BCG shortage for intravesical instillation is associated with early tumoral recurrence in patients with high-risk non-muscle invasive bladder tumours.

INTRODUCTION: During 2019 there was a worldwide shortage of BCG strains for intravesical instillation, limiting the availability of full dose schemes for maintenance courses. The main objective was to analyze the impact on tumoral relapse secondary to BCG shortage in our center. Secondary outcomes included recurrence and progression-free survival rates and tumoral relapse specific characteristics. METHODS: Retrospective cohort study including 158 subjects (64 treated during 2019 and 94 during 2017) with high-risk non-muscle invasive bladder cancer and treated with a combination of Transurethral bladder resection (TURB) followed by adjuvant intravesical instillation with BCG in a tertiary hospital in Spain. Basal characteristics of both groups were analyzed. Times to event of interest (relapse; including recurrence and/or progression) were estimated with Kaplan-Meier survival analysis. Disease-free survival rates were analyzed using a multivariable Cox regression model of proportional hazards. RESULTS: Median follow-up in the 2019 sample was 24 months and 50 months in the 2017 group with a median number of instillations of 8 and 12 respectively. Median time to relapse of 285 days (145-448) during 2019 and 382 days (215-567) in 2017 were observed (logRank p = 0.025). Further multivariable analysis revealed a proportional hazard ratio (HR) for disease-free survival rate of 1.87 (95% CI: 1.04-3.37 p = 0.036). No statistically significant differences in tumoral relapse characteristics were observed. CONCLUSION: BCG shortage and subsequent reduced-dose schemes used for intravesical instillation due to limited availability, increase early tumoral relapse rates. These findings are consistent with available evidence, showing the need for full-dose BCG courses.

Effect of Re-TUR time on recurrence and progression in high-risk non-muscle-invasive bladder cancer.

OBJECTIVE: We aimed to investigate the significance of time to re-staging transurethral resection (re-TUR) on recurrence and progression rates in patients with high-risk non-muscle-invasive bladder cancer as a prospective randomized study. METHODS: The patients were randomly separated into three groups according to Re-TUR timing. In Groups 1, 2, and 3, the time interval between initial and re-TUR was 14-28 days, 29-42 days, and 43-56 days, respectively. Cox regression analysis was used to assess the effect of time from initial TUR to re-TUR on oncological outcomes. RESULTS: Twenty patients in Group 1 (14-28 days), 22 patients in Group 2 (29-42 days), and 29 patients in Group 3 (43-56 days) completed the study. Kaplan-Meier plots showed no differences in recurrence-free survival (RFS) and progression-free survival (PFS) rates between the three groups. Cox regression analysis demonstrated that only tumor number was found to be a prognostic factor on RFS rates. CONCLUSION: Our prospective study demonstrated that time laps from initial TUR to re-TUR did not significantly affect on RFS and PFS rates.

OBJETIVO: Nuestro objetivo fue investigar la importancia del tiempo para volver a estadificar la resección transuretral (re-RTU) en las tasas de recurrencia y progresión en pacientes con cáncer de vejiga no músculo invasivo de alto riesgo como un estudio prospectivo aleatorizado. MÉTODO: Los pacientes se separaron aleatoriamente en 3 grupos de acuerdo con el tiempo de Re-TUR. En el grupo 1, 2 y 3, el intervalo de tiempo entre la RTU inicial y la nueva fue de 14 a 28 días, 29 a 42 días y 43 a 56 días, respectivamente. Cox para evaluar el efecto del tiempo desde la RTU inicial hasta la nueva RTU sobre los resultados oncológicos. RESULTADOS: Veinte pacientes del grupo 1, 22 pacientes del grupo 2, 29 pacientes del grupo 3 completaron el estudio. Los gráficos de Kaplan-Meier no mostraron diferencias en las tasas de SLR y SLP entre los tres grupos. El análisis de regresión de Cox demostró que solo se encontró que el número de tumores era un factor pronóstico en las tasas de RFS. CONCLUSIÓN: Nuestro estudio prospectivo demostró que los lapsos de tiempo desde la RTU inicial hasta la nueva RTU no afectaron significativamente las tasas de SLR y SLP.

Optimizing treatment for non muscle-invasive bladder cancer with an app.

