affect its prognosis. In addition, it requires strict surveillance due to its high recurrence rate (30–78% at 5 years) in the same stage/grade,<a class="elsevierStyleCrossRef" href="#bib0220">44</a> as well as the likelihood of progression to potentially lethal muscle-invasive disease (10–40% at 5 years).<a class="elsevierStyleCrossRef" href="#bib0225">45</a>Traditionally, the EAU Guidelines have recommended stratification of NMIBC into prognostic groups to guide treatment and follow-up. One of the most important factors in the classification of these risk groups is tumor grade. Until 2004, the 1973 WHO grading was used exclusively. It classified disease as grade 1 (G1), grade 2 (G2) and grade 3 (G3) categories. Recently, however, a histological classification has been introduced including papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade (LG) and high-grade (HG) papillary carcinoma. This system was included in the 2016 and 2022 updated WHO classifications.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>The new risk group definitions provided by the EAU Guidelines are based on a data analysis of individual patients with primary tumors and estimation of their risks of progression. As such, we can use one of the WHO classification systems (1973 or WHO 2004/2016), or both. Regarding this point, it should be noted that when comparing the WHO-1973 grading system with the WHO 2004/2016 grading system, the former has shown to be more accurate in predicting progression in NMIBC.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>The prognostic factors on which the EAU (progression) risk classification is based are stage (T), grade (with both classifications) and three additional factors: tumor diameter, with a threshold of 3cm, multifocality and age (70 years), which worsen the risk of progression.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Based on these parameters, four prognostic factor risk groups are established:<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0140">•Low risk (5-year risk of progression <1%). Low grade/G1 primary tumors without carcinoma in situ (CIS), which can be:<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0145">-Ta with one or no associated factors (size, multifocality, age).</li><li class="elsevierStyleListItem" id="lsti0150">-T1 with no associated factors: single < 3cm diameter < 70 years.</li></ul></li><li class="elsevierStyleListItem" id="lsti0155">•Intermediate risk (risk of progression at 5 years of 4–5%). Not specifically defined in the Guidelines: patients without CIS who are not included in either the low-, high-, or very high-risk groups.</li><li class="elsevierStyleListItem" id="lsti0160">•High risk (risk of progression at 5 years of 10%). These are primary or recurrent tumors, which include the following:<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0165">-Presence of CIS</li><li class="elsevierStyleListItem" id="lsti0170">-High grade (2016/2022) without CIS<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0175">▪T1HG (except those included in the very high-risk group).</li><li class="elsevierStyleListItem" id="lsti0180">▪TaHG/G3 with at least two risk factors (size, multifocality, age).</li></ul></li><li class="elsevierStyleListItem" id="lsti0185">-Low grade (2016/2022) without CIS with additional clinical risk factors (size, multifocality, age).<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0190">▪TaG2 (1973) with all 3 risk factors</li><li class="elsevierStyleListItem" id="lsti0195">▪T1G1 (1973) with at least two risk factors</li><li class="elsevierStyleListItem" id="lsti0200">▪T1G2 (1973) with at least 1 risk factor</li></ul></li></ul></li><li class="elsevierStyleListItem" id="lsti0205">•Very high risk (risk of progression at 5 years 40–44%). These are primary or recurrent tumors, which include the following:<ul class="elsevierStyleList" id="lis0095"><li class="elsevierStyleListItem" id="lsti0210">-Ta HG/G3 and CIS with all three risk factors (size, multifocality, age)</li><li class="elsevierStyleListItem" id="lsti0215">-T1 G2 and CIS with at least two risk factors</li><li class="elsevierStyleListItem" id="lsti0220">-T1HG/G3 and CIS with at least two risk factors</li><li class="elsevierStyleListItem" id="lsti0225">-T1AG/G3 no CIS with all three risk factors</li><li class="elsevierStyleListItem" id="lsti0230">-The 2023 EAU Guidelines also include those NMIBC patients with lymphovascular invasion, CIS in the prostatic urethra or histological variants.</li></ul></li></ul>The EAU Guidelines recommend that, once the prognostic group for progression has been established and, therefore, the treatment has been oriented, the tables published by the EORTC<a class="elsevierStyleCrossRef" href="#bib0240">48</a> scoring model or the CUETO risk scoring model (<a href="https://www.aeu.es/cueto.html">https://www.aeu.es/cueto.html</a>)<a class="elsevierStyleCrossRef" href="#bib0110">22</a> should be used to determine the risk of recurrence in individual patients and adapted to the treatment to be used in each risk group.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Tumors with BCG indication after TUR are undoubtedly those at high risk of progression in the EAU classification (progression rate of 14.1 and 14.2% after 10 years, according to the EAU 2021 scoring model).<a class="elsevierStyleCrossRef" href="#bib0235">47</a> In these patients, full-dose intravesical BCG for one to 3 years (induction plus 3-weekly instillations at 3, 6, 12, 18, 24, 30 and 36 months), is indicated. The additional beneficial effect of the second and third years of maintenance should be weighed against its added costs and side effects.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> As patients with CIS cannot be treated by an endoscopic procedure alone, intravesical BCG instillations or radical cystectomy should be considered if they are at very high risk. The treatment of CIS patients with BCG has shown to increase response rates, overall percentage of patients who remain disease free and reduce the risk of progression. The use of BCG in these cases avoids overtreatment and morbidity associated with radical cystectomy in high-risk tumors.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>Those patients at very high risk would have an indication for immediate cystectomy due to the high probability of tumor progression (53.1 and 58.6% after 10 years according to the 2021 EAU NMIBC scoring model).<a class="elsevierStyleCrossRef" href="#bib0235">47</a> However, in case RC is not feasible or refused by the patient, full-dose intravesical BCG for one to 3 years should be offered, with the same considerations as those for patients with high-risk tumors.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Tumors in the intermediate-risk group are associated with a low risk of disease progression of 7.4 and 8.5% after 10 years according to the 2021 EAU NMIBC scoring model.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> According to the EAU Guidelines, intravesical chemotherapy (optimal regimen is unknown) for up to one year or BCG treatment with one-year maintenance may be indicated in these cases. The final choice should reflect the individual patient’s risk of recurrence and progression as well as the efficacy and side effects of each treatment modality.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Therefore, the EAU Guidelines do not clearly specify in which intermediate-risk tumors BCG or chemotherapy would be indicated. In this regard, the International Bladder Cancer Group (IBCG) has recently published a review of randomized clinical trials, meta-analyses, systematic reviews and clinical practice guidelines on intermediate-risk NMIBC. The IBCG recommends that treatment of these tumors should be based on the following risk factors: multifocal tumor (more than one), early recurrence (<1yr.), frequent recurrence (>1/yr.), tumor size (≥3cm), and failure of prior intravesical chemotherapy. According to the authors, BCG should be used in intermediate-risk tumors with the following characteristics: TaG1 with 3 of the above risk factors, TaG2 with 2 risk factors, T1G1 with one risk factor, or T1G2 with no risk factors.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>It should be remembered that, according to the latest EAU Guidelines,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> if we want to obtain an estimate of the individualized risks of recurrence in patients treated with BCG, the CUETO tables<a class="elsevierStyleCrossRef" href="#bib0110">22</a> should be used, as mentioned above. However, the CUETO tables might also be more appropriate to obtain the probabilities of progression than the latest EAU tables,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> since the latter are based on a study that did not include cases of BCG-treated patients,<a class="elsevierStyleCrossRef" href="#bib0235">47</a> and the risks of progression in them may be overestimated.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>Management of adverse effectsIn general, toxicity attributed to intravesical treatment with BCG instillations can be local (68–72.5%), appearing within a few hours of instillation and lasting no more than 48–72h, or systemic (30%), which is a serious condition that may require multidisciplinary management with urology, infectious disease and even intensive care specialists.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>The key to effective treatment of adverse effects due to BCG lies in an adequate prevention, early diagnosis and appropriate treatment depending on the type and grade of the effect.In case of suspicion of toxicity associated with BCG treatment, the first step should be to carry out adequate identification and classification of the severity of the clinical picture. In this regard, several authors have classified cases into 4 categories (mild/moderate/severe/systemic complications) using a scale based on the recommendations of the World Health Organization (WHO). The use of this scale has shown that patients with a score higher than 1.5 during induction treatment suffer greater changes in the frequency and duration of instillations, both in induction and maintenance.<a class="elsevierStyleCrossRef" href="#bib0260">52</a><ul class="elsevierStyleList" id="lis0100"><li class="elsevierStyleListItem" id="lsti0235">-Grade 1: moderate and <48h (usually require no modification of intravesical therapy).</li><li class="elsevierStyleListItem" id="lsti0240">-Grade 2: severe and/or >48h (usually require suspension of instillations until resolution of symptoms).</li><li class="elsevierStyleListItem" id="lsti0245">-Grade 3: local, regional, systemic, and immunoallergic (usually require suspension of instillations until resolution of symptoms).</li><li class="elsevierStyleListItem" id="lsti0250">-Grade 4: systemic BCG reactions (cessation of BCG therapy is required).</li></ul>Regarding local toxicity, the most frequent conditions and symptoms are BCG-induced cystitis (35%), urinary frequency/urgency (23.6%), bacterial cystitis (23.3%), and hematuria (22.6%). Less frequent are prostatitis and orchitis.The most frequent systemic effects are general malaise and fever (15.5%), much less frequent and more severe are skin rash, uro-sepsis, systemic BCG infection.<a class="elsevierStyleCrossRefs" href="#bib0265">53,54</a>Therefore, and given the variety and potential severity of the associated toxicity, it can be deduced that BCG treatment should be accompanied by an appropriate informed consent signed by the patient.Prevention of complicationsIt is possible that certain systemic adverse effects are related to traumatic catheterization, which is why it is not recommended to start BCG before 14 days following TUR, or in case of persistent hematuria.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Likewise, it is advisable to delay instillation in the presence of bacterial cystitis, since inflammation of the urothelium may facilitate the systemic absorption of BCG.At the time of BCG administration, it is recommended to:Use a luer-lock, hydrophilic catheter of the smallest caliber necessary. If a hydrophilic catheter is not used, it is recommended to administer 10−15ml of lubricating jelly.<a class="elsevierStyleCrossRef" href="#bib0280">56</a>Specific complicationsHematuriaHematuria is a frequent symptom in the context of patients treated with BCG. It may occur in up to 90% of cases.<a class="elsevierStyleCrossRefs" href="#bib0285">57,53</a> It appears very frequently associated with cystitis and may be related to the length of the resection area. Urine culture should be performed to rule out hemorrhagic cystitis and instillations should be postponed until hematuria is completely resolved.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>BCG-induced cystitisIn general, local irritative symptoms are the most frequent complication associated with BCG treatment, as we have previously mentioned.This symptomatology may also be accompanied by hematuria with negative cultures in up to 23% of cases and by symptoms with a frequency-urgency>once/hour in up to 24% of cases.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>Since the immunological mechanism of action of BCG is not completely defined, it is clear that the diagnosis of cystitis due to a hypersensitivity response to BCG should be confirmed by the presence of granuloma with negative cultures. If we consider the hypothesis of bacterial invasion, there should be active bacilli in the urothelium.In any case and in a practical way, urine cultures/hemocultures should be performed to rule out bacterial infection or sepsis. If immune-mediated cystitis is suspected, it will be accompanied by flu-like symptoms and will resolve in 24−48h without any treatment or with symptomatic treatment consisting of spasmolytics, anticholinergics or non-steroidal anti-inflammatory drugs. There is no solid evidence to prove the superiority of one drug over the others, with the exception of oxybutynin, which does not appear to be effective according to the results of a randomized study.<a class="elsevierStyleCrossRef" href="#bib0290">58</a>If bacterial cystitis is diagnosed, antibiotic treatment should be initiated. Prophylaxis with ofloxacin has shown to reduce local complications related to BCG (18.5% reduction of moderate or severe adverse effects) during instillations.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Therefore, given the risk of associated bacterial cystitis in those patients with persistent voiding symptoms, ofloxacin 200mg/day can be started adjusting the regimen to the antibiogram. Likewise, 1 instillation/day for 5 days of an anesthetic-sedative formula composed of distilled water+200mg. nitrofurantoin+1g. tetracaine+165mg. prednisolone has shown a beneficial effect in the reduction of irritative voiding symptoms in these patients.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>BCG treatment should be withheld until completion of a specific antibiotic course.However, if patients with disabling symptoms are refractory to conservative treatment, a short course of 2–4 weeks of oral steroids interspersed during antituberculous therapy should be considered.