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Original article
Optimizing treatment for non muscle-invasive bladder cancer with an app
Optimización del tratamiento del cáncer de vejiga no músculo invasivo mediante una app
P. Beardoa,
Corresponding author
Beardo.pastora@gmail.com

Corresponding author.
, R. Pintob, H. Ayerrab, J. Agüeraa, S. Armijosc, J.L. Álvarez-Ossorioa
a UGC Urología, Hospital Universitario Puerta del Mar, Cádiz, Spain
b Servicio de Urología, Hospital Universitario de Álava, Vitoria-Gasteiz, Spain
c e-processmed, Vitoria-Gasteiz, Spain
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while in the case of NMIBC&#44; it is transurethral resection of the tumor &#40;TURBT&#41; and intravesical adjuvant treatment with bacillus Calmette-Guerin &#40;BCG&#41; immunotherapy or post-TUR chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Five-year survival rate for NMIBC is over 80&#37;&#44; but it is less than 40&#37; in the case of MIBC&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Between 70 to 75&#37; of primary bladder tumors are NMIBC &#40;pTa&#44; T1 and carcinoma in situ &#91;Cis&#93;&#41;&#44; but have high rates of recurrence &#40;73-84&#37;&#41; and progression to MIBC &#40;35-55&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In other words&#44; 75&#37; of patients with invasive bladder cancer have a history of NMIBC&#46; Therefore&#44; adequate management and treatment of NMIBC is a secondary prevention measure which translates into a potential substantial gain in terms of survival and quality of life&#46; The choice of complementary treatment and subsequent follow-up will depend on the patient and&#44; fundamentally&#44; on the risk group for recurrence and progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;6</span></a> The latter is defined by a series of anatomical and clinical variables&#58; sex&#44; gender&#44; tumor stage and grade&#44; number of tumors&#44; primary tumor or recurrence&#44; tumor recurrence rate&#44; tumor size &#40;understood as maximum tumor diameter in cm&#41;&#44; and presence of associated Cis&#46; Considering these variables and based on the analysis of data from several clinical trials&#44; the Bladder EORTC risk tables<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and the CUETO scoring system<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> define risk groups with different probabilities of recurrence and progression at one and five years&#46; Thus&#44; the indication of intravesical adjuvant treatment is variable according to the different anatomical-clinical characteristics&#44; meaning that the choice of treatment is often complex&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> In addition&#44; individual characteristics of each patient &#40;functional status&#44; life expectancy and comorbidity&#41; must be considered&#44; and will ultimately condition the applicability of the recommendations in the NMIBC&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;14</span></a> All the latter translates into high variability in the treatment<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;19</span></a> and follow-up of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;11&#44;20&#44;21</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Applications &#40;apps&#41; developed for smartphones and tablets&#44; aimed at patients and professionals&#44; are being increasingly used in healthcare&#46; The development of this technology is being applied to multiple fields of urology&#58; medical information for patients and professionals&#44; screening&#44; diagnosis&#44; treatment&#44; prognosis&#44; remote patient support and self-care promotion&#46; Among the apps with applicability in the specific field of bladder cancer are Bladder-cancer and Bladder cancer treatment &#40;general information for patients&#41;&#44; Bladder cancer risk assessment tool &#40;assessment of risk factors for screening&#41;&#44; EORTC risk tables &#40;calculation of recurrence risk&#41;&#44; the Blappder calculator &#40;NMIBC treatment recommendation based on the EORTC risk group&#41;&#44; BCG treatment &#40;information and recommendations for patients being treated with BCG&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> However&#44; an app with the main data of the decision tree for NMIBC treatment meeting the requirements of methodological validation has not been developed for the follow-up and treatment of NMIBC&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In this study we present the validation results of an app &#40;APPv&#41; incorporating all the clinicopathological parameters that provide an individualized proposal in line with the clinical practice guidelines &#40;CPG&#41; for treatment and follow-up of patients with NMIBC&#46; The main objective is to evaluate the overall and recurrence-progression