OBJECTIVES: To evaluate overall and recurrence-progression rate-adjusted concordance of treatment prescription in non-muscle-invasive bladder cancer (NMIBC) of an app based on the best available scientific evidence and the urologist's opinion. METHODS: Development of an app (APPv) 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. RESULTS: The treatment prescribed by the urologist agrees with that proposed by the APPv in 64% of cases (kappa index 0.55, P < 0.0001). Regarding low risk, the agreement is 77% (kappa 0.55, P = 0.002), 63% (kappa 0.52, P < 0.0001) for intermediate risk, 17% (kappa 0.143, P = 0.014) in high risk and 66% (kappa 0.71, P = 0.01) for very high risk. Of patients receiving adjuvant intravesical treatment according to APPv, 89.1% remain free of recurrence vs. 61.1% of those with disagreement (P = 0.0004), with a RR 0.46 (95%CI: 0.25-0.86) vs. RR 2.4 (95%CI: 1.5-3.8, P = 0.001). In the APPv-urologist agreement group, 100% of patients are free of progression and 88.9% in the disagreement group (P = 0.004) with a RR 1 vs. RR 1.125 (95%CI: 1-1.26, P = 0.004). CONCLUSIONS: APPv can improve adherence to treatment recommendations according to clinical practice guidelines and health outcomes at NMIBC.

Current treatments for BCG failure in non-muscle invasive bladder cancer (NMIBC). / Tratamientos actuales tras fracaso a BCG en cáncer de vejiga no músculo-invasivo.

The treatment of choice for high-risk non-muscle invasive bladder cancer (NMIBC) is bacillus Calmette-Guérin (BCG). However, when this fails, the indicated treatment is radical cystectomy. In recent years, trials are being developed with various drugs to avoid this surgery in patients with BCG failure. The aim of this article is to update the treatments under study for bladder preservation in this patient population. Non-systematic review, searching PubMed with the terms "Bladder cancer", "Non-muscle invasive bladder cancer", "NMIBC", "BCG", "BCG-refractory", "Mitomycin C", "MMC", "Hyperthermia", "Electromotive Drug Administration", "EMDA". We used the search engines clinicaltrials.gov and clinicaltrialsregister.eu to find clinical trials. The only intravesical drug approved by the Food and Drug Administration (FDA) for carcinoma in situ (CIS) after failure to BCG is Valrubicin. Recently, the FDA has approved intravenous Pembrolizumab, following the publication of preliminary data from the KEYNOTE-057 study. Atezolizumab has demonstrated similar preliminary efficacy results. Only microwave-induced chemohyperthermia and EMDA-MMC (Electromotive Drug Administration) are recognized as alternatives in European guidelines. Other options under investigation are taxanes and gemcitabine, alone or in combination, recombinant viruses and device-assisted intravesical chemohyperthermia. The results of new drugs are promising, with a large number of trials underway. Knowing the mechanisms of resistance to BCG is essential to explore new therapeutic options.

Risk factors for residual disease at re-TUR in a large cohort of T1G3 patients.

INTRODUCTION AND OBJECTIVES: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis in order to adequately stage the patient. It is well known that the presence of detrusor muscle in the specimen is a prerequisite to minimize the risk of under staging. Persistent disease after resection of bladder tumors is not uncommon and is the reason why the European Guidelines recommended a re-TUR for all T1 tumors. It was recently published that when there is muscle in the specimen, re-TUR does not influence progression or cancer specific survival. We present here the patient and tumor factors that may influence the presence of residual disease at re-TUR. MATERIAL AND METHODS: In our retrospective cohort of 2451 primary T1G3 patients initially treated with BCG, pathology results for 934 patients (38.1%) who underwent re-TUR are available. 74% had multifocal tumors, 20% of tumors were more than 3 cm in diameter and 26% had concomitant CIS. In this subgroup of patients who underwent re-TUR, there was no residual disease in 267 patients (29%) and residual disease in 667 patients (71%): Ta in 378 (40%) and T1 in 289 (31%) patients. Age, gender, tumor status (primary/recurrent), previous intravesical therapy, tumor size, tumor multi-focality, presence of concomitant CIS, and muscle in the specimen were analyzed in order to evaluate risk factors of residual disease at re-TUR, both in univariate analyses and multivariate logistic regressions. RESULTS: The following were not risk factors for residual disease: age, gender, tumor status and previous intravesical chemotherapy. The following were univariate risk factors for presence of residual disease: no muscle in TUR, multiple tumors, tumors > 3 cm, and presence of concomitant CIS. Due to the correlation between tumor multi-focality and tumor size, the multivariate model retained either the number of tumors or the tumor diameter (but not both), p < 0.001. The presence of muscle in the specimen was no longer significant, while the presence of CIS only remained significant in the model with tumor size, p < 0.001. CONCLUSIONS: The most significant factors for a higher risk of residual disease at re-TUR in T1G3 patients are multifocal tumors and tumors more than 3 cm. Patients with concomitant CIS and those without muscle in the specimen also have a higher risk of residual disease.