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> Major surgery, such as bladder augmentation for contracted bladder or cystectomy, is required only in exceptional cases (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>ProstatitisGranulomatous prostatitis is a complication whose actual prevalence is underestimated by symptomatic case series. In fact, only about 10% of men develop clinical prostatitis associated with BCG instillations. More than 40% present with elevated serum PSA and 41–75% of patients undergoing post BCG prostate biopsy or radical cystoprostatectomy present histologically proven granulomatous prostatitis.<a class="elsevierStyleCrossRef" href="#bib0310">62</a>Granulomatous prostatitis demonstrates early and prolonged ring enhancement on MRI, which might be a key finding to differentiate it from prostate cancer.<a class="elsevierStyleCrossRef" href="#bib0315">63</a>Patients with clinical BCG-induced prostatitis may present with atypical symptoms or signs, including perineal pain, enlarged gland tender prostate, firm prostate nodules, and elevated PSA that returns to normal 3 months after the end of treatment.<a class="elsevierStyleCrossRef" href="#bib0320">64</a> Prostatic fluid staining for acid-fast bacilli is helpful to identify tuberculous prostatitis. There are sporadic reports of tubercular prostatic abscess treated with drainage and anti-TBC drugs. Only cases of symptomatic granulomatous prostatitis may require treatment based on anti-TB therapy and fluoroquinolones<a class="elsevierStyleCrossRef" href="#bib0310">62</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).Epididymo-orchitisTuberculous epididymo-orchitis is an uncommon granulomatous infection resulting from intravesical BCG treatment (0.2–10%).<a class="elsevierStyleCrossRef" href="#bib0325">65</a> Episodes occurring during instillations are most often caused by gram-negative rods as a consequence of catheterization. They usually manifest as scrotal swelling, pain, dysuria and fever, and those appearing within a few weeks of BCG instillations, and even up to several years after discontinuation of treatment are most likely due to TB. Several distinct sonographic patterns have been described, the most frequent being enlarged epididymis or hypoechoic nodules. Orchitis ultrasound may exhibit a miliary pattern with multiple intratesticular hypoechoic nodules.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> Other typical findings, such as hydrocele, scrotal skin edema, intrascrotal calcifications, and abscesses are also possible. The biopsy result shows granulomatous changes, caseous necrosis and positive acid-fast bacilli in the biopsy specimen. BCG-induced epididymo-orchitis usually responds adequately to anti-TB therapy. If the lesion is accompanied by persistent pain, swelling, fever and/or leukocytosis refractory to antituberculous treatment, scrotal exploration and orchidectomy may be necessary (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).Since gram-negative bacilli can cause this condition, the use of fluoroquinolones is initially recommended. In case of persistent symptomatology, anti-TB should be started.Systemic toxicity associated to BCGAs previously mentioned, systemic toxicity associated with BCG instillations is less frequent but potentially more severe and may require co-management with infectious disease specialists.Up to 30% of patients may present low-grade fever, general malaise and nausea. Fever above 39°C is less frequent (up to 20% of cases). This symptomatology usually resolves within 24−48h with symptomatic and/or antipyretic treatment. If fever >38.5°C persists for more than 48h, immediate suspension of instillations should be indicated, empiric broad-spectrum antibiotics should be started, cultures should be obtained and infectious diseases should be consulted.Systemic granulomatous disease caused by BCG, also called "BCG-osis", occurs immediately after administration of the instillation associated with absorption of BCG as a result of traumatic catheterization or a very early administration after TUR. Since it is very difficult to isolate mycobacteria from the affected organs, there are doubts about the infectious or inflammatory origin of the condition, which is why it is also called "systemic BCG reaction".It manifests with high fever, leukopenia, hemodynamic instability, hepatomegaly, bilateral crackles in both lung bases and altered liver function tests.Treatment of this condition consists of discontinuation of BCG and isoniazid, rifampicin and ethambutol for 6 months associated with fluoroquinolones and steroids since the latter have been shown to improve survival.<a class="elsevierStyleCrossRef" href="#bib0335">67</a> The addition of a broad-spectrum antibiotic for gram-negatives bacteria is also recommended (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Reactive arthritisIntravesical BCG therapy-associated osteoarticular complications are uncommon (0.5−1%),<a class="elsevierStyleCrossRef" href="#bib0340">68</a> although they account for 64% of all autoimmune complications following BCG treatment.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> This is a reactive arthritis caused by a systemic immune response. According to prevalence, the most frequently affected joints are knee (84.3%), ankle (55.1%), hand (39.3%), wrist (32.6%) and foot (28.1%), with polyarthritis being the most frequent clinical manifestation. Although inflammatory joint involvement is induced by an autoimmune reaction, synovial fluid analysis is required to rule out septic arthritis. Treatment should be discontinued. Fifty-seven percent of cases are associated with fever, and 67% respond adequately to anti-inflammatory treatment with NSAIDs.ConclusionsFor decades, adjuvant treatment with BCG has been indicated in most clinical practice guidelines for high- and intermediate-risk NMIBC. However, supply shortages and unresolved controversies regarding the optimal dose, duration of treatment, maintenance schedule and strains used have resulted in treatment protocols that have had to adapt to these new circumstances. In Spain, however, the situation is currently normalized.Given the heterogeneity of NMIBC, the EAU risk groups should be applied to stratify patients, since they are the most widely used and validated in our setting. High-risk and also selected intermediate-risk patients should be treated with one BCG induction and maintenance schedule for at least 1year. No strain has been shown to be superior to any other, and it is possible to combine different strains depending on supply availability.Inclusion of patients in clinical trials with novel immunotherapeutic treatments is important to validate their future implementation in clinical practice. BCG toxicity should be adequately prevented, and in case it appears, it should be treated according to the grade and established treatment recommendations.Conflict of interestsNone of the authors of this article has any conflict of interest with the information reflected in it." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres2267254" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1890889" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2267255" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1890888" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Efficacy of BCG" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Mechanism of action" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Strain differences and their impact on clinical outcome" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Efficacy according to treatment duration and dose" ] ] ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Alternatives to BCG in case of supply shortage" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Intravesical chemotherapy and radical cystectomy" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "BCG: strains, prioritization, treatment duration and dose reduction" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Device-assisted intravesical chemotherapy" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Novel therapies for BCG failure" ] ] ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Updated guidelines for NMIBC treatment with BCG" ] 9 => array:3 [ "identificador" => "sec0065" "titulo" => "Management of adverse effects" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Prevention of complications" ] 1 => array:3 [ "identificador" => "sec0075" "titulo" => "Specific complications" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Hematuria" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "BCG-induced cystitis" ] 2 => array:2 [ "identificador" => "sec0090" "titulo" => "Prostatitis" ] 3 => array:2 [ "identificador" => "sec0095" "titulo" => "Epididymo-orchitis" ] 4 => array:2 [ "identificador" => "sec0100" "titulo" => "Systemic toxicity associated to BCG" ] 5 => array:2 [ "identificador" => "sec0105" "titulo" => "Reactive arthritis" ] ] ] ] ] 10 => array:2 [ "identificador" => "sec0110" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0115" "titulo" => "Conflict of interests" ] 12 => array:2 [ "identificador" => "xack780110" "titulo" => "Acknowledgement" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2024-05-30" "fechaAceptado" => "2024-06-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1890889" "palabras" => array:4 [ 0 => "BCG" 1 => "BCG shortage" 2 => "BCG supply standardization" 3 => "Non-muscle-invasive bladder cancer" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1890888" "palabras" => array:4 [ 0 => "BCG" 1 => "Desabastecimiento BCG" 2 => "Normalización BCG" 3 => "Tumor vesical no-músculo invasor" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Patients with non-muscle-invasive bladder cancer (NMIBC) in the intermediate and high-risk groups must receive adjuvant treatment with intravesical Bacillus Calmette–Guérin (BCG) following transurethral resection (TUR), as it reduces the risk of recurrence and presumably the risk of progression as well. Optimization of BCG efficacy is achieved by administering maintenance therapy. However, since many immunological aspects of the mechanism of action of BCG in the bladder remain unknown, the implementation of the optimal dose, number of instillations, strains and adequate maintenance regimen over the last decades has been heterogeneous. Additionally, this has hindered the interpretation of efficacy in terms of oncologic outcomes. This, together with the shortages of BCG in recent years, have forced scientific societies to adapt their clinical practice guidelines and modify their protocols of adjuvant treatment with BCG. This includes changes to strains, doses, and maintenance during this period of time. This consensus document evaluates the current status of adjuvant BCG treatment and the implications of BCG supply availability in the treatment of patients with NMIBC. It also addresses the implementation of novel therapies that will improve cancer prognosis and the quality of life of patients with NMIBC in the future." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los pacientes con TVNMI de los grupos de riesgo intermedio y alto deben ser tratados con BCG intravesical adyuvante después de la resección transuretral (RTU), ya que dicho tratamiento disminuye el riesgo de recurrencia y probablemente también el de progresión. La optimización de la eficacia de la BCG se consigue administrando un tratamiento de mantenimiento. Sin embargo, dado que se desconocen muchos detalles inmunológicos del mecanismo de acción de la BCG en la vejiga, la implementación a lo largo de las últimas décadas de la dosis óptima, número de instilaciones, cepas y régimen adecuado de mantenimiento, se ha realizado de manera heterogénea, lo que ha generado dificultades para interpretar los resultados de eficacia oncológica. Esto unido con el desabastecimiento de BCG que se ha sufrido en los últimos años, ha hecho que las diferentes sociedades científicas tengan que adaptar sus guías de práctica clínica a esta situación, modificando durante este tiempo sus protocolos de tratamiento adyuvante con BCG en relación con cepas, dosis y mantenimiento. En este documento de consenso, se evalúa el estado actual del tratamiento adyuvante con BCG y las implicaciones de la normalización del suministro de la BCG en el tratamiento oncológico de los pacientes con TVNMI así como la implementación de nuevos tratamientos que en el futuro mejoren el pronóstico oncológico y la calidad de vida de los pacientes con TVNMI." ] ] "multimedia" => array:6 [ 0 => array:9 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Audisio et al.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1088 "Ancho" => 1475 "Tamanyo" => 146509 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanism of action of BCG." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1209 "Ancho" => 1475 "Tamanyo" => 131286 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mechanism of action of new treatments for BCG failure." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\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" scope="col" style="border-bottom: 2px solid black">Strain \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Name \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Manufacturer \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Connaugh \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">TheraCys/ImmuCyst \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">Sanofi Pasteur (Canada) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TICE \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">OncoTice \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">Organon-Merck(US) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Danish \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">Urovac/BCG-Onco \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">GSBPL (India) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japanese \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">Immunobladder \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">Japan BCG Lab. (Japan) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Russian \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">SII-Onco BCG \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">Serum institute of India \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RIVM \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">BCG-Medac/Vejicur \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">Medac GmbH (Germany) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moreau RJ \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">BCG-Moreau RJ \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">Biofabri (Spain) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3683522.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Main BCG strains for NMIBC." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "RFS: Recurrence-free survival; CR: Complete response." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\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" scope="col" style="border-bottom: 2px solid black">Author \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Follow-up (months) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">RFS \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">CR \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Balar et al. <a class="elsevierStyleCrossRef" href="#bib0195">39</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">Pembrolizumab (cohort A) KEYNOTE057Pembrolizumab (cohort B) EYNOTE057 \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">12m \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">43.