rate-adjusted concordance of treatment prescription in NMIBC using the APPv&#44; based on the best available scientific evidence and a urologist&#39;s opinion&#46; The secondary objective is to evaluate overall survival and cancer-specific survival &#40;CSS&#41; in the groups with agreement in the treatment proposal and without agreement&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and Method</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">1<span class="elsevierStyleSup">st</span>&#46; stage&#58; APPv Development</span><p id="par0030" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0035" class="elsevierStylePara elsevierViewall">Review of NMIBC treatment and follow-up protocol based on the MEB in 2018&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0040" class="elsevierStylePara elsevierViewall">Elaboration of the APPv architecture for the automated decision algorithm based on the protocol designed for treatment and follow-up&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0045" class="elsevierStylePara elsevierViewall">Development of the mobile application&#46;</p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">The following output variables related to the following concepts are generated through a series of input variables&#44; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Risk group for predicting recurrence and progression and the risk of both at 1 and 5 years&#44; based on the EORTC risk tables<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and the CUETO scoring system<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> &#40;for patients with prior BCG treatment&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Treatment of choice &#40;primary endpoint&#41;&#58; the program generates the variable corresponding to the most appropriate treatment in each case&#44; in addition to alternative treatment options&#44; if any&#44; in order of preference&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">Follow-up&#58; the program provides each patient with a personalized follow-up schedule&#44; including the number of annual cystoscopies&#44; cytologies&#44; CT scans and biopsies&#44; their frequency&#44; and the duration of follow-up&#46;</p></li></ul></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleHsp" style=""></span>4&#46; Testing and improvement stage</p><p id="par0075" class="elsevierStylePara elsevierViewall">The computer application was tested by means of practical assumptions with each possible combination of input variables&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">2<span class="elsevierStyleSup">nd</span>&#46; stage&#58; APPv validation</span><p id="par0080" class="elsevierStylePara elsevierViewall">Target population</p><p id="par0085" class="elsevierStylePara elsevierViewall">Prospective double-blind&#44; paired-sample&#44; observational concordance study of 100 patients with initial or successive histological diagnosis of non-muscle invasive bladder urothelial cancer treated by transurethral resection &#40;TUR&#41; from January through October 2019&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Inclusion criteria</span><p id="par0090" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patients aged 18 years or older&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0100" class="elsevierStylePara elsevierViewall">De novo or successive histological diagnosis of NMIBC &#40;pTa&#44; pT1 or Cis&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">ECOG 0-2&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">Patients who have given written consent to participate in the study&#46;</p></li></ul></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Exclusion criteria</span><p id="par0115" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">-</span><p id="par0120" class="elsevierStylePara elsevierViewall">History of MIBC&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">-</span><p id="par0125" class="elsevierStylePara elsevierViewall">Non-urothelial bladder carcinoma or mixed histologies&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0130" class="elsevierStylePara elsevierViewall">Absence of muscular layer in the histological specimen of TUR or re-TUR&#44; hindering the correct staging of the tumor&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0135" class="elsevierStylePara elsevierViewall">Treatment with radiotherapy&#44; intravenous chemotherapy or immunosuppressants during study period&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0140" class="elsevierStylePara elsevierViewall">Untreated urinary tract infection&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall">Severe systemic infection&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall">Other neoplasms during the 5 years prior study inclusion &#40;except basal cell carcinoma&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0155" class="elsevierStylePara