Editorial by Harry W. Herr on pp. 781–782 of this issue
Should All Patients with Non–Muscle-Invasive Bladder Cancer Receive Early Intravesical Chemotherapy after Transurethral Resection? The Results of a Prospective Randomised Multicentre Study☆
To decrease recurrences in non–muscle-invasive bladder cancer (NMIBC), the European Association of Urology (EAU) guidelines recommend immediate, intravesical chemotherapy after transurethral resection (TUR) for all patients with Ta/T1 tumours.
In this prospective randomised multicentre trial, 305 patients with primary as well as recurrent low- to intermediate-risk (Ta/T1, G1/G2) tumours were enrolled between 1997 and 2004. Patients were randomly allocated to receive 80 mg of epirubicin in 50 ml of saline intravesically within 24 h of TUR or no further treatment after TUR.
Measurements
The primary end point was time to first recurrence.
Results and limitations
A total of 219 patients remained for analysis after exclusions. The median follow-up time was 3.9 yr. During the study period, 62% (63 of 102) of the patients in the epirubicin group and 77% (90 of 117) in the control group experienced recurrence (p = 0.016). In a multivariate model, the hazard ratio (HR) for recurrence was 0.56 (p = 0.002) for early instillation of epirubicin versus no treatment. In a subgroup analysis, the treatment had a profound recurrence-reducing effect on patients with primary, solitary tumours, whereas it provided no benefits in patients with recurrent or multiple tumours. Furthermore, patients with a modified European Organisation for Research and Treatment of Cancer (EORTC) risk score of 0–2 with and without single instillation had recurrence rates of 41% and 69%, respectively (p = 0.003), whereas the corresponding rates for those with a risk score of ≥3 were 81% and 85%, respectively (p = 0.35).
Conclusions
A single, early instillation of epirubicin after TUR for NMIBC reduces the likelihood of tumour recurrence; however, the benefit seems to be minimal in patients at intermediate or high risk of recurrence. Future trials will determine the value of early instillation in addition to serial instillations in NMIBC.
Introduction
The majority of patients diagnosed with non–muscle-invasive bladder cancer (NMIBC) will have one or more recurrences after transurethral resection (TUR). Prior recurrences, prior recurrence rate, and tumour multiplicity are the strongest risk factors for recurrent disease, although the stage, grade, and size of tumours are also of importance. The estimated risk of recurrence and progression can be calculated for the individual patient by using the risk score introduced by the European Organisation for Research and Treatment of Cancer (EORTC) [1]. According to the European Association of Urology (EAU) guidelines [2], to decrease the risk of recurrences, “one, post-operative instillation of chemotherapy should be given in all patients after TUR of presumably non–muscle-invasive bladder cancer.” This recommendation is based on several randomised trials [3], [4], [5], [6], [7], [8], [9], [10], [11], [12] as well as a meta-analysis [13] indicating that one out of 8.5 treated patients can be spared a subsequent recurrence by use of the mentioned approach. Epirubicin (4′epidoxorubicin) is a chemotherapeutic drug that has a favourable tolerability profile and has been shown to prevent recurrences in patients with low- and intermediate-risk NMIBC [4], [8], [9], [14]. Our aim was to conduct a randomised, multicentre trial to study the benefits of a single, early, intravesical instillation of epirubicin after TUR in all patients with such disease.
Section snippets
Materials and methods
Between 1997 and 2004, 305 patients with cystoscopy-verified bladder tumours who were scheduled for TUR were included in the study. Patients with primary or recurrent low- to intermediate-risk (Ta/T1, G1/G2) tumours were enrolled. Single as well as multiple tumours were included, and there was no upper limit on tumour size. Patients with carcinoma in situ (CIS), grade 3 cancers, or muscle-invasive tumours on histopathologic examination were excluded. A history of high-risk bladder tumours (G3
Results
Eighty-six (28%) of the 305 randomised patients were excluded (Fig. 2) for the reasons given in Table 2. Of the 219 patients eligible for the final analysis, 115 (53%) had primary tumours and 104 (47%) recurrent tumours. At inclusion, 46% had solitary tumours, 25% had two or three tumours, and 30% had four or more tumours. Other patient characteristics are outlined in Table 3. The median follow-up time was 3.6 yr (range: 0.4–7.4 yr) for patients without recurrence and 3.9 yr for all patients.
Discussion
The unacceptably high recurrence rate after TUR has driven the search for supplementary treatments for NMIBC. A recurrence can be the result of either a true reappearance of a previously resected tumour or the development of a new primary tumour from genetically unstable urothelium [15]. Unfortunately, in clinical practice, it is impossible to distinguish between the two types of recurrence. True recurrence is probably most often the result of incomplete TUR, although animal studies have shown
Conclusions
Single, early instillation of epirubicin after TUR for NMIBC prevents tumour recurrences, mainly in cases of primary, solitary tumours—that is, in patients at low risk of recurrence. By comparison, we found that such post-TUR treatment was not beneficial in patients at intermediate or high risk of recurrence. In our view, there are insufficient data supporting the general recommendation of the EAU that all patients with NMIBC should be treated with early instillation. Future prospective
2022, Urologic Oncology: Seminars and Original Investigations
Partial cystectomy (PC) is a bladder sparing option to treat bladder cancer in a carefully selected group of patients. We sought to analyze outcomes of partial cystectomy (PC) in a contemporary cohort of patients at a single institution.