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chamie et al. <a class="elsevierStyleCrossRef" href="#bib0210">42</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">ALT-803 (cohort A, CIS)ALT-803 (cohort B, papillary) \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">24m \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">48% \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">71% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Boorjian et al.<a class="elsevierStyleCrossRef" href="#bib0200">40</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">Nadofaragene-Firadenovec (cohort A, CIS)Nadofaragene-Firadenovec (cohort B, TaHG or T1) \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">12m \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">43.8% \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24.3% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Packiam et al. <a class="elsevierStyleCrossRef" href="#bib0205">41</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">CG0070 \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">6m \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"> \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">47 % \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Daneshmand et al. <a class="elsevierStyleCrossRef" href="#bib0130">26</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">TAR- 200 \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"> \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"> \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">76.7 % \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Catto et al. <a class="elsevierStyleCrossRef" href="#bib0215">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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TAR-210 (cohort 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"> \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">82 % \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3683525.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Results obtained with novel treatments for BCG-unresponsive patients." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="13" align="left" valign="middle">BCG-Associated Cystitis(25%)</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">Grade 1 \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"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•NSAIDS</li><li class="elsevierStyleListItem" id="lsti0010">•Phenazopyridine (200mg/8h-15 days)</li><li class="elsevierStyleListItem" id="lsti0015">•Propantheline (0.5mg/kg/12h-15 days)</li></ul> \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">If improvement: continue instillations \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">Grade 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">Worsening : \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"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020">•Postpone instillation until resolution</li><li class="elsevierStyleListItem" id="lsti0025">•Urine culture</li><li class="elsevierStyleListItem" id="lsti0030">•Empiric antibiotic (Fluoroquinolones: Ofloxacin 200mg/day)</li></ul> \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">If symptoms persist with antibiotic treatment: \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"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035">•Positive urine culture: 7-day treatment adjusted to antibiogram</li><li class="elsevierStyleListItem" id="lsti0040">•Negative urine culture: Fluoroquinolones, anesthetic solution instillation (1 daily/5 days)</li></ul> \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">Grade>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">If symptoms persist: \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"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0045">•Isoniazid (300mg/day) and Rifampicin (600mg/day) for 3 months+steroids (prednisone 20mg/day, tapering schedule).</li></ul> \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">No response/contracted bladder: \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"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0050">•Hydrodistension, bladder augmentation Cystectomy.</li></ul> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="middle"></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">Grade 1−2 \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"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0055">•Postpone instillations until urine is clear.</li><li class="elsevierStyleListItem" id="lsti0060">•Urine culture to rule out hemorrhagic cystitis.</li></ul> \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">If+culture: \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"><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0065">•Targeted antibiotic 3−5 days prior to instillation.</li></ul> \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">If persistent, cystoscopy to rule out tumor \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Granulomatous prostatitis</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">Grade>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">Rare symptoms: Urine culture \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">(10%, symptomatic prostatitis)</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"><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0070">•Fluoroquinolones (Levofloxacin 500/24h)-4 weeks</li></ul> \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">If quinolones are not effective: \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"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0075">•Isoniazid (300mg/day) and rifampicin (600mg/day) for 3 months.</li></ul> \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">Cessation of intravesical therapy. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="7" align="left" valign="middle">Epididymo-orchitis(10%)</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">Grade>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">Urine culture+quinolones \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"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0080">•Fluoroquinolones (Levofloxacin 500/24h)-4 weeks</li></ul> \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">Negative urine culture or no response: \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"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0085">•Isoniazid (300mg/day) and rifampicin (600mg/day) for 3 months, (prednisone 20mg/day, tapering schedule).</li></ul> \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">Cessation of intravesical therapy. \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">Orchidectomy if abscess or no response to treatment. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3683523.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of treatments for local effects." ] ] 5 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">General malaise, fever(30%) \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">Grade 1Resolves in 48h/Antipyretics.If improvement: Resume instillations. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Persistent fever(20%)</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">Grade>2Permanent discontinuation of BCG instillations.Close monitoring \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">Urine culture, blood tests, chest x-ray, AS \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">Prompt broad-spectrum antibiotic treatment (fluoroquinolones, isoniazid, rifampicin) until the diagnosis is established. \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">Consultation with an infectious disease specialist. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BCG sepsis1/15.000 \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">Grade 4Prevention: initiate BCG 2 weeks post-TUR(if no hematuria). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Cessation of BCG \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle"></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">Treatment: \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"><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0090">•High-dose quinolones</li><li class="elsevierStyleListItem" id="lsti0095">•Isoniazid, rifampicin, ethambutol 6 months.</li><li class="elsevierStyleListItem" id="lsti0100">•Corticosteroids</li><li class="elsevierStyleListItem" id="lsti0105">•Empirical non-specific antibiotic to cover Gram-negative bacteria</li><li class="elsevierStyleListItem" id="lsti0110">•and/or Enterococcus.</li><li class="elsevierStyleListItem" id="lsti0115">•Management by infectious diseases.</li></ul> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Arthralgias/arthritis0.5−1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rare/ Autoimmune reaction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Arthralgia: NSAIDs (naproxen 500mg/2 times a day, diclofenac 50mg/8h, indomethacin 50mg/8h) for symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Reactive arthritis: NSAIDs (naproxen 500mg/2 times a day, diclofenac 50mg/8h, indomethacin 50mg/8h) for symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">No response: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Corticosteroids (prednisone 20mg/day, tapering schedule) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">High-dose quinolones. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Anti TB: Isoniazid (300mg/day) y Rifampicin (600mg/day) 3 months. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3683524.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of treatments for systemic effects." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:69 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of Bacillus Calmette-Guerin infection on transplanted tumours in the mouse" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L.J. 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Consensus document on the implications of standardization of BCG supply in the management of patients with non-muscle-invasive bladder cancer

Documento de consenso sobre las implicaciones de la normalización del suministro del BCG en el manejo del paciente con tumor vesical no-músculo invasivo (TVNMI)

Ó. Rodríguez Fabaa,

Corresponding author

orodriguez@fundacio-puigvert.es

Corresponding author.

, J.M. Fernández Gómezb, F. Guerrero-Ramosc, M. Álvarez-Maestrod, M.J. Ledo Ceperoe, M. Unda Urzaizf, L. Martínez-Piñeirod, J.M. Cózar Olmog, J. Palou Redortaa, J.L. Álvarez-Ossorioh

a Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain

b Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Asturias, Spain

c Hospital Universitario 12 de Octubre, Madrid, ROC Clinic y Hospital Universitario HM Sanchinarro, Madrid, Spain

d Hospital Universitario La Paz – IdiPAZ, Madrid, Spain

e Hospital Universitario Puerta del Mar, Cádiz, Spain

f Laboratorio Mixto de Investigación Traslacional en Cáncer de Próstata, CICbioGUNE-Basurto, IIS Biobizkaia, Spain

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

h Hospital Universitario Puerta del del Mar, Cádiz, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0120" class="elsevierStylePara elsevierViewall">The origin of the BCG vaccine dates back to the years 1908&#8722;1921&#46; Albert Calmette and Camille Gu&#233;rin discovered the tuberculosis &#40;TB&#41; vaccine from a virulent strain of <span class="elsevierStyleItalic">Mycobacterium bovis</span> by gradually reducing its toxicity through consecutive sub-passages&#46; The widespread use of the vaccine led to a drastic reduction in TB-related deaths worldwide&#46; Later&#44; it was proven to inhibit the growth of transplanted tumors in mice&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In 1969&#44; BCG was combined with chemotherapy for the treatment of acute lymphoblastic leukemia showing beneficial effects&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and in 1970 it was reported that intralesional BCG could inhibit the growth of malignant melanomas&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> However&#44; the discovery and broad applicability of chemotherapy and radiotherapy led to the gradual abandonment of BCG for oncological treatments&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In 1976&#44; Morales<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> was the first to use BCG for the treatment of 9 patients with recurrent NMIBC&#46; Since then&#44; multiple clinical trials have shown the oncologic efficacy of BCG in this group of patients&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Different strains were developed over the years as laboratories around the world mass-produced BCG for tuberculosis vaccines in their own countries&#46; Likewise&#44; when the use of BCG for the treatment of NMIBC was well established&#44; manufacturers modified the vial concentration &#40;one dose of BCG for bladder cancer is similar to over 4000 doses of BCG for vaccination&#41;&#44; although few companies produce or have produced BCG for this indication as an adjuvant treatment in bladder cancer &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In late 2012&#44; an unforeseen incident caused the collapse of the Sanofi factory that produced BCG Connaught in Canada&#46; In a routine inspection by the Food and Drug Administration &#40;FDA&#41;&#44; mold was found in the BCG production area due to previous natural flooding&#46; The factory was forced to close&#44; and production of the BCG vaccine was suspended as a result&#46; At that time&#44; the BCG Connaught produced and distributed by Sanofi was one of the main sources for BC treatment in North America and Europe&#46; Later&#44; Sanofi made the decision to halt production of BCG and confirmed their exit from the market in mid-2017&#46; Furthermore&#44; over the past five years&#44; issues with BCG production in other companies have led to supply constraints from the main suppliers&#46; Hence&#44; the situation has become significantly more critical due to both the rising global demand for NMIBC treatment and the announced anticipated shortages caused by suppliers depleting their stocks&#46; Even the increased production of BCG by Merck of more than one hundred percent was not enough to solve the enormous scarcity problem&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">This shortage has had a clinical impact&#46; First&#44; patients might have received fewer doses than those recommended&#44; with the consequent impact on earlier recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> They might have also received instillations of different strains depending on their availability in each region&#44; and last&#44; they might have received a reduced length of the maintenance therapy recommended by clinical guidelines&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Moreover&#44; there was an increased number of patients who had to be treated by cystectomy&#46; Ourfali et al&#46; estimated the clinical impact of BCG shortages between 2013 and 2016 and found a significantly higher 2-year recurrence rate for patients in the intermediate- and high-risk group treated in this period compared to a control group&#46; In addition&#44; they found an increased cost due to decreased BCG