elsevierViewall">Pregnancy&#46;</p></li></ul></p></span></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Method</span><p id="par0160" class="elsevierStylePara elsevierViewall">APPv simulation&#58; complementary treatment proposal according to the APPv under study&#44; plus additional information regarding the proposed follow-up and the risk group for recurrence and progression according to the EORTC risk tables or the CUETO scoring system&#44; if the patient has received previous treatment with BCG &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">In-person prescription visit&#58; postoperative visit with prescription of complementary treatment&#44; if necessary&#44; by the urologist &#40;2 urologists specialized in bladder cancer&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Treatment proposals and follow-up by APPv and urologist are carried out by different professionals &#40;double-blind&#41;&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Analysis</span><p id="par0175" class="elsevierStylePara elsevierViewall">The primary dependent variable is overall and recurrence-progression rate adjusted concordance &#40;yes&#47;no&#41; between the treatment prescribed by the application &#40;including the standard option and the alternative treatment&#41; and the treatment prescribed by the urologist regarding re-TUR and complementary treatment&#46; As secondary variables&#44; overall survival&#44; and CSS in both groups &#40;with and without agreement between the treatments proposed by the APPv and the urologist&#41; are analyzed&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">All statistical analysis will be performed with the SPSS 21&#46;0 statistical package &#40;SPSS Inc&#46; Headquarters&#44; Chicago&#44; Illinois&#44; USA&#41;&#46; All tests will be calculated at a&#8239;&#61;&#8239;0&#46;05 significance level and confidence intervals will be calculated at the 1-to&#8239;&#61;&#8239;0&#46;95 confidence level&#46; The concordance index &#40;kappa index&#41; is estimated for the assessment of the primary endpoint &#40;the study hypothesis is accepted if c-index &#8805; 0&#46;7&#41;&#46; The risk of recurrence&#44; tumor progression&#44; overall survival&#44; and CSS in the urologist-APPv treatment agreement group and in the disagreement group is assessed by log-rank test&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">This study has the approval of the Ethics Committee of the Basque Country &#40;internal code PS2018004&#41; dated April 12&#44; 2018&#46; All patients included in the study have provided written consent&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">This project has been partly funded by the Department of Health of the Basque Country &#40;File No&#46; 2017111087&#44; BOPV n&#46; 133&#44; dated July 13&#44; 2017&#41;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0195" class="elsevierStylePara elsevierViewall">Overall and subgroup clinicopathological characteristics &#40;urologist-APPv treatment agreement and disagreement&#41; are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Primary endpoint</span><p id="par0200" class="elsevierStylePara elsevierViewall">Adjuvant intravesical therapy prescribed by the urologist coincides with the treatment proposed by APPv in 64&#37; of cases &#40;kappa index 0&#46;55&#59; p&#8239;&#60;&#8239;0&#46;0001&#41;&#46; When the treatment proposed by APPv is taken as reference&#44; 31&#37; of patients are being undertreated and 5&#37; are being overtreated &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Based on risk groups&#44; treatment coincides for low risk in 77&#37; &#40;kappa 0&#46;55&#59; p&#8239;&#61;&#8239;0&#46;002&#41;&#44; in 63&#37; &#40;kappa 0&#46;52&#59; p&#8239;&#60;&#8239;0&#46;0001&#41; for intermediate risk&#44; in 17&#37; &#40;kappa 0&#46;143&#59; p&#8239;&#61;&#8239;0&#46;014&#41; for high risk and in 66&#37; &#40;kappa 0&#46;71&#59; p&#8239;&#61;&#8239;0&#46;01&#41; for very high risk&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0205" class="elsevierStylePara elsevierViewall">Twenty-five percent of patients present recurrence during follow-up &#40;52&#37; pTa&#59; 20&#37; pT1&#59; 16&#37; pT2&#59; 12&#37; Cis&#44; 64&#37; high-grade and 36&#37; low-grade&#41;&#46; Based on APPv-urologist agreement and disagreement on treatment&#44; recurrence by risk group is 0&#37; vs&#46; 3&#46;8&#37; &#40;p&#8239;&#61;&#8239;0&#46;23&#41; in low risk&#44; 14&#46;6&#37; vs&#46; 50&#37; &#40;p&#8239;&#61;&#8239;0&#46;002&#41; for intermediate risk&#44; 0&#37; vs&#46; 80&#37; &#40;p&#8239;&#61;&#8239;0&#46;02&#41; for high risk and 0&#37; vs&#46; 50&#37; &#40;p&#8239;&#61;&#8239;0&#46;51&#41; for very high risk&#46; When adjusting the agreement analysis for urologist-APPv treatment&#44; the kappa index is 0&#46;7 &#40;p&#8239;&#60;&#8239;0&#46;0001&#41; for