History of urological malignancies before kidney transplantation, oncological outcome on the long term. / Antecedentes de neoplasias urológicas previos al trasplante renal. Resultados oncológicos a largo plazo.

INTRODUCTION: We aimed to report the oncological outcomes of ESRD patients with histories of urological malignancies who were subsequently submitted to kidney transplantation (KT). MATERIAL AND METHOD: Retrospective study lead in the Puigvert Foundation (Barcelona) registry of 1,200 KT performed from 1988 to 2018. Eighty-five urological malignancies that were treated before KT in 81 patients were identified: 15 (18%) prostate cancers, 49 (58%) RCC, 19 (22%) urothelial carcinomas and 2 (2%) testicular cancers. Baseline characteristics, cancer staging, treatment and follow-up were registered as well as the chronology of the start of dialysis, inscription on the waiting list and kidney transplantation. Endpoints included were cancer recurrence, metastatic progression, cancer-specific death and overall survival. RESULTS: In a median follow-up of 13.1 years (2.2-32), 16/85 (19%) cancer recurrences were reported, with 3 (4%) who progressed to metastasis and died of cancer. Median overall survival after cancer treatment was 25.3 years and cancer-specific survival was 95% at 25 years. Median time from cancer treatment to kidney transplantation was 4.8 years: 3.7 years in prostate cancer, 3.9 years in RCC and 8.8 years in bladder cancer. The median time from start of dialysis to kidney transplantation was 1.8 years in patients with histories of urological malignancy versus 0.5 year in the total cohort of 1,200 renal transplanted over the same period. CONCLUSIONS: Well-selected patients with histories of urological malignancies greatly benefit from kidney transplantation with infrequent and late cancer recurrence. Waiting time could be optimized in low-risk prostate cancer and RCC, but more robust data are needed.

History of urological malignancies before kidney transplantation, oncological outcome on the long term.

INTRODUCTION: We aimed to report the oncological outcomes of ESRD patients with histories of urological malignancies who were subsequently submitted to kidney transplantation (KT). MATERIAL AND METHOD: Retrospective study lead in the Puigvert Foundation (Barcelona) registry of 1,200 KT performed from 1988 to 2018. Eighty-five urological malignancies that were treated before KT in 81 patients were identified: 15 (18%) prostate cancers, 49 (58%) RCC, 19 (22%) urothelial carcinomas and 2 (2%) testicular cancers. Baseline characteristics, cancer staging, treatment and follow-up were registered as well as the chronology of the start of dialysis, inscription on the waiting list and kidney transplantation. Endpoints included were cancer recurrence, metastatic progression, cancer-specific death and overall survival. RESULTS: In a median follow-up of 13.1 years (2.2-32), 16/85 (19%) cancer recurrences were reported, with 3 (4%) who progressed to metastasis and died of cancer. Median overall survival after cancer treatment was 25.3 years and cancer-specific survival was 95% at 25 years. Median time from cancer treatment to kidney transplantation was 4.8 years: 3.7 years in prostate cancer, 3.9 years in RCC and 8.8 years in bladder cancer. The median time from start of dialysis to kidney transplantation was 1.8 years in patients with histories of urological malignancy versus 0.5 year in the total cohort of 1,200 renal transplanted over the same period. CONCLUSIONS: Well-selected patients with histories of urological malignancies greatly benefit from kidney transplantation with infrequent and late cancer recurrence. Waiting time could be optimized in low-risk prostate cancer and RCC, but more robust data are needed.

