[BCG Immunotherapy, past, present and future.] / Inmunoterapia con BCG: pasado, presente y futuro.

Since its introduction more than 40 years ago, adjuvant treatment with BCG (Bacillus Calmette-Guérin) for non-muscle invasive bladder cancer (NMIBC) continues to be the treatment recommended in the highrisk group, and one of the most successful immunotherapies for cancer treatment. However, up to 20% of patients will progress to muscle-invasive disease after BCG treatment. On the other hand, we are facing a shortage of BCG supply worldwide. Despite its extensive clinical use, there is no clear certainty of the mechanism of action of BCG, and controversy persists regarding to the most effective dose and strains, as well as their usefulness in combined treatments with other drugs and with devices that could facilitate their action on the bladder. This article historically reviews the impact that has had BCG in the treatment of NMIBC, the current guidelines in terms of doses, strains and treatments combination, and the future that will happen with the results of the ongoing clinical trials with systemic immunotherapy, vaccines and gene therapy.

Desde su introducción hace más de 40 años, el tratamiento adyuvante con BCG (Bacilo Calmette-Guérin) para el tumor vesical no-músculo invasivo (TVNMI) sigue siendo el tratamiento de elección en el grupo de alto riesgo, y una de las inmunoterapias para el cáncer de mayor éxito. Sin embargo, hasta el 20% de los pacientes progresarán a enfermedad músculo-invasiv adespués del tratamiento con BCG. Por otra parte,nos encontramos ante una escasez de suministro de BCG a nivel mundial. A pesar de su extenso uso clínico, no existe una clara certeza del mecanismo de acción de la BCG, y todavía persiste controversia en cuanto a las dosis y cepas más eficaces, así como su utilidad en tratamientos combinados con otros fármacos y con dispositivos que podrían facilitan su acción en la vejiga. En este artículo se revisa históricamente el impacto que ha tenido la BCG en el tratamiento del TVNMI, las directrices actuales en cuanto a dosis, cepas y tratamientos de combinación, y el futuro que acontecerá con los resultados de los ensayos clínicos sobre inmunoterapia sistémica, inmuno moduladores, vacunas y terapia génicaen el TVNMI.

Inmunoterapia con BCG: pasado, presente y futuro / BCG Immunotherapy, past, present and future

Desde su introducción hace más de 40 años, el tratamiento adyuvante con BCG (Bacilo Calmette-Guérin) para el tumor vesical no-músculo invasivo (TVNMI) sigue siendo el tratamiento de elección en el grupo de alto riesgo, y una de las inmunoterapias para el cáncer de mayor éxito. Sin embargo, hasta el 20% de los pacientes progresarán a enfermedad músculo-invasiva después del tratamiento con BCG. Por otra parte, nos encontramos ante una escasez de suministro de BCG a nivel mundial. A pesar de su extenso uso clínico, no existe una clara certeza del mecanismo de acción de la BCG, y todavía persiste controversia en cuanto a las dosis y cepas más eficaces, así como su utilidad en tratamientos combinados con otros fármacos y con dispositivos que podrían facilitan su acción en la vejiga. En este artículo se revisa históricamente el impacto que ha tenido la BCG en el tratamiento del TVNMI, las directrices actuales en cuanto a dosis, cepas y tratamientos de combinación, y el futuro que acontecerá con los resultados de los ensayos clínicos sobre inmunoterapia sistémica, inmunomoduladores, vacunas y terapia génica en el TVNMI

Since its introduction more than 40 years ago, adjuvant treatment with BCG (Bacillus Calmette-Guérin) for non-muscle invasive bladder cancer (NMIBC) continues to be the treatment recommended in the highrisk group, and one of the most successful immunotherapies for cancer treatment. However, up to 20% of patients will progress to muscle-invasive disease after BCG treatment. On the other hand, we are facing a shortage of BCG supply worldwide. Despite its extensive clinical use, there is no clear certainty of the mechanism of action of BCG, and controversy persists regarding to the most effective dose and strains, as well as their usefulness in combined treatments with other drugs and with devices that could facilitate their action on the bladder. This article historically reviews the impact that has had BCG in the treatment of NMIBC, the current guidelines in terms of doses, strains and treatments combination, and the future that will happen with the results of the ongoing clinical trials with systemic immunotherapy, vaccines and gene therapy

The management of active surveillance in prostate cancer: validation of the Canary Prostate Active Surveillance Study risk calculator with the Spanish Urological Association Registry.