patients without recurrence&#46; Of the patients receiving adjuvant intravesical therapy in agreement with the recommendation of APPv&#44; 89&#46;1&#37; remain free of recurrence&#44; vs&#46; 61&#46;1&#37; in those without agreement &#40;p&#8239;&#61;&#8239;0&#46;0004&#41;&#44; with a RR 0&#46;46 &#40;95&#37; CI&#58; 0&#46;25-0&#46;86&#41; vs&#46; RR 2&#46;4 &#40;95&#37; CI&#58; 1&#46;5-3&#46;8&#59; p&#8239;&#61;&#8239;0&#46;001&#41;&#46; In the agreement group&#44; 100&#37; of patients were free of progression vs&#46; 88&#46;9&#37; in the disagreement group &#40;p&#8239;&#61;&#8239;0&#46;004&#41;&#44; with RR 1 vs&#46; RR 1&#46;125 &#40;95&#37; CI&#58; 1-1&#46;26&#59; p&#8239;&#61;&#8239;0&#46;004&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0210" class="elsevierStylePara elsevierViewall">APPv recommends completing local treatment with re-TUR in 46&#37; of patients&#44; while the urologist recommends this management in 20&#37; &#40;kappa 0&#46;41&#59; p&#8239;&#60;&#8239;0&#46;0001&#41;&#46; When the APPv recommended re-TUR and this was not performed&#44; 40&#37; of patients relapsed&#44; compared to 18&#46;7&#37; of recurrences in the group who underwent re-TUR &#40;p&#8239;&#61;&#8239;0&#46;031&#41;&#44; with a RR 0&#46;34 &#40;95&#37; CI&#58; 02&#46;-0&#46;91&#41; vs&#46; RR 1&#46;4 &#40;95&#37; CI&#58; 0&#46;97-1&#46;9&#59; p&#8239;&#61;&#8239;0&#46;058&#41;&#46; When applying both criteria at the same time&#44; adjuvant treatment and re-TUR prescribed by urologist and proposed by APPv&#44; 92&#37; of patients remain free of recurrence in the agreement group vs&#46; 66&#37; in the disagreement group &#40;p&#8239;&#61;&#8239;0&#46;001&#41; with a RR 0&#46;23 &#40;95&#37; CI&#58; 0&#46;08-0&#46;65&#41; vs&#46; RR 1&#46;4 &#40;95&#37; CI&#58; 1&#46;12-1&#46;73&#59; p&#8239;&#61;&#8239;0&#46;001&#41;&#46; In this case&#44; the progression-free percentage in the agreement group is 100&#37; and 92&#37; in the disagreement group &#40;p&#8239;&#61;&#8239;0&#46;004&#41;&#44; with RR 1 vs&#46; RR 1&#46;09 &#40;95&#37; CI&#58; 1-1&#46;18&#59; p&#8239;&#61;&#8239;0&#46;017&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Secondary endpoints</span><p id="par0215" class="elsevierStylePara elsevierViewall">Overall survival and CSS based on the treatment received in agreement and disagreement with the APPv prescription is 96&#46;9&#37; vs&#46; 88&#46;9&#37; &#40;p&#8239;&#61;&#8239;0&#46;153&#41; and 100&#37; vs&#46; 91&#46;4&#37; &#40;p&#8239;&#61;&#8239;0&#46;028&#41;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0220" class="elsevierStylePara elsevierViewall">Fifty-two percent of patients complete the prescribed adjuvant intravesical therapy&#44; 57&#37; in the agreement group and 39&#37; in the disagreement group &#40;p&#8239;&#61;&#8239;0&#46;273&#41;&#46; Treatment discontinuation causes are recurrence &#40;14&#37;&#41;&#44; adverse events &#40;10&#46;2&#37;&#41;&#44; drug delivery problems &#40;7&#46;2&#37;&#41;&#44; comorbidity &#40;7&#46;2&#37;&#41;&#44; medical judgement &#40;7&#46;2&#37;&#41; and patient refusal &#40;3&#37;&#41;&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0225" class="elsevierStylePara elsevierViewall">There is a high percentage of discordance between the proposal made by APPv based on clinical practice guidelines and the urologist&#8217;s prescription &#40;36&#37;&#41;&#46; This differences in NMIBC treatment are similar to those documented in previous studies&#44; which report between 47&#37; and 64&#37; prescription of the appropriate treatment&#46; This heterogeneity has been explained by the fact that the decisions of the urologist are affected by subjective data based on personal experience&#44; in addition to the clinical practice guidelines only&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Low adherence to the recommendations of these guidelines translates into 15-20&#37; of patients not receiving any adjuvant intravesical therapy after TUR&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> These patients are distributed by risk group as 6-62&#37;&#44; 2-33&#37; and 1-35&#37; of patients with low&#44; intermediate&#44; and high or very high risk&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> In addition to those patients who do receive adjuvant intravesical therapy&#44; up to 53&#37; do not receive adjuvant therapy according to clinical practice guideline recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Specifically&#44; 35-50&#37; of patients with high or very high risk NMIBC are prescribed post-TUR intravesical treatment with BCG for less than one year or in a different treatment schedule from the one recommended&#46; On the other hand&#44; 65&#37; of treatment interruptions are not related to adverse events of BCG&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">In our study&#44; the greatest differences between