New immunotherapies for high-risk non-muscle invasive bladder cancer: Current state and future perspectives. / Nuevas inmunoterapias en el cáncer de vejiga no músculo-invasivo de alto riesgo: estado actual y perspectivas de futuro.

BACKGROUND: The standard treatment for high-risk non-muscle invasive bladder tumors (NMIBT) is transurethral resection of the bladder and BCG instillations. However, responses are limited, and new therapeutic alternatives for these patients are required. The results of checkpoint inhibitors in advanced tumors have led to interest in the use of these molecules in NMIBT. METHODS: We conducted a search on PubMed using the terms «bladder cancer¼ and «check point inhibitors¼. We have used the search engines clinicaltrials.gov and clinicaltrialsregister.eu for the search of clinical trials. RESULTS: There are currently 5 trials in progress on BCG untreated patients. There are no results available. As for BCG non-responders, there are 15 ongoing trials, two of them with preliminary results: Keynote 057, with promising results with pembrolizumab, which has led the FDA to approve its use in January 2020, and SWOG S1605, which has shown similar results with atezolizumab. Other trials are using intravesical administration of these drugs, which is an attractive option if it is effective for cancer control. CONCLUSIONS: Checkpoint inhibitors offer a new possibility for patients who do not respond to BCG. These will probably be used in the future for previously BCG untreated patients. Preliminary data from clinical trials show promising results. A good understanding of these molecules by urologists and the creation of multidisciplinary teams are crucial in order to offer the best therapeutic alternatives to these patients.

New immunotherapy treatments in non-muscle invasive bladder cancer.

Non-muscle invasive bladder cancer (NMIBC) is a highly heterogeneous disease that hides classes of patients who behave significantly differently under a favorable overall prognosis facade. Individual risk stratification and good decision making improve the patient outcomes. To date, radical cystectomy remains the treatment of choice in particularly aggressive subsets of disease, also due to the lack of proven alternative bladder-sparing strategies.Cancer immunotherapy, by inhibiting the PD-1/PD-L1axis, has shown durable efficacy in the treatment of advanced and metastatic unresectable urothelial carcinoma, and is studied with great interest in early disease settings. The updated data of the KEYNOTE-057 study have recently promoted the United States (US) Food and Drug Administration (FDA) approval of pembrolizumabin patients with CIS-containing BCG-unresponsive NMIBC. This significant step forward paves the way to a new window of therapeutic opportunities, while underlining new needs and questions to be addressed.

El cáncer de vejiga no músculo-invasivoes una enfermedad bastante heterogénea que incluye varias clases de pacientes diferentes que se comportan de forma diferente en términos de pronóstico. La clasificación individualizada de riesgo y una buena herramienta de decisión nos permite mejorar los resultados de estos pacientes. Hasta la actualidad, la cistectomía radical sigue siendo la alternativa de tratamiento en un subgrupo de pacientes con tumores altamente agresivos debido a la falta de tratamientos alternativos para preservar la vejiga. La inmunoterapia en cáncer, a través de la inhibición del eje PD-1/PD-L1, ha demostrado una eficacia duradera en el tratamiento del cáncer de vejiga avanzado y metastático. Además se esta estudiando con mucho interés en la fase temprana de la enfermedad. Los resultados actualizados de KEYNOTE-057 han proporcionado en Estados Unidos la aprobación de la FDA depembrolizumab en pacientes con CIS no-respondedores a BCG por cáncer de vejiga no músculo invasivo. Este es un paso importante que nos lleva hacia una nueva ventana de oportunidades, mientras nuevas necesidades y preguntas están esperando respuesta.

Correlation of neutrophil-lymphocyte ratio and risk scores in non-muscle invasive bladder cancer. / Correlación entre el índice neutrófilo/linfocito y las puntuaciones de riesgo en el cáncer de vejiga no músculo-invasivo.