The follow up of patients on active surveillance requires to repeat prostate biopsies. Predictive models that identify patients at low risk of progression or reclassification are essential to reduce the number of unnecessary biopsies. The aim of this study is to validate the Prostate Active Surveillance Study risk calculator (PASS-RC) in the multicentric Spanish Urological Association Registry of patients on active surveillance (AS), from common clinical practice. RESULTS: We find significant differences in age, PSA and clinical stage between our validation cohort and the PASS-RC generation cohort (p < .0001), with a reclassification rate of 10-22% on the follow-up Bx, no cancer was found in 43% of the first follow-up Bx. The calibration curve shows underestimation of real appearance of reclassification. The AUC is 0.65 (C.I.95%: 0.60-0.71). PDF and CUC do not suggest a specific cut-off point of clinical use. METHODS: We select 498 patients on AS with a minimum of one follow-up biopsy (Bx) from the 1,024 males registered by 36 Spanish centers recruiting patients on the Spanish Urological Association Registry on AS. PASS-RC external validation is carried by means of calibration curve and area under de ROC-curve (AUC), identifying cut-offs of clinical utility by probability density functions (PDF) and clinical utility curves (CUC). CONCLUSIONS: In our first external validation of the PASS-RC we have obtained a moderate discrimination ability, although we cannot recommend cut-off points of clinical use. We suggest the exploration of new biomarkers and/or morpho-functional parameters from multiparametric magnetic resonance image, to improve those necessary tools on AS.

La cistectomía es una buena opción para el cáncer vesical infiltrante en ancianos mayores de 80 años / Cistectomy is a good option in infiltrant vesical cancer in elderly older than 80 years

Objetivo: evaluar la morbilidad y supervivencia en pacientes mayores de 80 años de edad con tumor vesical infiltrante (TVI) tratados con cistectomía radical. Material y métodos: La serie incluye 27 pacientes mauores de 80 años de edad que fueron sometidos a cistectomía radical (TVI inicial en 14 casos, con u na edad media de 82 años seguimiento de 16,4 meses). Resultados: El estadio patológico del espécimen de cistectomía fue pT3 en 18 casos (66,7%). Estancia media hospitalaria: 16 días. Las complicaciones tempranas fueron valoradas en 8 pacientes (29,6%), con una supervivencia global del 42,94%, y cáncer-específica del 60,54%. Conclusiones: La cistectomía radical en los ancianos es un procedimiento seguro, con tasas de complicación y supervivencia comparables a los menores de 80 años. La edad per se no es una contraindicación de la cirugía radical

To evaluate and compare morbidity and survival in patients more than 80 years old with invasive bladder cancer (IBC) treated with cystectomy. Method: Twenty-seven patient older than 80 with IBC were submitted to radical cystectomy. Mean age was 82+/-3 years. Mean follow-up of 16.4 onths. Cystectomy was carried out following diagnosis of initially invasive tumour in 14 cases (51.9%). Results: The stage of the cystectomy specimen was pT3 in 18 cases (66.7%). Mean hospital stay was 16 days. Early complications were appraised in 8 patients (29,6%). Overall survival was of 42.94% and cancer-specific survival of 60.54%. Conclusions: Radical cystectomy of the octogenarian patient is a safe procedure, with complication and survival rates comparable to younger than 80. Age per se is not a contraindication of radical surgery

[Determination of P53 in infiltrative primary bladder tumors as a prognostic factor for understaging]. / La determinación de p53 en tumor vesical primario infiltrante como factor pronóstico de subestadiaje.