production&#44; estimated at approximately &#8364;783 per patient&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The decreased availability of BCG stocks is having a particularly detrimental effect in countries where only one specific BCG strain has been approved&#46; In USA and Canada&#44; OncoTICE from Merck is the only strain available&#46; Importing BCG from other countries is a reasonable option&#44; but regulatory issues hinder a rapid supply&#46; In some cases&#44; clinical trials must be conducted to introduce new strains&#46; The SWOG Cancer Research Network is conducting a randomized control trial&#44; S1602&#44; that compares the Tokyo and TICE strains&#46; This trial aims to approve the use of other therapeutic options&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In this context&#44; the Spanish Association of Urology &#40;AEU&#41; through its Research Institute &#40;IDI-URO&#41; is conducting a prospective clinical trial<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> ENCORE-01 &#40;<a href="ctgov:NCT03982797">NCT03982797</a>&#41; in patients with high-risk NMIBC with or without associated CIS or CIS without associated papillary tumor&#46; The trial uses the MOREAU RJ strain developed by BIOFABRI &#40;Porri&#241;o-Pontevedra&#41; after an audit that corroborated the quality of the manufacturing and the stability of the batches&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Throughout all these years of BCG shortage&#44; international urological societies have developed and adapted recommendations to address the problem&#44; although each strategy depends specifically on the availability of BCG in each particular country&#46; In Spain&#44; the AEU advised the Spanish Agency of Medicines and Medical Products &#40;AEMPS&#41; to publish recommendations on the use of BCG&#46; These were followed by all hospitals and Hospital Pharmacy Services in Spain&#44; along with alternatives available at the time&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Finally&#44; after multiple incidents with the supply of the drug since 2012&#44; the Spanish Ministry of Health announced the complete reestablishment of the supply of BCG RIVM strain without any limitations in October 2023&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methodology</span><p id="par0165" class="elsevierStylePara elsevierViewall">A group of 10 urologists with expertise in bladder cancer and members of the AEU gathered together&#46; The thematic framework was elaborated and developed jointly&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">A literature search was carried out including the first publications on BCG up to the present &#40;clinical trials&#44; published papers or with results reported at congresses&#44; adequately designed retrospective studies&#44; prospective studies and meta-analysis&#41; in the databases of the Cochrane Library&#44; Medline &#40;Pubmed&#41;&#44; with the combination of the keywords in the title or abstract &#34;BCG and NMIBC&#34;&#44; &#34;BCG strains&#34; and &#34;BCG dose&#34; &#34;clinical trials BCG&#34; &#34;non-muscle invasive bladder cancer&#34;&#46; The clinical guidelines of the EAU&#44; AUA&#44; NCCN&#44; ASCO&#44; ESMO were also reviewed&#46; The document sections were based on the selected publications&#44; in relation to the effectiveness of BCG&#44; previous procurement issues&#44; toxicity and treatment recommendations in the context of restoration of supplies&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Efficacy of BCG</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Mechanism of action</span><p id="par0175" class="elsevierStylePara elsevierViewall">BCG immunotherapy results in a massive local immune response characterized by induced cytokine expression in urine and bladder tissue&#44; and an influx of monocytes&#44; granulocytes and mononuclear cells into the bladder wall&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> After instillation into the bladder&#44; BCG attaches to the urothelium through fibronectin and after being kept in contact with the wall for the appropriate time&#44; with monocytes and granulocytes present&#44; these phagocytose the bacilli and activate the production of a considerable variety of cytokines inside the cell&#46; These include tumor necrosis factor alpha &#40;TNF-a&#41;&#44; granulocyte colony-stimulating factor&#44; interferon gamma &#40;IFN-g&#41;&#44; interleukins &#40;IL&#41;-1&#44; IL-2&#44; IL-5&#44; IL-6&#44; IL8&#44; IL-10&#44; IL-12 and IL18&#44; as well as the development of membrane antigens such as HLA-DR&#44; CD25 and intracellular adhesion molecule 1&#46; Production of membrane antigens within monocytes also occurs in the urothelium and the urothelium expresses major histocompatibility complex class II &#40;MHC-II&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">The presence of membrane antigens in monocytes activates CD4 helper cells and these produce IL-2 and IFN-g&#44; which in turn activate effector or natural killer &#40;NK&#41; cells&#46; Once these cells are activated&#44; CD8&#43;&#47;CD16dim and CD56&#43; cell subpopulations lyse the tumor via perforin production&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">BCG does not induce a tumor-specific immune response&#46; In this regard&#44; the lack of precise knowledge of the mechanism of action complicates the understanding of the mechanisms by which BCG failure occurs&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">It is important to note that these changes in the patients&#39; bladder may be present for more than one year after the first contact with the bacillus&#44; but usually diminish after three to six months&#44; thus providing a rational basis for maintenance therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#59; Adapted from Audisio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Strain differences and their impact on clinical outcome</span><p id="par0195" class="elsevierStylePara elsevierViewall">There are several strains of BCG currently available&#46; The original strain was Pasteur&#44; obtained by Calmette and Guerin in 1921&#46; Although the EAU &#40;European Association of Urology&#41; Guidelines do not recommend any specific strain&#44; there are studies that have compared the clinical differences in terms of efficacy between some of them&#46; Rentsch et al&#46; in 2014 demonstrated that treatment with BCG Connaught prevented recurrences more efficiently than TICE BCG&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Similarly&#44; Wegt et al&#46; published the inferiority of TICE compared to RIVM in reducing the risk of recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Witjes et al&#46; also compared the efficacy of Connaught and TICE in a population of 2099 patients and their results did not demonstrate a significant difference between the two strains in terms of time to progression and overall survival&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> A meta-analysis published in 2017 identified up to 10 different strains currently in use but did not confirm the superiority of any strain over another&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">In 2017&#44; the Spanish BCG Strain Registry Group published an observational&#44; prospective&#44; multicenter registry including 433 patients&#46; The study evaluated disease-free survival &#40;DFS&#41;&#44; progression-free survival &#40;PFS&#41;&#44; cancer-specific survival &#40;CSS&#41; and adverse events in 12 months of follow-up&#46; TICE&#44; Russian&#44; Tokyo&#44; Connaught and RIVM strains were studied&#46; The results demonstrated that there were no significant differences in any of the parameters evaluated&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Therefore&#44; any of them can be used in both induction and maintenance courses&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Efficacy according to treatment duration and dose</span><p id="par0205" class="elsevierStylePara elsevierViewall">The first intravesical BCG dose was empirically determined to be 120<span class="elsevierStyleHsp" style=""></span>mg &#40;Frappier strain&#41; based on the observation that it was well tolerated by intradermal scarification&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Several studies have been conducted to determine whether a lower dose of BCG can guarantee the same efficacy and less toxicity&#46; Either 80&#44; 81&#44; or 120<span class="elsevierStyleHsp" style=""></span>mg was used as a standard dose in most studies&#44; and the low dose was defined as a half or one&#47;two-third of the standard dose in the most studies&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">An induction course is required in order to provoke an immune response in the bladder&#46; The treatment should be initiated two to four weeks after TUR and can be applied until the sixth week if necessary&#46; The six-week weekly application schedule was chosen arbitrarily&#44; and most patients develop an adequate immune response with six instillations&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">In this regard&#44; Grimm et al&#46; reported that reducing the total number of instillations from 15 &#40;standard&#41; to 9 significantly increases recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">According to data published by the EORTC&#44; the comparison between full-dose and 1&#47;3 dose of TICE reported that the efficacy of a 1&#47;3 dose for 1<span class="elsevierStyleHsp" style=""></span>year is lower than that of a full dose for 3 years in patients with intermediate- or high-risk NMIBC&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> There was no difference in toxicity between the 1&#47;3 dose and the full dose&#46; The CUETO group published a similar study in 2005&#46; In this work&#44; a lower efficacy of 1&#47;3 dose compared to full dose BCG Connaught strain could not be confirmed &#40;progression rate of 26&#37; and 24&#46;7&#37;&#44; respectively&#41;&#46; The population of this study included 90 T1G3 and subgroup analysis by stage did not differ significantly&#46; Moreover&#44; the 1&#47;3 dose was associated with significantly lower toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Furthermore&#44; this review confirmed that 27<span class="elsevierStyleHsp" style=""></span>mg BCG represents the minimum effective dose&#46; Many different maintenance schedules have been proposed in recent years&#44; ranging from a total of 10 instillations given in 18&#8211;27 weeks over 3 years&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> However&#44; there is still no consensus on the optimal duration of maintenance courses&#46; The most commonly used maintenance schedule is that proposed by Lamm and the Southwest Oncology Group &#40;SWOG&#41;&#58; a six-week weekly induction instillation followed by a course of a three-week weekly instillation at three and six months&#44; with subsequent three-week weekly instillation every six months for up to three years&#46; Globally&#44; it has been established that the benefit of 2 additional years of BCG maintenance needs to be accurately assessed as it may increase toxicity and costs&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Alternatives to BCG in case of supply shortage</span><p id="par0225" class="elsevierStylePara elsevierViewall">Given the circumstances previously outlined&#44; various scientific societies&#44; such as the EUA&#44; promptly published documents with recommendations for treating patients with NMIBC who had a BCG indication&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> As a preliminary comment&#44; we must stress the importance of performing a second TUR in patients with an indication given its prognostic and oncologic value&#46; Considering the association between TUR quality and oncologic outcomes&#44; it must be performed with the utmost care&#44; aiming to achieve the highest quality&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">The following are the recommendations made by different expert committees&#58;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Intravesical chemotherapy and radical cystectomy</span><p id="par0235" class="elsevierStylePara elsevierViewall">Although adjuvant treatment with Mitomycin C &#40;MMC&#41; does not seem to be clearly recommended in high-risk tumors&#44; it could provide some benefit in cases of BCG shortage and could be an advisable action in cases of supply shortage&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Other agents evaluated or under study are&#58;<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">-</span><p id="par0245" class="elsevierStylePara elsevierViewall">Intravesical gemcitabine&#44; with definitive results pending in BCG na&#239;ve NNMIBC &#40;Sunrise-3 trial&#41; based on the incorporation of TAR-200&#44; a 21-day intravesical gemcitabine delivery system combined with systemic administration of cetrelimab &#40;anti-PD1 antibody&#41; in one arm of the trial&#46; Encouraging preliminary results have also been reported &#40;Sunrise-1&#41; in BCG unresponsive &#40;82&#46;8&#37; overall complete response in the group of CIS patients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">-</span><p id="par0250" class="elsevierStylePara elsevierViewall">Intravesical combination therapy of gemcitabine with Docetaxel &#40;Gem&#47;Doce&#41; weekly for 6 weeks&#44; followed by monthly maintenance for one year&#46; It presents similar recurrence rates to BCG for any&#47;high-grade recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">-</span><p id="par0255" class="elsevierStylePara elsevierViewall">The BRIDGE prospective phase 3 clinical trial of Gem&#47;Doce versus BCG instillations in high-risk NMIBC is underway&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">-</span><p id="par0260" class="elsevierStylePara elsevierViewall">Combination therapy of BCG with interferon alpha&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></li></ul></p><p id="par0265" class="elsevierStylePara elsevierViewall">In patients with very high risk NMIBC according to EAU criteria&#44; it is advisable to offer immediate radical cystectomy&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">BCG&#58; strains&#44; prioritization&#44; treatment duration and dose reduction</span><p id="par0270" class="elsevierStylePara elsevierViewall">There are several studies in the literature that compare different BCG strains&#44; with results that are not always consistent&#46; However&#44; according to the most recent evidence&#44; it is generally accepted that there are no significant differences in the efficacy between strains&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> There are even data in the literature combining Connaught for induction and OncoTICE for maintenance&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> This shows that if the same BCG strain is not available for the entire treatment of one patient&#44; different strains can be used&#44; depending on stock availability&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">On the other hand&#44; regarding the prioritization of the BCG available&#44; it should be reserved for high-risk patients&#44; using intravesical chemotherapy for patients with intermediate-risk tumors&#59; even for patients with allergy or relapse after MMC&#44; another alternative to BCG would be the use of other