Records were reviewed for 43 patients with a primary urothelial carcinoma (UC) who had a partial cystectomy with curative intent at Columbia University Medical Center from 2004 to 2019. Endpoints of interest were noninvasive recurrence (defined as any recurrent nonmuscle invasive disease), advanced recurrence (defined as a muscle invasive recurrence or metastasis), and death. We used unadjusted Cox proportional hazards regressions and log rank tests to estimate the association between clinical characteristics and endpoints of interest.
Among 43 patients with bladder cancer treated with partial cystectomy, median patient age was 73 years (interquartile range 67–77.5) and 86% were male. Twenty-three percent of patients received preoperative neoadjuvant chemotherapy (NAC) and 49% of patients were given perioperative intravesical chemotherapy at the time of PC. Pathologic stage was <T2 for 23 (53%) patients and ≥T2 for 20 (47%) patients. Pathology showed 14% of patients had lymph node involvement, and 9% had positive surgical margins. Mean follow-up was 51 months (range 1–176). Five-year overall survival was 78%. Of 43 patients, 23 patients (53%) had no recurrence, 9 patients (21%) experienced noninvasive intravesical recurrence, and 11 patients (26%) experienced advanced recurrences. Two patients (5%) required salvage radical cystectomy and 8 patients (19%) died of bladder cancer. On univariate analysis, lymphovascular invasion (hazard ratio [HR] 4.4, confidence interval [CI] 1.3–14.3), pathological stage (HR 5.9, CI 1.3–27.4), and NAC (HR 6.5, CI 1.9–22.7) were associated with advanced recurrence. Noninvasive recurrence was associated with not receiving perioperative intravesical chemotherapy (HR 0.7, CI 0.1–6.0).
In well-selected patients, partial cystectomy offers adequate local control of bladder cancer. The risk of systemic progression is similar to reported case series of RC.
Evaluar si existe alguna diferencia entre el efecto de la instilación intravesical de quimioterapia postoperatoria inmediata (IQPI) y el del lavado vesical continuo con suero salino (LVCS) en la recidiva del cáncer de vejiga (CV) en pacientes con CV primario de riesgo bajo o intermedio sin invasión muscular (CVSIM).
Se revisaron retrospectivamente las historias clínicas de 1.482 pacientes sometidos a resección transuretral de tumor de vejiga entre marzo de 1994 y agosto de 2020. Los pacientes se dividieron en 2 grupos según el tratamiento administrado de IQPI y/o LVCS (Grupo 1: solo LVCS; Grupo 2: LVCS tras IQPI). Los pacientes con CVSIM de riesgo bajo e intermedio también se dividieron en subgrupos según el tipo de tratamiento administrado: IQPI y/o LVCS.
Se incluyeron 594 pacientes con CVSIM primario. De los pacientes, 86 (14,5%) eran mujeres y 508 (85,5%) eran varones, con una edad media de 69 (60-78) años. La frecuencia de pacientes en el grupo 1 y el grupo 2 fue de 361 (60,8%) y 233 (39,2%), respectivamente. Se observó enfermedad recurrente en 213 (35,9%) pacientes. No hubo diferencias entre los grupos al comprar la frecuencia de la enfermedad recurrente, la mediana de tiempo hasta la primera recidiva y la frecuencia de la recidiva en los primeros 12 meses (p = 0,064; p = 0,671 y p = 0,145, respectivamente). Las tasas de recidiva en los pacientes con CVSIM de bajo riesgo fueron menores cuando recibieron tratamiento con «LVCS tras IQPI” en comparación con «solo LVCS» (p = 0,042). Sin embargo, no se observaron diferencias en los subgrupos de CVSIM de bajo riesgo al comparar las características patológicas de los tumores recurrentes como el número, el tamaño, el grado, el estadio y la presencia de carcinoma in situ (p > 0,05, para cada una).
La combinación «LVCS tras IQPI» no fue superior al tratamiento único con «LVCS» en la prevención de resultados patológicos adversos en el CVSIM recurrente de riesgo bajo e intermedio.
To evaluate whether there is any difference between immediate postoperative instillation of intravesical chemotherapy (IPOIC) and continuous saline bladder irrigation(CSBI) in terms of bladder cancer(BC) recurrence in patients with primary low- or intermediate-risk non-muscle-invasive BC (NMIBC).
Medical records of 1482 patients who underwent transurethral resection of bladder tumor between March 1994 and August 2020 were reviewed retrospectively. Patients were divided into two groups according to IPOIC and/or CSBI administration status (Group 1: CSBI alone; Group 2: CSBI following IPOIC). Low- and intermediate-risk NMIBC patients were also divided into subgroups according to IPOIC and/or CSBI administration status.