OBJECTIVES: To determine if p53 expression in patients with infiltrative bladder cancer is a prognostic factor on clinical staging and cancer specific survival. METHODS: Immunohistochemical analysis of p53 in 34 patients (33 males and 1 female) undergoing radical cystectomy for infiltrative bladder cancer, with a mean follow-up of 16 months. RESULTS: p53 overexpression was detected in 18 patients (64%). In the p53 positive group two patients were stage T1G3, 18 patients T2, 1 patient T3, and 2 patients T4. In the negative group a better correspondence between TUR and cystectomy stage was found, with stage worsening only in 3 patients. On follow-up, p53 positive patients showed worse outcomes due to their worse stages, although no statistical differences were found (p = 0.24). In the group of patients following a bladder sparing protocol (n = 6), p53 negative patients had complete remission of the disease. CONCLUSIONS: We see significant differences on understaging/more aggressive local outcome in p53 positive patients, with no greater mortality in this group. P53 expression does not contraindicate the inclusion of a patient in a bladder sparing protocol, although larger studies would be necessary to confirm these results.

La determinación de P53 en tumor vesical primario infiltrante como factor pronóstico de subestadiaje / Determination of P53 in infiltrative primary bladder tumors as a prognostic factor for understaging

OBJETIVO: Determinar si la expresión de p53 en pacientes con carcinoma vesical infiltrante tiene valor pronóstico en el estadiaje clínico y supervivencia del tumor.MÉTODOS: El análisis inmunohistoquímico de p53 se realizó en 34 pacientes (33 hombres y 1 mujer) tratadoscon cistectomía por carcinoma vesical infiltrante con seguimiento medio de 16 meses.RESULTADOS: Se detectó sobreexpresión de p53 en 18 pacientes (64%). En el grupo con positividad p53 se encontraron 2 pacientes con estadio T1G3, 18 pacientesT2, 1 paciente T3 y 2 pacientes T4. En el grupo con negatividad inmunohistoquímica se encontró una mejor correspondencia entre el estadiaje de la RTU y de la cistectomíaencontrándose empeoramiento del estadio en solo 3 pacientes. Tras el seguimiento los pacientes p53 positivos presentaron peor evolución al tener peor estadio,aunque no significativa estadísticamente (p 0,24). En los pacientes que pasaron a protocolo de conservaciónvesical (n=6), los p53 negativos experimentaron una remisión completa de la enfermedad.CONCLUSIONES: Observamos una diferencia significativade infraestadiaje/evolución local más agresiva en pacientes p53 positivos y no mayor mortalidad en este grupo. La expresión de p53 no contraindica la entrada de un paciente en protocolo de conservación vesical aunque serán necesarios estudios más amplios para confirmar estos resultados

OBJECTIVES: To determine if p53 expression in patients with infiltrative bladder cancer is a prognostic factor on clinical staging and cancer specific survival. METHODS: Immunohistochemical analysis of p53 in 34 patients (33 males and 1 female) undergoing radical cystectomy for infiltrative bladder cancer, with a mean follow-up of 16 months. RESULTS: p53 overexpression was detected in 18 patients (64%). In the p53 positive group two patients were stage T1G3, 18 patients T2, 1 patient T3, and 2 patients T4. In the negative group a better correspondence between TUR and cystectomy stage was found, with stage worsening only in 3 patients. On follow-up, p53 positive patients showed worse outcomes due to their worse stages, although no statistical differences were found (p = 0.24). In the group of patients following a bladder sparing protocol (n = 6), p53 negative patients had complete remission of the disease. CONCLUSIONS: We see significant differences on understaging/more aggressive local outcome in p53 positive patients, with no greater mortality in this group. P53 expression does not contraindicate the inclusion of a patient in a bladder sparing protocol, although larger studies would be necessary to confirm these results

Intravesical instillations with bacillus calmette-guérin for the treatment of carcinoma in situ involving prostatic ducts.