chemotherapy drugs such as gemcitabine&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Regarding the duration of treatment&#44; it is recommended to reduce it from 3 years to 1<span class="elsevierStyleHsp" style=""></span>year in high-risk patients&#44; with a reduced dose in the second and third year in patients with CIS&#44; based on data from previous studies&#44; and assuming a slight increase in recurrence rates&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">The data available in the literature when consensus documents were issued by expert committees established that the administration of reduced doses of BCG &#40;one-third of the full dose&#41; had no impact on progression rates compared to full doses&#44; although there was an increased risk of recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> A recent systematic review and meta-analysis demonstrated that recurrence rates are comparable provided that a maintenance schedule is administered despite using a reduced dose&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Consequently&#44; another recommendation is to administer reduced doses of BCG&#44; so that one vial can be used to treat three patients&#44; although with certain limitations in terms of logistics and dose preparation&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Device-assisted intravesical chemotherapy</span><p id="par0290" class="elsevierStylePara elsevierViewall">In those extreme situations of absolute lack of BCG for patients with high-risk tumors&#44; and in those cases in which immediate radical cystectomy is not considered&#44; the use of device-assisted intravesical chemotherapy is recommended&#46; Patients should be referred to centers equipped with this technology in case it is not available&#46; This recommendation is based on the results of previous studies that showed promising response rates with this therapeutic alternative&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Regarding the use of devices for the administration of chemotherapy in high-risk tumors&#44; the strongest evidence up to the date when the stockouts began was a randomized clinical trial that used sequential BCG and electromotive mitomycin versus BCG alone&#46; This study reports more favorable results for sequential treatment&#44; with longer recurrence-free survival &#40;69 vs 21 months&#41;&#44; lower recurrence rate &#40;41&#46;9&#37; vs 57&#46;9&#37;&#41;&#44; lower progression rate &#40;9&#46;1&#37; vs 21&#46;9&#37;&#41;&#44; and lower overall &#40;21&#46;5&#37; vs 32&#46;4&#37;&#41; and cancer-specific &#40;5&#46;6&#37; vs 16&#46;2&#37;&#41; mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall">As a consequence of the shortages&#44; and in search for the best alternative for these patients&#44; evidence was generated showing the results of treatments other than BCG&#46; Accordingly&#44; the HIVEC-HR phase II randomized clinical trial was designed to compare BCG versus MMC with recirculating hyperthermia &#40;HIVEC&#41; in patients with high-risk tumors&#46; The main objective of this trial was to determine the non-inferiority of HIVEC in terms of recurrence-free survival&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> In their per-protocol analysis&#44; recurrence-free survival at 2 years showed no significant difference between the two groups &#40;86&#46;5&#37; HIVEC vs 71&#46;8&#37; BCG&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;064&#41;&#44; and progression-free survival at 24 months was found to be better for patients who received HIVEC &#40;95&#46;7&#37; vs 71&#46;8&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;043&#41;&#46; Although the results were not published until some years after the first stock-out&#44; this study generates the first evidence based on a randomized trial in favor of the use of HIVEC in high-risk tumors in certain situations&#44; such as BCG stock-out or BCG intolerance&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Novel therapies for BCG failure</span><p id="par0305" class="elsevierStylePara elsevierViewall">One of the most common scenarios evaluated in current studies is BCG-failure in high-grade non-muscle invasive disease&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In this context&#44; two treatments have been approved by the FDA for patients with CIS &#40;with or without associated papillary tumor&#41; unresponsive to BCG&#44; systemic immunotherapy &#40;pembrolizumab&#41; with 3-month complete response rates of 41&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Other novel therapies include intravesical viral delivery systems&#46; Two promising viral delivery systems include Nadofaragene-Firadenovac &#40;Adstiladrin&#174;&#41; with 3-month complete response rates of 53&#46;4&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> and which has FDA approval and CG0070 &#40;oncolytic adenovirus&#41; with 6-month overall complete response rates of 47&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">Furthermore&#44; the BOND-003 &#40;Intravesical Cretostimogene-Grenadenorepvec&#41; Phase 3 trial has reported a 3-month complete response rate of 68&#46;2&#37; in SUO 2023&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Subsequently&#44; other drugs have reported preliminary results that exceed those of pembrolizumab and Nadofaragene-Firadenovec&#46; Thus&#44; the combination of BCG and N-803 &#40;an IL-15 superagonist&#41; reported a complete response rate of 71&#37;&#44; and the use of intravesical TAR-200 reaches 76&#46;7&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">In general&#44; most trials based on this stage of disease present an additional cohort of papillary-only disease&#44; without CIS&#46; The objective in these patients&#44; rather than assessment of complete response rate&#44; and due to the fact that these are adjuvant treatments&#44; is focused on high-grade recurrence-free survival&#46; Being a theoretically less aggressive entity than CIS&#44; the results of these cohorts are even more encouraging&#46; There are still no approvals by regulatory agencies in this population&#46; In addition to the results reported in these accessory cohorts of papillary disease from studies initially designed for patients with CIS&#44; the recently reported results with erdafitinib are noteworthy&#46; The only randomized study to date randomly allocated patients to receive oral erdafitinib versus investigator&#39;s choice of mitomycin C or gemcitabine &#40;patients with BCG-unresponsive high-grade papillary tumor&#41;&#44; after molecular screening for alterations or fusions for FGFR genes&#59; the median high-grade recurrence-free survival was not achieved for erdafitinib and was 11&#46;6 months for the chemotherapy group&#44; with a Hazard Ratio of 0&#46;28 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0008&#41;&#46; However&#44; a grade 3 or higher toxicity rate in the erdafitinib group of 38&#46;8&#37; limits the use of this treatment&#44; among other problems&#44; such as the recruitment of 73 patients when 240 were initially expected&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> To avoid the toxicity derived from systemic administration&#44; it is possible to administer the drug intravesically using the TAR-210 device in the same patient population&#46; Cohort 1 of the ErdaRIS clinical trial evaluates TAR-210 in a single arm in this patient population&#44; preliminarily achieving 82&#37; of patients free of high-grade disease with an excellent toxicity profile &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Updated guidelines for NMIBC treatment with BCG</span><p id="par0325" class="elsevierStylePara elsevierViewall">NMIBC is a heterogeneous disease that is often difficult to treat&#44; given the number of clinicopathologic factors that affect its prognosis&#46; In addition&#44; it requires strict surveillance due to its high recurrence rate &#40;30&#8211;78&#37; at 5 years&#41; in the same stage&#47;grade&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> as well as the likelihood of progression to potentially lethal muscle-invasive disease &#40;10&#8211;40&#37; at 5 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">Traditionally&#44; the EAU Guidelines have recommended stratification of NMIBC into prognostic groups to guide treatment and follow-up&#46; One of the most important factors in the classification of these risk groups is tumor grade&#46; Until 2004&#44; the 1973 WHO grading was used exclusively&#46; It classified disease as grade 1 &#40;G1&#41;&#44; grade 2 &#40;G2&#41; and grade 3 &#40;G3&#41; categories&#46; Recently&#44; however&#44; a histological classification has been introduced including papillary urothelial neoplasm of low malignant potential &#40;PUNLMP&#41;&#44; low-grade &#40;LG&#41; and high-grade &#40;HG&#41; papillary carcinoma&#46; This system was included in the 2016 and 2022 updated WHO classifications&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">The new risk group definitions provided by the EAU Guidelines are based on a data analysis of individual patients with primary tumors and estimation of their risks of progression&#46; As such&#44; we can use one of the WHO classification systems &#40;1973 or WHO 2004&#47;2016&#41;&#44; or both&#46; Regarding this point&#44; it should be noted that when comparing the WHO-1973 grading system with the WHO 2004&#47;2016 grading system&#44; the former has shown to be more accurate in predicting progression in NMIBC&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0340" class="elsevierStylePara elsevierViewall">The prognostic factors on which the EAU &#40;progression&#41; risk classification is based are stage &#40;T&#41;&#44; grade &#40;with both classifications&#41; and three additional factors&#58; tumor diameter&#44; with a threshold of 3<span class="elsevierStyleHsp" style=""></span>cm&#44; multifocality and age &#40;70 years&#41;&#44; which worsen the risk of progression&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Based on these parameters&#44; four prognostic factor risk groups are established&#58;<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8226;</span><p id="par0345" class="elsevierStylePara elsevierViewall">Low risk &#40;5-year risk of progression &#60;1&#37;&#41;&#46; Low grade&#47;G1 primary tumors without carcinoma in situ &#40;CIS&#41;&#44; which can be&#58;<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">-</span><p id="par0350" class="elsevierStylePara elsevierViewall">Ta with one or no associated factors &#40;size&#44; multifocality&#44; age&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">-</span><p id="par0355" class="elsevierStylePara elsevierViewall">T1 with no associated factors&#58; single &#60; 3<span class="elsevierStyleHsp" style=""></span>cm diameter &#60; 70 years&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#8226;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Intermediate risk &#40;risk of progression at 5 years of 4&#8211;5&#37;&#41;&#46; Not specifically defined in the Guidelines&#58; patients without CIS who are not included in either the low-&#44; high-&#44; or very high-risk groups&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">&#8226;</span><p id="par0365" class="elsevierStylePara elsevierViewall">High risk &#40;risk of progression at 5 years of 10&#37;&#41;&#46; These are primary or recurrent tumors&#44; which include the following&#58;<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">-</span><p id="par0370" class="elsevierStylePara elsevierViewall">Presence of CIS</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">-</span><p id="par0375" class="elsevierStylePara elsevierViewall">High grade &#40;2016&#47;2022&#41; without CIS<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">&#9642;</span><p id="par0380" class="elsevierStylePara elsevierViewall">T1HG &#40;except those included in the very high-risk group&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">&#9642;</span><p id="par0385" class="elsevierStylePara elsevierViewall">TaHG&#47;G3 with at least two risk factors &#40;size&#44; multifocality&#44; age&#41;&#46;</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">-</span><p id="par0390" class="elsevierStylePara elsevierViewall">Low grade &#40;2016&#47;2022&#41; without CIS with additional clinical risk factors &#40;size&#44; multifocality&#44; age&#41;&#46;<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">&#9642;</span><p id="par0395" class="elsevierStylePara elsevierViewall">TaG2 &#40;1973&#41; with all 3 risk factors</p></li><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">&#9642;</span><p id="par0400" class="elsevierStylePara elsevierViewall">T1G1 &#40;1973&#41; with at least two risk factors</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">&#9642;</span><p id="par0405" class="elsevierStylePara elsevierViewall">T1G2 &#40;1973&#41; with at least 1 risk factor</p></li></ul></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">&#8226;</span><p id="par0410" class="elsevierStylePara elsevierViewall">Very high risk &#40;risk of progression at 5 years 40&#8211;44&#37;&#41;&#46; These are primary or recurrent tumors&#44; which include the following&#58;<ul class="elsevierStyleList" id="lis0095"><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">-</span><p id="par0415" class="elsevierStylePara elsevierViewall">Ta HG&#47;G3 and CIS with all three risk factors &#40;size&#44; multifocality&#44; age&#41;</p></li><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">-</span><p id="par0420" class="elsevierStylePara elsevierViewall">T1 G2 and CIS with at least two risk factors</p></li><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">-</span><p id="par0425" class="elsevierStylePara elsevierViewall">T1HG&#47;G3 and CIS with at least two risk factors</p></li><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">-</span><p id="par0430" class="elsevierStylePara elsevierViewall">T1AG&#47;G3 no CIS with all three risk factors</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">-</span><p id="par0435" class="elsevierStylePara elsevierViewall">The 2023 EAU Guidelines also include those NMIBC patients with lymphovascular invasion&#44; CIS in the prostatic urethra or histological variants&#46;</p></li></ul></p></li></ul></p><p id="par0440" class="elsevierStylePara elsevierViewall">The EAU Guidelines recommend that&#44; once the prognostic group for progression has been established and&#44; therefore&#44; the treatment has been oriented&#44; the tables published by the EORTC<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> scoring model or the CUETO risk scoring model &#40;<a href="https://www.aeu.es/cueto.html">https&#58;&#47;&#47;www&#46;aeu&#46;es&#47;cueto&#46;html</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> should be used to determine the risk of recurrence in individual patients and adapted to the treatment to be used in each risk group&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">Tumors with BCG indication after TUR are undoubtedly those at high risk of progression in the EAU classification &#40;progression rate of 14&#46;1 and 14&#46;2&#37; after 10 years&#44; according to the EAU 2021 scoring model&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> In these patients&#44; full-dose intravesical BCG for one to 3 years &#40;induction plus 3-weekly instillations at 3&#44; 