OBJECTIVES: Aim of this study is to evaluate the correlation between European Organization for Research and Treatment of Cancer (EORTC) risk score and neutrophil-lymphocyte ratio (NLR) in patients with non-muscle invasive bladder cancer and the relationship between NLR and risk groups. METHODS: We retrospectively reviewed data of 212 patients with non-muscle invasive bladder cancer were included in the study. The tumors were graded according to the 1973 World Health Organization grading system and the tumor node metastasis (TNM) 2012 staging system. Patients were categorized low, intermediate and high risk for recurrence and progression, according to European Association of Urology guidelines. Serum values for the NLR were measured on the day before the operation to ascertain the baseline value for neutrophil and lymphocyte counts and statistically analyzed. RESULTS: Of the 212 patients, 193 were male and 19 were female. Mean age was 66.7. Mean NLR score was 3.04±2.11. T1 tumors, G3 tumors, multiple tumors and>3cm tumors seen mostly in patients with NLR>2.41. Low, intermediate and high risk groups compared and NLR rates were significantly higher in high risk group patients (P<.001). When the correlation between NLR and EORTC recurrence and progression scores was evaluated, it was observed that as NLR value increased, recurrence (r=0.252, P<.001) and progression (r=0.145, P=.034) scores increased significantly. CONCLUSIONS: This study demonstrated the association of high NLR value with T1 tumor, high grade, multiple tumor,>3cm tumor and EORTC high risk group in non-muscle invasive bladder cancer patients. There was also a positive correlation between NLR and EORTC recurrence and progression scores.

Cuestionario CAVICAVENMI: calidad de vida en pacientes con cáncer de vejiga no músculo invasivo / CAVICAVENMI: Quality of Life Survey in Non-muscle-invasive Bladder Cancer Patients

Objetivo Evaluar la calidad de vida en pacientes diagnosticados de cáncer de vejiga no músculo invasivo a lo largo del estudio utilizando el cuestionario CAVICAVENMI. Material y Método Se incluyen 180 pacientes diagnosticados de TVNMI (febrero 2013 - junio 2015). Todos rellenaron el cuestionario CAVICAVENMI en cuatro ocasiones: previo a la cirugía y la primera, segunda y tercera visita postintervención. Aquellos que reciben tratamiento adyuvante completan el cuestionario en dos ocasiones más: a mitad y final del ciclo de tratamiento. Estudiamos la variabilidad en la calidad de vida con una T-Student para datos apareados. Realizamos T - Student para muestras independientes entre el decremento porcentual (antes de la intervención frente a tercera visita postintervención) y determinadas características tumorales (tamaño, número de siembras, localización y CIS - carcinoma in situ). Realizamos un estudio de regresión múltiple para determinar valores de confusión entre las características tumorales. Resultados Evidenciamos una mejora significativa en la calidad de vida a partir de la tercera visita postintervención en pacientes sin tratamiento adyuvante; y a partir del segundo momento postintervención en aquellos con tratamiento adyuvante. No existen diferencias significativas entre las características tumorales, pero observamos una mayor puntuación en presencia de las mismas. No encontramos factores de confusión. Conclusiones La calidad de vida en pacientes TVNMI, presenta una mejoría a lo largo del estudio. Esos cambios son más tempranos en los apartados de percepción de enfermedad, autoestima y estado emocional. Aquellos pacientes con presencia de las características tumorales estudiadas, presentan una peor calidad de vida, aunque no es estadísticamente significativo.

Purpose To evaluate the quality of life of patients diagnosed with NMIBC throughout the time of the study, using the CAVICAVENMI questionnaire. Material and Methods 180 patients diagnosed with NMIBC were included (February 2013 - June 2015) and completed the questionnaire on four occasions: prior to surgery, and in the first, second and third visits post-surgery. Patients on adjuvant treatment also completed it at the middle and final treatment cycle. Student's t-test was used to study the variability of the paired data in the quality of life questionnaire. An analysis (Student's-t Test) was made between the percentage decrease (before the intervention compared with the third post-surgery visit) and certain tumor characteristics (size, seeding number, location and carcinoma in situ) using. Multiple regression analysis was performed to determine confundant elements between tumor characteristics Result A statistically significant improvement in the quality of life was observed from the third post-intervention visit in patients that did not receive instillations, and in patients that received instillations, this significant improvement appeared from the second post-intervention visit. No statistically significant differences were found in the tumor characteristics, but a higher score was observed in the presence of these. We do not find confundant elements. Conclusions The quality of life in NMIBC patients showed an improvement throughout the study. These changes are seen earlier in the perception of the disease, in self-esteem and emotional state. Those patients with the presence of the tumor characteristics studied had a poorer, but not statistically significant, quality of life.