OBJECTIVES: Bacillus Calmette-Guérin (BCG) has proven its efficacy in the treatment of carcinoma in situ (CIS) of the prostatic urethra. We performed a retrospective study to evaluate the use of intravesical instillations of BCG in patients with carcinoma in situ involving prostatic ducts after complete transurethral resection (TUR). MATERIAL AND METHODS: Eligibility for the study was CIS of the prostatic urethra involving prostatic ducts. Previous instillation with BCG was an exclusion criterion. Patients were treated with intravesical BCG Connaught (81 mg) administered once a week, over a 6-wk period. TUR loop biopsies of the prostate were performed only when a macroscopic tumor was present. RESULTS: In this retrospective study of 11 patients, 8 (73%) presented with macroscopic tumor in the prostatic urethra. Ten patients (91%) had a simultaneous superficial bladder carcinoma. Eight patients (73%) had tumoral involvement of the bladder neck region. After a median follow-up of 27 mo (n=10 patients), the response in the prostatic urethra was 82%, and the response in the bladder due to superficial tumor recurrence was 64%. Two patients with residual ductal disease in the prostatic urethra were subsequently treated with cystoprostatectomy and are currently free of disease. In one of those patients, the cystoprostatectomy specimen did show prostatic stromal invasion. Another patient developed distant metastatic disease and died a few months after diagnosis. Thus, progression was encountered in two patients (18%). Currently, 90% of patients are alive without evidence of disease and 72.7% have benefitted from this bladder preservation strategy. CONCLUSION: Intravesical BCG is a feasible treatment option for patients with CIS involving prostatic ducts. In this retrospective study, bladder preservation was successful in 8 of 11 patients (70%) and there was only one oncologic death. Obviously, these patients need a careful follow-up with cystoscopy and cytology to detect either recurrence or progression and in those with persistent disease after the initial BCG induction therapy, prompt cystectomy is indicated.

[Percutaneous treatment with BCG in multiple upper tract transitional cell carcinoma]. / BCG terapéutica por vía percutánea en el tratamiento del carcinoma urotelial múltiple de via superior.

Upper tract transitional cell carcinoma is a low prevalent tumour and frequently associated to bladder carcinoma. The antegrade endoscopic access represents a safe, efficient and minimally invasive access. The association to immunotherapy seems effective in decreasing recurrence. We present one patient with multiple upper tract carcinoma treated with percutaneous surgery and BCG.

BCG terapéutica por vía percutánea en el tratamiento del carcinoma urotelial múltiple de vía superior / Percutaneous treatment with bcg in multiple upper tract transitional cell carcinoma

El tumor urotelial del tracto urinario superior constituye un tipo de tumor de baja prevalencia, frecuentemente asociado a tumor vesical. El uso de la vía endoscópica con acceso anterógrado representa un método de tratamiento seguro, eficaz y mínimamente invasivo. La asociación con inmunoterapia parece efectiva para disminuir la recurrencia. Presentamos un caso de tumor de tramo urinario superior múltiple tratado mediante exéresis percutánea e inmunoterapia terapéutica (AU)

Upper tract transitional cell carcinoma is a low prevalent tumour and frequently associated to bladder carcinoma. The antegrade endoscopic access represents a safe, efficient and minimally invasive access. The association to immunotherapy seems effective in decreasing recurrence. We present one patient with multiple upper tract carcinoma treated with percutaneous surgery and BCG (AU)

[Radical cystectomy for superficial tumors in the BCG era]. / Cistectomía radical en tumores superficiales en la era de la BCG.