6&#44; 12&#44; 18&#44; 24&#44; 30 and 36 months&#41;&#44; is indicated&#46; The additional beneficial effect of the second and third years of maintenance should be weighed against its added costs and side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> As patients with CIS cannot be treated by an endoscopic procedure alone&#44; intravesical BCG instillations or radical cystectomy should be considered if they are at very high risk&#46; The treatment of CIS patients with BCG has shown to increase response rates&#44; overall percentage of patients who remain disease free and reduce the risk of progression&#46; The use of BCG in these cases avoids overtreatment and morbidity associated with radical cystectomy in high-risk tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0450" class="elsevierStylePara elsevierViewall">Those patients at very high risk would have an indication for immediate cystectomy due to the high probability of tumor progression &#40;53&#46;1 and 58&#46;6&#37; after 10 years according to the 2021 EAU NMIBC scoring model&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> However&#44; in case RC is not feasible or refused by the patient&#44; full-dose intravesical BCG for one to 3 years should be offered&#44; with the same considerations as those for patients with high-risk tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0455" class="elsevierStylePara elsevierViewall">Tumors in the intermediate-risk group are associated with a low risk of disease progression of 7&#46;4 and 8&#46;5&#37; after 10 years according to the 2021 EAU NMIBC scoring model&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> According to the EAU Guidelines&#44; intravesical chemotherapy &#40;optimal regimen is unknown&#41; for up to one year or BCG treatment with one-year maintenance may be indicated in these cases&#46; The final choice should reflect the individual patient&#8217;s risk of recurrence and progression as well as the efficacy and side effects of each treatment modality&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Therefore&#44; the EAU Guidelines do not clearly specify in which intermediate-risk tumors BCG or chemotherapy would be indicated&#46; In this regard&#44; the International Bladder Cancer Group &#40;IBCG&#41; has recently published a review of randomized clinical trials&#44; meta-analyses&#44; systematic reviews and clinical practice guidelines on intermediate-risk NMIBC&#46; The IBCG recommends that treatment of these tumors should be based on the following risk factors&#58; multifocal tumor &#40;more than one&#41;&#44; early recurrence &#40;&#60;1<span class="elsevierStyleHsp" style=""></span>yr&#46;&#41;&#44; frequent recurrence &#40;&#62;1&#47;yr&#46;&#41;&#44; tumor size &#40;&#8805;3<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; and failure of prior intravesical chemotherapy&#46; According to the authors&#44; BCG should be used in intermediate-risk tumors with the following characteristics&#58; TaG1 with 3 of the above risk factors&#44; TaG2 with 2 risk factors&#44; T1G1 with one risk factor&#44; or T1G2 with no risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0460" class="elsevierStylePara elsevierViewall">It should be remembered that&#44; according to the latest EAU Guidelines&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> if we want to obtain an estimate of the individualized risks of recurrence in patients treated with BCG&#44; the CUETO tables<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> should be used&#44; as mentioned above&#46; However&#44; the CUETO tables might also be more appropriate to obtain the probabilities of progression than the latest EAU tables&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> since the latter are based on a study that did not include cases of BCG-treated patients&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> and the risks of progression in them may be overestimated&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Management of adverse effects</span><p id="par0465" class="elsevierStylePara elsevierViewall">In general&#44; toxicity attributed to intravesical treatment with BCG instillations can be local &#40;68&#8211;72&#46;5&#37;&#41;&#44; appearing within a few hours of instillation and lasting no more than 48&#8211;72<span class="elsevierStyleHsp" style=""></span>h&#44; or systemic &#40;30&#37;&#41;&#44; which is a serious condition that may require multidisciplinary management with urology&#44; infectious disease and even intensive care specialists&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">The key to effective treatment of adverse effects due to BCG lies in an adequate prevention&#44; early diagnosis and appropriate treatment depending on the type and grade of the effect&#46;</p><p id="par0475" class="elsevierStylePara elsevierViewall">In case of suspicion of toxicity associated with BCG treatment&#44; the first step should be to carry out adequate identification and classification of the severity of the clinical picture&#46; In this regard&#44; several authors have classified cases into 4 categories &#40;mild&#47;moderate&#47;severe&#47;systemic complications&#41; using a scale based on the recommendations of the World Health Organization &#40;WHO&#41;&#46; The use of this scale has shown that patients with a score higher than 1&#46;5 during induction treatment suffer greater changes in the frequency and duration of instillations&#44; both in induction and maintenance&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a><ul class="elsevierStyleList" id="lis0100"><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">-</span><p id="par0480" class="elsevierStylePara elsevierViewall">Grade 1&#58; moderate and &#60;48<span class="elsevierStyleHsp" style=""></span>h &#40;usually require no modification of intravesical therapy&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">-</span><p id="par0485" class="elsevierStylePara elsevierViewall">Grade 2&#58; severe and&#47;or &#62;48<span class="elsevierStyleHsp" style=""></span>h &#40;usually require suspension of instillations until resolution of symptoms&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">-</span><p id="par0490" class="elsevierStylePara elsevierViewall">Grade 3&#58; local&#44; regional&#44; systemic&#44; and immunoallergic &#40;usually require suspension of instillations until resolution of symptoms&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">-</span><p id="par0495" class="elsevierStylePara elsevierViewall">Grade 4&#58; systemic BCG reactions &#40;cessation of BCG therapy is required&#41;&#46;</p></li></ul></p><p id="par0500" class="elsevierStylePara elsevierViewall">Regarding local toxicity&#44; the most frequent conditions and symptoms are BCG-induced cystitis &#40;35&#37;&#41;&#44; urinary frequency&#47;urgency &#40;23&#46;6&#37;&#41;&#44; bacterial cystitis &#40;23&#46;3&#37;&#41;&#44; and hematuria &#40;22&#46;6&#37;&#41;&#46; Less frequent are prostatitis and orchitis&#46;</p><p id="par0505" class="elsevierStylePara elsevierViewall">The most frequent systemic effects are general malaise and fever &#40;15&#46;5&#37;&#41;&#44; much less frequent and more severe are skin rash&#44; uro-sepsis&#44; systemic BCG infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;54</span></a></p><p id="par0510" class="elsevierStylePara elsevierViewall">Therefore&#44; and given the variety and potential severity of the associated toxicity&#44; it can be deduced that BCG treatment should be accompanied by an appropriate informed consent signed by the patient&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Prevention of complications</span><p id="par0515" class="elsevierStylePara elsevierViewall">It is possible that certain systemic adverse effects are related to traumatic catheterization&#44; which is why it is not recommended to start BCG before 14 days following TUR&#44; or in case of persistent hematuria&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0520" class="elsevierStylePara elsevierViewall">Likewise&#44; it is advisable to delay instillation in the presence of bacterial cystitis&#44; since inflammation of the urothelium may facilitate the systemic absorption of BCG&#46;</p><p id="par0525" class="elsevierStylePara elsevierViewall">At the time of BCG administration&#44; it is recommended to&#58;</p><p id="par0530" class="elsevierStylePara elsevierViewall">Use a luer-lock&#44; hydrophilic catheter of the smallest caliber necessary&#46; If a hydrophilic catheter is not used&#44; it is recommended to administer 10&#8722;15<span class="elsevierStyleHsp" style=""></span>ml of lubricating jelly&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Specific complications</span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Hematuria</span><p id="par0535" class="elsevierStylePara elsevierViewall">Hematuria is a frequent symptom in the context of patients treated with BCG&#46; It may occur in up to 90&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;53</span></a> It appears very frequently associated with cystitis and may be related to the length of the resection area&#46; Urine culture should be performed to rule out hemorrhagic cystitis and instillations should be postponed until hematuria is completely resolved&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">BCG-induced cystitis</span><p id="par0540" class="elsevierStylePara elsevierViewall">In general&#44; local irritative symptoms are the most frequent complication associated with BCG treatment&#44; as we have previously mentioned&#46;</p><p id="par0545" class="elsevierStylePara elsevierViewall">This symptomatology may also be accompanied by hematuria with negative cultures in up to 23&#37; of cases and by symptoms with a frequency-urgency<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>once&#47;hour in up to 24&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall">Since the immunological mechanism of action of BCG is not completely defined&#44; it is clear that the diagnosis of cystitis due to a hypersensitivity response to BCG should be confirmed by the presence of granuloma with negative cultures&#46; If we consider the hypothesis of bacterial invasion&#44; there should be active bacilli in the urothelium&#46;</p><p id="par0555" class="elsevierStylePara elsevierViewall">In any case and in a practical way&#44; urine cultures&#47;hemocultures should be performed to rule out bacterial infection or sepsis&#46; If immune-mediated cystitis is suspected&#44; it will be accompanied by flu-like symptoms and will resolve in 24&#8722;48<span class="elsevierStyleHsp" style=""></span>h without any treatment or with symptomatic treatment consisting of spasmolytics&#44; anticholinergics or non-steroidal anti-inflammatory drugs&#46; There is no solid evidence to prove the superiority of one drug over the others&#44; with the exception of oxybutynin&#44; which does not appear to be effective according to the results of a randomized study&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="par0560" class="elsevierStylePara elsevierViewall">If bacterial cystitis is diagnosed&#44; antibiotic treatment should be initiated&#46; Prophylaxis with ofloxacin has shown to reduce local complications related to BCG &#40;18&#46;5&#37; reduction of moderate or severe adverse effects&#41; during instillations&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Therefore&#44; given the risk of associated bacterial cystitis in those patients with persistent voiding symptoms&#44; ofloxacin 200<span class="elsevierStyleHsp" style=""></span>mg&#47;day can be started adjusting the regimen to the antibiogram&#46; Likewise&#44; 1 instillation&#47;day for 5 days of an anesthetic-sedative formula composed of distilled water<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>200<span class="elsevierStyleHsp" style=""></span>mg&#46; nitrofurantoin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>g&#46; tetracaine<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>165<span class="elsevierStyleHsp" style=""></span>mg&#46; prednisolone has shown a beneficial effect in the reduction of irritative voiding symptoms in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><p id="par0565" class="elsevierStylePara elsevierViewall">BCG treatment should be withheld until completion of a specific antibiotic course&#46;</p><p id="par0570" class="elsevierStylePara elsevierViewall">However&#44; if patients with disabling symptoms are refractory to conservative treatment&#44; a short course of 2&#8211;4 weeks of oral steroids interspersed during antituberculous therapy should be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Major surgery&#44; such as bladder augmentation for contracted bladder or cystectomy&#44; is required only in exceptional cases &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Prostatitis</span><p id="par0575" class="elsevierStylePara elsevierViewall">Granulomatous prostatitis is a complication whose actual prevalence is underestimated by symptomatic case series&#46; In fact&#44; only about 10&#37; of men develop clinical prostatitis associated with BCG instillations&#46; More than 40&#37; present with elevated serum PSA and 41&#8211;75&#37; of patients undergoing post BCG prostate biopsy or radical cystoprostatectomy present histologically proven granulomatous prostatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p><p id="par0580" class="elsevierStylePara elsevierViewall">Granulomatous prostatitis demonstrates early and prolonged ring enhancement on MRI&#44; which might be a key finding to differentiate it from prostate cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a></p><p id="par0585" class="elsevierStylePara elsevierViewall">Patients with clinical BCG-induced prostatitis may present with atypical symptoms or signs&#44; including perineal pain&#44; enlarged gland tender prostate&#44; firm prostate nodules&#44; and elevated PSA that returns to normal 3 months after the end of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> Prostatic fluid staining for acid-fast bacilli is helpful to identify tuberculous prostatitis&#46; There are sporadic reports of tubercular prostatic abscess treated with drainage and anti-TBC drugs&#46; Only cases of symptomatic granulomatous prostatitis may require treatment based on anti-TB therapy and fluoroquinolones<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Epididymo-orchitis</span><p id="par0590" class="elsevierStylePara elsevierViewall">Tuberculous epididymo-orchitis is an uncommon granulomatous infection resulting from intravesical BCG treatment &#40;0&#46;2&#8211;10&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> Episodes occurring during instillations are most often caused by gram-negative rods as a consequence of catheterization&#46; They usually manifest as scrotal swelling&#44; pain&#44; dysuria and fever&#44; and those appearing within a few weeks of BCG instillations&#44; and even up to several years after discontinuation of treatment are most likely due to TB&#46; Several distinct sonographic patterns have been described&#44; the most frequent being enlarged epididymis or hypoechoic nodules&#46; Orchitis ultrasound may exhibit a miliary pattern with multiple intratesticular hypoechoic nodules&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> Other typical findings&#44; such as hydrocele&#44; scrotal skin edema&#44; intrascrotal