A total of 594 patients with primary NMIBC were included. Of the patients, 86 (14.5%) were female and 508 (85.5%) were male with a median age of 69 (60-78) years. The frequency of patients in group 1 and group 2 were 361 (60.8%) and 233 (39.2%), respectively. Recurrent disease was observed in 213 (35.9%) patients. There was no difference between the groups when they were compared for recurrent disease frequency, median time to first recurrence and frequency of recurrence within first 12 months (P=.064, P=.671, and P=.145, respectively). Disease recurrence rates in low-risk NMIBC patients was lower when they were treated with “CSBI following IPOIC” when compared to “CSBI alone” (P=.042). However, no difference was observed in low-risk NMIBC subgroups when they were compared for pathological features of recurrent tumors such as number, size, grade, stage, and presence of carcinoma in situ (P>.05, for each).
“CSBI following IPOIC” combination was not superior to “CSBI alone” for preventing adverse pathological outcomes in recurrent low- and intermediate-risk NMIBC.
2022, Urologic Oncology: Seminars and Original Investigations
To investigate the outcomes of mixed-grade non-muscle invasive bladder cancer (NMIBC) based on the degree of high-grade predominance.
We identified patients in our institutional database who had a transurethral resection of bladder tumor(s) for NMIBC. Tumors with mixed-grade features on pathology report were reanalyzed, assigned the percentage high-grade component, and stratified into ≤ 5% high-grade and > 5% high-grade groups. All others were classified as low-grade or high-grade NMIBC. Differences in recurrence-free survival were assessed by log-rank test. A multivariable Cox regression model was used to evaluate the impact of tumor grade on recurrence, controlling for tumor stage, size, multifocality, and intravesical therapy.
Two hundred and twenty patients were followed for a median of 2 years; 127 (58%) had low-grade NMIBC, 66 (30%) had high-grade NMIBC, and 27 (12%) had mixed-grade NMIBC. Of the mixed-grade patients, 14 had a ≤ 5% high-grade component, and 13 had a > 5% high-grade component. Recurrence rates across all groups ranged from 42% to 79%. There was no significant difference in intravesical recurrence-free survival among the grade categories as assessed by log-rank test. On multivariable Cox regression analysis, grade category was not significantly associated with likelihood of recurrence.
The prognosis of mixed-grade histology in NMIBC has not previously been well defined. Although grade category was not found to be an independent significant predictor of recurrence, the recurrence rate for mixed-grade tumors was quite high overall. Further studies are required to better understand appropriate risk stratification and treatment of mixed-grade NMIBC.
2021, Hematology/Oncology Clinics of North America
Citation Excerpt :
For those at low risk of recurrence, single postoperative intravesical therapy is likely satisfactory. Single instillation of epirubicin after transurethral resection has also been shown in a randomized trial by Gudjonsson and colleagues8 to reduce the likelihood of tumor recurrence, primarily in patients with small, low-risk tumors; however, this agent is not currently available in the United States. In addition to the standard adjuvant intravesical therapy, mitomycin C is also being explored as a chemoablative agent in a phase IV trial (NCT03348969) and results are forthcoming.
The European Association of Urology (EAU) non–muscle-invasive bladder cancer (NMIBC) guidelines are meant to help minimise morbidity and improve the care of patients with NMIBC. However, there may be underuse of guideline-recommended care in this potentially curable cohort.
To assess European physicians’ current practice in the management of NMIBC and evaluate its concordance with the EAU 2013 guidelines.
Initial 45-min telephone interviews were conducted with 20 urologists to develop a 26-item questionnaire for a 30-min online quantitative interview. A total of 498 physicians with predefined experience in treatment of NMIBC patients, from nine European countries, completed the online interviews.
Descriptive statistics of absolute numbers and percentages of the use of diagnostic tools, risk group stratification, treatment options chosen, and follow-up regimens were used.
Guidelines are used by ≥87% of physicians, with the EAU guidelines being the most used ones (71–100%). Cystoscopy (60–97%) and ultrasonography (42–95%) are the most used diagnostic techniques. Using EAU risk classification, 40–69% and 88–100% of physicians correctly identify all the prognostic factors for low- and high-risk tumours, respectively. Re-transurethral resection of the bladder tumour (re-TURB) is performed in 25–75% of low-risk and 55–98% of high-risk patients. Between 21% and 88% of patients received a single instillation of chemotherapy within 24 h after TURB. Adjuvant intravesical treatment is not given to 6–62%, 2–33%, and 1–20% of the patients with low-, intermediate-, and high-risk NMIBC, respectively. Patients with low-risk NMIBC are likely to be overmonitored and those with high-risk NMIBC undermonitored. Our study is limited by the possible recall bias of the selected physicians.
Although most European physicians claim to apply the EAU guidelines, adherence to them is low in daily practice.
Our survey among European physicians investigated discrepancies between guidelines and daily practice in the management of non–muscle-invasive bladder cancer (NMIBC). We conclude that the use of the recommended diagnostic tools, risk-stratification of NMIBC, and performance of re-TURB have been adopted, but adjuvant intravesical treatment and follow-up are not uniformly applied.