the recommendations of APPv &#40;based on clinical practice guidelines&#41; and the urologist&#39;s proposal are found within the high-risk group &#40;83&#37; of patients without adequate treatment in our study&#41; and in the performance or not of re-TUR &#40;26&#37; of patients in our study who are eligible for re-TUR and who do not receive this treatment&#41;&#46; As for undertreatment of high-risk NMIBC&#44; it is likely to indicate low adherence to 3-year BCG treatment regimens&#44;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;17</span></a> despite superiority in terms of recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> Undertreatment takes place especially in older patients &#40;&#8805;70 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> However&#44; this does not happen with APPv&#44; since in its decision algorithm&#44; it applies the geriatric assessment scale following current recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Regarding the underuse of re-TUR&#44; these data are in line with what has been previously documented&#44; since 20-45&#37; of patients with high-grade tumors do not undergo re-TUR&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">According to our results&#44; non-compliance with recommendations in the treatment of NMIBC &#40;group without agreement with APPv&#41; translates into higher recurrence and progression rates and worse CSS&#46; This has not been evaluated in studies of adherence to guidelines&#44; since they are mostly based on routine clinical practice surveys&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">At present&#44; we cannot compare the results proposed by APPv&#44; since there are no other applications with these characteristics<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> available and developed according to a validated scientific methodology&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a> Therefore&#44; further multicenter validation studies with APPv are required&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The main limitations of this study are that it is single-center and the potential existence of information bias in the subjective nature of tumor size measurement&#46; Although the observers are trained&#44; the latter can lead to a risk group classification bias&#44; probably not differential between groups&#46; On the other hand&#44; the mean follow-up of less than 5 years may limit the occurrence of events &#40;recurrence and progression&#41; in both groups&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusion</span><p id="par0250" class="elsevierStylePara elsevierViewall">This work shows how an app developed according to scientific methodology could contribute to improving adherence to the recommendations of clinical practice guidelines and&#44; therefore&#44; the health outcomes of patients with NMIBC by decreasing the rate of recurrence and progression and increasing CSS&#46; Even so&#44; further studies are needed to confirm the validity of this APPv&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Funding</span><p id="par0255" class="elsevierStylePara elsevierViewall">This project has been funded by the <span class="elsevierStyleGrantSponsor" id="gs0005">Department of Health of the Basque Government</span> &#40;file number <span class="elsevierStyleGrantNumber" refid="gs0005">2017111003</span>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflicts of interest</span><p id="par0260" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Material and Method"
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              "titulo" => "1&#46; stage&#58; APPv Development"
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              "titulo" => "2&#46; stage&#58; APPv validation"
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          "titulo" => "References"
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    "fechaRecibido" => "2021-09-28"
    "fechaAceptado" => "2021-12-11"
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        0 => array:4 [
          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Non-muscle-invasive bladder cancer"
            1 => "Apps medica"
            2 => "reTUR"
            3 => "Intravesical BCG"
            4 => "Adherence to clinical guideline"
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            0 => "C&#225;ncer de vejiga no m&#250;sculo-invasivo"
            1 => "Apps m&#233;dicas"
            2 => "Re-RTU"
            3 => "BCG intravesical"