calcifications&#44; and abscesses are also possible&#46; The biopsy result shows granulomatous changes&#44; caseous necrosis and positive acid-fast bacilli in the biopsy specimen&#46; BCG-induced epididymo-orchitis usually responds adequately to anti-TB therapy&#46; If the lesion is accompanied by persistent pain&#44; swelling&#44; fever and&#47;or leukocytosis refractory to antituberculous treatment&#44; scrotal exploration and orchidectomy may be necessary &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><p id="par0595" class="elsevierStylePara elsevierViewall">Since gram-negative bacilli can cause this condition&#44; the use of fluoroquinolones is initially recommended&#46; In case of persistent symptomatology&#44; anti-TB should be started&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Systemic toxicity associated to BCG</span><p id="par0600" class="elsevierStylePara elsevierViewall">As previously mentioned&#44; systemic toxicity associated with BCG instillations is less frequent but potentially more severe and may require co-management with infectious disease specialists&#46;</p><p id="par0605" class="elsevierStylePara elsevierViewall">Up to 30&#37; of patients may present low-grade fever&#44; general malaise and nausea&#46; Fever above 39<span class="elsevierStyleHsp" style=""></span>&#176;C is less frequent &#40;up to 20&#37; of cases&#41;&#46; This symptomatology usually resolves within 24&#8722;48<span class="elsevierStyleHsp" style=""></span>h with symptomatic and&#47;or antipyretic treatment&#46; If fever &#62;38&#46;5<span class="elsevierStyleHsp" style=""></span>&#176;C persists for more than 48<span class="elsevierStyleHsp" style=""></span>h&#44; immediate suspension of instillations should be indicated&#44; empiric broad-spectrum antibiotics should be started&#44; cultures should be obtained and infectious diseases should be consulted&#46;</p><p id="par0610" class="elsevierStylePara elsevierViewall">Systemic granulomatous disease caused by BCG&#44; also called &#34;BCG-osis&#34;&#44; occurs immediately after administration of the instillation associated with absorption of BCG as a result of traumatic catheterization or a very early administration after TUR&#46; Since it is very difficult to isolate mycobacteria from the affected organs&#44; there are doubts about the infectious or inflammatory origin of the condition&#44; which is why it is also called &#34;systemic BCG reaction&#34;&#46;</p><p id="par0615" class="elsevierStylePara elsevierViewall">It manifests with high fever&#44; leukopenia&#44; hemodynamic instability&#44; hepatomegaly&#44; bilateral crackles in both lung bases and altered liver function tests&#46;</p><p id="par0620" class="elsevierStylePara elsevierViewall">Treatment of this condition consists of discontinuation of BCG and isoniazid&#44; rifampicin and ethambutol for 6 months associated with fluoroquinolones and steroids since the latter have been shown to improve survival&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> The addition of a broad-spectrum antibiotic for gram-negatives bacteria is also recommended &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Reactive arthritis</span><p id="par0625" class="elsevierStylePara elsevierViewall">Intravesical BCG therapy-associated osteoarticular complications are uncommon &#40;0&#46;5&#8722;1&#37;&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> although they account for 64&#37; of all autoimmune complications following BCG treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> This is a reactive arthritis caused by a systemic immune response&#46; According to prevalence&#44; the most frequently affected joints are knee &#40;84&#46;3&#37;&#41;&#44; ankle &#40;55&#46;1&#37;&#41;&#44; hand &#40;39&#46;3&#37;&#41;&#44; wrist &#40;32&#46;6&#37;&#41; and foot &#40;28&#46;1&#37;&#41;&#44; with polyarthritis being the most frequent clinical manifestation&#46; Although inflammatory joint involvement is induced by an autoimmune reaction&#44; synovial fluid analysis is required to rule out septic arthritis&#46; Treatment should be discontinued&#46; Fifty-seven percent of cases are associated with fever&#44; and 67&#37; respond adequately to anti-inflammatory treatment with NSAIDs&#46;</p></span></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusions</span><p id="par0630" class="elsevierStylePara elsevierViewall">For decades&#44; adjuvant treatment with BCG has been indicated in most clinical practice guidelines for high- and intermediate-risk NMIBC&#46; However&#44; supply shortages and unresolved controversies regarding the optimal dose&#44; duration of treatment&#44; maintenance schedule and strains used have resulted in treatment protocols that have had to adapt to these new circumstances&#46; In Spain&#44; however&#44; the situation is currently normalized&#46;</p><p id="par0635" class="elsevierStylePara elsevierViewall">Given the heterogeneity of NMIBC&#44; the EAU risk groups should be applied to stratify patients&#44; since they are the most widely used and validated in our setting&#46; High-risk and also selected intermediate-risk patients should be treated with one BCG induction and maintenance schedule for at least 1<span class="elsevierStyleHsp" style=""></span>year&#46; No strain has been shown to be superior to any other&#44; and it is possible to combine different strains depending on supply availability&#46;</p><p id="par0640" class="elsevierStylePara elsevierViewall">Inclusion of patients in clinical trials with novel immunotherapeutic treatments is important to validate their future implementation in clinical practice&#46; BCG toxicity should be adequately prevented&#44; and in case it appears&#44; it should be treated according to the grade and established treatment recommendations&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interests</span><p id="par0645" class="elsevierStylePara elsevierViewall">None of the authors of this article has any conflict of interest with the information reflected in it&#46;</p></span></span>"
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          "titulo" => "Methodology"
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          "titulo" => "Efficacy of BCG"
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              "titulo" => "Strain differences and their impact on clinical outcome"
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              "titulo" => "Efficacy according to treatment duration and dose"
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          "titulo" => "Alternatives to BCG in case of supply shortage"
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              "titulo" => "Intravesical chemotherapy and radical cystectomy"
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              "titulo" => "BCG&#58; strains&#44; prioritization&#44; treatment duration and dose reduction"
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              "titulo" => "Device-assisted intravesical chemotherapy"
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              "titulo" => "Novel therapies for BCG failure"
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          "titulo" => "Updated guidelines for NMIBC treatment with BCG"
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                  "titulo" => "Prostatitis"
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Patients with non-muscle-invasive bladder cancer &#40;NMIBC&#41; in the intermediate and high-risk groups must receive adjuvant treatment with intravesical Bacillus Calmette&#8211;Gu&#233;rin &#40;BCG&#41; following transurethral resection &#40;TUR&#41;&#44; as it reduces the risk of recurrence and presumably the risk of progression as well&#46; Optimization of BCG efficacy is achieved by administering maintenance therapy&#46; However&#44; since many immunological aspects of the mechanism of action of BCG in the bladder remain unknown&#44; the implementation of the optimal dose&#44; number of instillations&#44; strains and adequate maintenance regimen over the last decades has been heterogeneous&#46; Additionally&#44; this has hindered the interpretation of efficacy in terms of oncologic outcomes&#46; This&#44; together with the shortages of BCG in recent years&#44; have forced scientific societies to adapt their clinical practice guidelines and modify their protocols of adjuvant treatment with BCG&#46; This includes changes to strains&#44; doses&#44; and maintenance during this period of time&#46; This consensus document evaluates the current status of adjuvant BCG treatment and the implications of BCG supply availability in the treatment of patients with NMIBC&#46; It also addresses the implementation of novel therapies that will improve cancer prognosis and the quality of life of patients with NMIBC in the future&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los pacientes con TVNMI de los grupos de riesgo intermedio y alto deben ser tratados con BCG intravesical adyuvante despu&#233;s de la resecci&#243;n transuretral &#40;RTU&#41;&#44; ya que dicho tratamiento disminuye el riesgo de recurrencia y probablemente tambi&#233;n el de progresi&#243;n&#46; La optimizaci&#243;n de la eficacia de la BCG se consigue administrando un tratamiento de mantenimiento&#46; Sin embargo&#44; dado que se desconocen muchos detalles inmunol&#243;gicos del mecanismo de acci&#243;n de la BCG en la vejiga&#44; la implementaci&#243;n a lo largo de las &#250;ltimas d&#233;cadas de la dosis &#243;ptima&#44; n&#250;mero de instilaciones&#44; cepas y r&#233;gimen adecuado de mantenimiento&#44; se ha realizado de manera heterog&#233;nea&#44; lo que ha generado dificultades para interpretar los resultados de eficacia oncol&#243;gica&#46; Esto unido con el desabastecimiento de BCG que se ha sufrido en los &#250;ltimos a&#241;os&#44; ha hecho que las diferentes sociedades cient&#237;ficas tengan que adaptar sus gu&#237;as de pr&#225;ctica cl&#237;nica a esta situaci&#243;n&#44; modificando durante este tiempo sus protocolos de tratamiento adyuvante con BCG en relaci&#243;n con cepas&#44; dosis y mantenimiento&#46; En este documento de consenso&#44; se eval&#250;a el estado actual del tratamiento adyuvante con BCG y las implicaciones de la normalizaci&#243;n del suministro de la BCG en el tratamiento oncol&#243;gico de los pacientes con TVNMI as&#237; como la implementaci&#243;n de nuevos tratamientos que en el futuro mejoren el pron&#243;stico oncol&#243;gico y la calidad de vida de los pacientes con TVNMI&#46;</p></span>"
      ]
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "fuente" => "Adapted from Audisio et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of BCG&#46;</p>"
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        "figura" => array:1 [
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of new treatments for BCG failure&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\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" scope="col" style="border-bottom: 2px solid black">Strain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Manufacturer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Connaugh&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">TheraCys&#47;ImmuCyst&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">Sanofi Pasteur &#40;Canada&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TICE&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">OncoTice&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">Organon-Merck&#40;US&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Danish&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">Urovac&#47;BCG-Onco&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">GSBPL &#40;India&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japanese&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">Immunobladder&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">Japan BCG Lab&#46; &#40;Japan&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Russian&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">SII-Onco BCG&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">Serum institute of India&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RIVM&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">BCG-Medac&#47;Vejicur&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">Medac GmbH &#40;Germany&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moreau RJ&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">BCG-Moreau RJ&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">Biofabri &#40;Spain&#41;&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="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main BCG strains for NMIBC&#46;</p>"
        ]
      ]
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        "etiqueta" => "Table 2"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">RFS&#58; Recurrence-free survival&#59; CR&#58; Complete response&#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"><th 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" scope="col" style="border-bottom: 2px solid black">Author&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Follow-up &#40;months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">RFS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">CR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Balar et al&#46; <a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</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">Pembrolizumab &#40;cohort A&#41; KEYNOTE057Pembrolizumab &#40;cohort B&#41; EYNOTE057&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">12<span class="elsevierStyleHsp" style=""></span>m&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">43&#46;5&#37;&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">19&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chamie et al&#46; <a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</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">ALT-803 &#40;cohort A&#44; CIS&#41;ALT-803 &#40;cohort B&#44; papillary&#41;&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">24<span class="elsevierStyleHsp" style=""></span>m&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">48&#37;&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">71&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Boorjian et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</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">Nadofaragene-Firadenovec &#40;cohort A&#44; CIS&#41;Nadofaragene-Firadenovec &#40;cohort B&#44; TaHG or T1&#41;&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">12<span class="elsevierStyleHsp" style=""></span>m&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">43&#46;8&#37;&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">24&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Packiam et al&#46; <a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</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">CG0070&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">6<span class="elsevierStyleHsp" style=""></span>m&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">&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">47 &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Daneshmand et al&#46; <a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</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">TAR- 200&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">&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">&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">76&#46;7 &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Catto et al&#46; <a class="elsevierStyleCrossRef" href="#bib0215"><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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TAR-210 &#40;cohort A&#41;&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">&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">82 &#37;&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">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3683525.