OBJECTIVE: To analyze the indications and outcome of cystectomy for superficial bladder cancer since the introduction of BCG therapy. METHODS: From June 1990 to December 1996, 384 patients underwent cystectomy for transitional cell bladder tumor. A retrospective study was carried out on 43 cases (11.1%) that underwent cystectomy for Tis, Ta, T1 tumors. The characteristics of patients with superficial bladder cancer, correlation between the clinical stage (determined after TUR) and pathological findings (cystectomy specimen) and outcome were analyzed. RESULTS: 36 patients were male and 7 were female; mean age 63 years (range 39-79). Mean follow-up was 48 months (8-120). Twenty-nine patients received BCG therapy prior to surgery. No response to BCG was the main indication for cystectomy. By clinical stage, 79% were high grade, 65% T1 and 65% CIS. A correlation between the clinical stage and the pathological findings was found in 32.5%, overstaging in 28% and understaging in 39.5%. The increase in stage after analysis of the surgical specimen in 13 patients (30%) was due to progression of the superficial bladder tumor to infiltrating or metastatic tumor. Urinary tract tumor was found during follow-up in 8 patients (18.6%). Eleven patients died of bladder cancer, 3 of other causes and 29 (67%) are free of disease. Seven of the 13 patients (53%) that were clinically understaged and had infiltrating tumor or metastasis died. CONCLUSIONS: No response to BCG therapy was the main indication for cystectomy. Before starting conservative treatment for high risk superficial bladder cancer, the possibility of endoscopic understaging should be taken into account. Patients undergoing cystectomy for superficial bladder cancer have a high risk of developing urinary tract tumor.

Cistectomía radical en tumores superficiales en la era de la BCG / Radical cystectomy for superficial bladder cancer in the era of BCG therapy

OBJETIVO: Estudio de las indicaciones y evolución de las cistectomías realizadas por tumor vesical superficial (TVS) desde la introducción de la BCG.MÉTODOS: Entre junio de 1990 y diciembre de 1996, 384 pacientes fueron cistectomizados por tumor vesical transicional. Realizamos el estudio retrospectivo de 43 casos (11,1 por ciento) en que la cistectomía se efectuó por tumores en estadios clínicos Tis, Ta, T1. Analizamos las características de los TVS a los que se indicó cistectomía, la correlación entre su estadio clínico (obtenido tras la RTU) y patológico (pieza de cistectomía) y la evolución posterior.RESULTADOS: Fueron 36 hombres y 7 mujeres con una edad media de 63 años (39-79). La mediana de seguimiento fue de 48 meses (8-120). Veintinueve casos (67 por ciento) recibieron tratamiento previo con BCG. La ausencia de respuesta a la BCG fue la indicación principal de cistectomía. Tras el estadiaje clínico, el 79 por ciento de los tumores fueron de alto grado, el 65 por ciento T1 y el 65 por ciento presentaron CIS. En el 32,5 por ciento de los casos el estadio clínico coincidió con el patológico, en el 28 por ciento fue superior (supraestadiaje clínico) y en el 39,5 por ciento fue inferior (infraestadiaje clínico). En 13 pacientes (30 por ciento) el aumento del estadio de la pieza quirúrgica supuso el paso de tumor superficial a infiltrante o metastásico. En 8 casos (18,6 por ciento) apareció durante el seguimiento un tumor de vías. Once pacientes fallecieron por cáncer vesical, 3 por otras causas y 29 (67 por ciento) se encontraban libres de enfermedad. Fallecieron 7 de los 13 pacientes (53 por ciento) con infraestadiaje clínico y estadio patológico de tumor infiltrante o metastásico.CONCLUSIONES: El fracaso al tratamiento con BCG fue la indicación principal de cistectomía en TVS. Antes de iniciar un tratamiento conservador en un TVS de alto riesgo hay que tener en cuenta la posibilidad del infraestadiaje endoscópico. Los pacientes cistectomizados por TVS presentan un elevado riesgo de presentar tumor de vías (AU)