            4 => "Adherencia a las recomendaciones de las gu&#237;as cl&#237;nicas"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">To evaluate overall and recurrence-progression rate-adjusted concordance of treatment prescription in non-muscle-invasive bladder cancer &#40;NMIBC&#41; of an app based on the best available scientific evidence and the urologist&#39;s opinion&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Development of an app &#40;APPv&#41; specifically designed for the treatment and follow-up of NMIBC and validation of the proposed APPv treatment endpoint by means of a prospective double-blind observational concordance study of related samples in 100 patients with initial or successive histological diagnosis of NMIBC&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The treatment prescribed by the urologist agrees with that proposed by the APPv in 64&#37; of cases &#40;kappa index 0&#46;55&#44; <span class="elsevierStyleItalic">P</span> &#60; 0&#46;0001&#41;&#46; Regarding low risk&#44; the agreement is 77&#37; &#40;kappa 0&#46;55&#44; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;002&#41;&#44; 63&#37; &#40;kappa 0&#46;52&#44; <span class="elsevierStyleItalic">P</span> &#60; 0&#46;0001&#41; for intermediate risk&#44; 17&#37; &#40;kappa 0&#46;143&#44; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;014&#41; in high risk and 66&#37; &#40;kappa 0&#46;71&#44; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;01&#41; for very high risk&#46; Of patients receiving adjuvant intravesical treatment according to APPv&#44; 89&#46;1&#37; remain free of recurrence vs&#46; 61&#46;1&#37; of those with disagreement &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;0004&#41;&#44; with a RR 0&#46;46 &#40;95&#37;CI&#58; 0&#46;25-0&#46;86&#41; vs&#46; RR 2&#46;4 &#40;95&#37;CI&#58; 1&#46;5-3&#46;8&#44; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;001&#41;&#46; In the APPv-urologist agreement group&#44; 100&#37; of patients are free of progression and 88&#46;9&#37; in the disagreement group &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;004&#41; with a RR 1 vs&#46; RR 1&#46;125 &#40;95&#37;CI&#58; 1-1&#46;26&#44; <span class="elsevierStyleItalic">P</span> &#61; 0&#46;004&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">APPv can improve adherence to treatment recommendations according to clinical practice guidelines and health outcomes at NMIBC&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Evaluar la concordancia global y ajustada por tasa de recidiva-progresi&#243;n de la prescripci&#243;n del tratamiento en el c&#225;ncer de vejiga no m&#250;sculo-invasivo &#40;NMIBC&#41; de una app basada en la mejor evidencia cient&#237;fica disponible y la opini&#243;n del ur&#243;logo&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Desarrollo de una app espec&#237;fica para el tratamiento y seguimiento del NMIBC &#40;APPv&#41; y validaci&#243;n de la variable de salida propuesta de tratamiento mediante un estudio de concordancia observacional prospectivo de muestras relacionadas a doble ciego en 100 pacientes con primer o sucesivo diagn&#243;stico histol&#243;gico de NMIBC&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">El tratamiento prescrito por el ur&#243;logo coincide con el propuesto por la APPv en el 64&#37; de los casos &#40;&#237;ndice kappa 0&#44;55&#59; <span class="elsevierStyleItalic">p</span> &#60; 0&#44;0001&#41;&#46; La coincidencia para el bajo riesgo es del 77&#37; &#40;kappa 0&#44;55&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#44;002&#41;&#44; 63&#37; &#40;kappa 0&#44;52&#59; <span class="elsevierStyleItalic">p</span> &#60; 0&#44;0001&#41; para el riesgo intermedio&#44; 17&#37; &#40;kappa 0&#44;143&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#44;014&#41; en alto riesgo y 66&#37; &#40;kappa 0&#44;71&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#44;01&#41; para muy alto riesgo&#46; El 89&#44;1&#37; de los pacientes que reciben el tratamiento complementario intravesical acorde con la APPv contin&#250;an libres de recidiva&#44; frente al 61&#44;1&#37; en que no hay acuerdo &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#44;0004&#41;&#44; con un RR de 0&#44;46 &#40;IC 95&#37;&#58; 0&#44;25-0&#44;86&#41; vs&#46; RR de 2&#44;4 &#40;IC 95&#37;&#58; 1&#44;5-3&#44;8&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#44;001&#41;&#46; El 100&#37; de los pacientes est&#225;n libres de progresi&#243;n en el grupo de acuerdo y el 88&#44;9&#37; en el grupo sin acuerdo &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#44;004&#41; con un RR de 1 vs&#46; RR de 1&#44;125 &#40;IC 95&#37;&#58; 1-1&#44;26&#59; <span class="elsevierStyleItalic">p</span> &#61; 0&#44;004&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">La APPv puede mejorar la adherencia a las recomendaciones de tratamiento seg&#250;n las gu&#237;as de pr&#225;ctica cl&#237;nica y los resultados en salud en el NMIBC&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Beardo P&#44; Pinto R&#44; Ayerra H&#44; Ag&#252;era J&#44; Armijos S&#44; &#193;lvarez-Ossorio JL&#46; Optimizaci&#243;n del tratamiento del c&#225;ncer de vejiga no m&#250;sculo invasivo mediante una app&#46; Actas Urol Esp&#46; 2022&#59;46&#58;230&#8211;237&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Input and output variables for the development of the APPv architecture in NMIBC&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Survival curves and univariate analysis &#40;log rank test&#41; of cancer-specific survival &#40;A&#41; and overall survival &#40;B&#41; in the urologist-APPv agreement and urologist-APPv disagreement groups&#46;</p>"
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                  \t\t\t\t">17&#44;8 &#40;1-34&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Very high&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinicopathological characteristics in both treatment groups &#40;urologist-APPv agreement group&#44; urologist-APPv disagreement group&#41; and in the overall series&#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">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="7" align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment proposed by APPv</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Urologist treatment&nbsp;\t\t\t\t\t\t\n
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                  \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">None&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">Passive CT&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">CT hyperthermia&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">BCG 1 year&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">BCG 3 years&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">Cystectomy&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">Total&nbsp;\t\t\t\t\t\t\n
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                  \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">None&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
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                  \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">11&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">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&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">Passive CT&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">0&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">23</span>&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">0&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">0&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">0&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">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&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">CT hyperthermia&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">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\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">4</span>&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">0&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">0&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">0&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&nbsp;\t\t\t\t\t\t\n
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                  \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 1 year&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">0&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">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">13</span>&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">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&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 3 years&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">0&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">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&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">0&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">11</span>&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">0&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&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">Cystectomy&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">0&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">0&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">0&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">0&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">0&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
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                  \t\t\t\t"><span class="elsevierStyleBold">1</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&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">Total&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
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                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">38&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">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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