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Results obtained with novel treatments for BCG-unresponsive patients&#46;</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0025"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="13" align="left" valign="middle">BCG-Associated Cystitis&#40;25&#37;&#41;</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"><span class="elsevierStyleBold">Grade 1</span>&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"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0005" class="elsevierStylePara elsevierViewall">NSAIDS</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0010" class="elsevierStylePara elsevierViewall">Phenazopyridine &#40;200<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h-15 days&#41;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0015" class="elsevierStylePara elsevierViewall">Propantheline &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;12<span class="elsevierStyleHsp" style=""></span>h-15 days&#41;</p></li></ul>&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">If improvement&#58; continue instillations&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="elsevierStyleBold">Grade 2</span>&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">Worsening &#58;&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"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0020" class="elsevierStylePara elsevierViewall">Postpone instillation until resolution</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Urine culture</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Empiric antibiotic &#40;Fluoroquinolones&#58; Ofloxacin 200<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;</p></li></ul>&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">If symptoms persist with antibiotic treatment&#58;&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"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Positive urine culture&#58; 7-day treatment adjusted to antibiogram</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall">Negative urine culture&#58; Fluoroquinolones&#44; anesthetic solution instillation &#40;1 daily&#47;5 days&#41;</p></li></ul>&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="elsevierStyleBold">Grade<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2</span>&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">If symptoms persist&#58;&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"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">Isoniazid &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and Rifampicin &#40;600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; for 3 months<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>steroids &#40;prednisone 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; tapering schedule&#41;&#46;</p></li></ul>&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">No response&#47;contracted bladder&#58;&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"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Hydrodistension&#44; bladder augmentation Cystectomy&#46;</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="middle"></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">Grade 1&#8722;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"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Postpone instillations until urine is clear&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Urine culture to rule out hemorrhagic cystitis&#46;</p></li></ul>&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">If<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>culture&#58;&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"><ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Targeted antibiotic 3&#8722;5 days prior to instillation&#46;</p></li></ul>&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">If persistent&#44; cystoscopy to rule out tumor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Granulomatous prostatitis</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"><span class="elsevierStyleBold">Grade<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2</span>&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">Rare symptoms&#58; Urine culture&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">&#40;10&#37;&#44; symptomatic prostatitis&#41;</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"><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0070" class="elsevierStylePara elsevierViewall">Fluoroquinolones &#40;Levofloxacin 500&#47;24<span class="elsevierStyleHsp" style=""></span>h&#41;-4 weeks</p></li></ul>&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">If quinolones are not effective&#58;&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"><ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Isoniazid &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and rifampicin &#40;600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; for 3 months&#46;</p></li></ul>&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">Cessation of intravesical therapy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="7" align="left" valign="middle">Epididymo-orchitis&#40;10&#37;&#41;</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"><span class="elsevierStyleBold">Grade<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2</span>&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">Urine culture<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>quinolones&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"><ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Fluoroquinolones &#40;Levofloxacin 500&#47;24<span class="elsevierStyleHsp" style=""></span>h&#41;-4 weeks</p></li></ul>&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">Negative urine culture or no response&#58;&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"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Isoniazid &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; and rifampicin &#40;600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; for 3 months&#44; &#40;prednisone 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; tapering schedule&#41;&#46;</p></li></ul>&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">Cessation of intravesical therapy&#46;&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">Orchidectomy if abscess or no response to treatment&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab3683523.png"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Summary of treatments for local effects&#46;</p>"
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      ]
      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0030"
            "detalle" => "Table "
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        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">General malaise&#44; fever&#40;30&#37;&#41;&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"><span class="elsevierStyleBold">Grade 1</span>Resolves in 48<span class="elsevierStyleHsp" style=""></span>h&#47;Antipyretics&#46;If improvement&#58; Resume instillations&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Persistent fever&#40;20&#37;&#41;</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"><span class="elsevierStyleBold">Grade<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>2</span>Permanent discontinuation of BCG instillations&#46;Close monitoring&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">Urine culture&#44; blood tests&#44; chest x-ray&#44; AS&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">Prompt broad-spectrum antibiotic treatment &#40;fluoroquinolones&#44; isoniazid&#44; rifampicin&#41; until the diagnosis is established&#46;&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">Consultation with an infectious disease specialist&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BCG sepsis1&#47;15&#46;000&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"><span class="elsevierStyleBold">Grade 4</span>Prevention&#58; initiate BCG 2 weeks post-TUR&#40;if no hematuria&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">Cessation of BCG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle"></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">Treatment&#58;&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"><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0090" class="elsevierStylePara elsevierViewall">High-dose quinolones</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Isoniazid&#44; rifampicin&#44; ethambutol 6 months&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Corticosteroids</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Empirical non-specific antibiotic to cover Gram-negative bacteria</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">and&#47;or Enterococcus&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">Management by infectious diseases&#46;</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arthralgias&#47;arthritis0&#46;5&#8722;1&#37;&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">Rare&#47; Autoimmune reaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">Arthralgia&#58; NSAIDs &#40;naproxen 500<span class="elsevierStyleHsp" style=""></span>mg&#47;2 times a day&#44; diclofenac 50<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#44; indomethacin 50<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#41; for symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">Reactive arthritis&#58; NSAIDs &#40;naproxen 500<span class="elsevierStyleHsp" style=""></span>mg&#47;2 times a day&#44; diclofenac 50<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#44; indomethacin 50<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#41; for symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">No response&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">Corticosteroids &#40;prednisone 20<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; tapering schedule&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">High-dose quinolones&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><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">Anti TB&#58; Isoniazid &#40;300<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; y Rifampicin &#40;600<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; 3 months&#46;&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="spar0035" class="elsevierStyleSimplePara elsevierViewall">Summary of treatments for systemic effects&#46;</p>"
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      "titulo" => "References"
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                        0 => array:2 [
                          "etal" => false
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                            1 => "D&#46; Eidinger"
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                    0 => array:2 [
                      "doi" => "10.1016/j.juro.2016.10.101"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "X&#46; Perez-Aizpurua"
                            1 => "J&#46;I&#46; Monzo-Gardiner"
                            2 => "J&#46; Maqueda-Arellano"
                            3 => "E&#46; Buendia-Gonzalez"
                            4 => "L&#46; Cuello-Sanchez"
                            5 => "I&#46;J&#46;J&#46;J&#46; Tufet"
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                    0 => array:2 [
                      "doi" => "10.1016/j.acuroe.2023.01.005"
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                        "tituloSerie" => "Actas Urol Esp &#40;Engl Ed&#41;"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of high-grade non-muscle-invasive Bladder Carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations&#58; results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial &#34;NIMBUS&#34;"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;O&#46; Grimm"
                            1 => "A&#46;G&#46; van der Heijden"
                            2 => "M&#46; Colombel"
                            3 => "T&#46; Muilwijk"
                            4 => "L&#46; Martinez-Pineiro"
                            5 => "M&#46;M&#46; Babjuk"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.eururo.2020.04.066"
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                        "tituloSerie" => "Eur Urol"
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                        "paginaFinal" => "698"
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              "etiqueta" => "7"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recurrence rate and cost consequence of the shortage of bacillus Calmette-Guerin Connaught strain for bladder cancer patients"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Ourfali"
                            1 => "R&#46; Ohannessian"
                            2 => "H&#46; Fassi-Fehri"
                            3 => "A&#46; Pages"
                            4 => "L&#46; Badet"
                            5 => "M&#46; Colombel"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.euf.2019.04.002"
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                        "tituloSerie" => "Eur Urol Focus"
                        "fecha" => "2021"
                        "volumen" => "7"
                        "paginaInicial" => "111"
                        "paginaFinal" => "116"
                        "link" => array:1 [
                          0 => array:2 [
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            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Background and update for S1602 &#34;A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming with Intradermal BCG Before Intravesical Therapy for BCG-naive High-grade Non-muscle-invasive Bladder Cancer&#8221;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "R&#46;S&#46; Svatek"
                            1 => "C&#46; Tangen"
                            2 => "S&#46; Delacroix"
                            3 => "W&#46; Lowrance"
                            4 => "S&#46;P&#46; Lerner"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.euf.2018.08.015"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Urol Focus"
                        "fecha" => "2018"
                        "volumen" => "4"
                        "paginaInicial" => "522"
                        "paginaFinal" => "524"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30197040"
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            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparative effectiveness of intravesical BCG-tice and BCG-Moreau in patients with non-muscle-invasive bladder cancer"
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