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The second-line conservative device-assisted intravesical treatment in selected patients with recurrent high risk non-muscle invasive bladder cancer
Abstract
Introduction
In cases of recurrent high-risk non–muscle-invasive bladder cancer, radical cystectomy (RC) is recommended. We compared oncologic and treatment-related outcomes of second-line conservative device-assisted therapy to RC.
Patients and Methods
In a retrospective cohort study, we analyzed 209 consecutive patients with recurrent bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer; 107 subjects refused RC and were offered electromotive drug administration (n = 44) or chemohyperthermia (n = 63) (group A), and 102 patients underwent RC (group B). In group A, patients who did not benefit from device-assisted treatment underwent RC. The endpoints were high-grade disease-free survival, progression-free survival, cancer-specific survival, overall survival, and treatment-related complications. Follow-up was based on international guideline recommendations. Analyses were performed with log-rank and Fisher exact tests.
Results
The median follow-up was 59 months (SD ± 5.3). When comparing group A to B, overall survival rates were 91.6% and 90.2%, respectively (P > .05); cancer-specific survival was 94.4% and 96.1%, respectively (P > .05); high-grade disease-free survival was 43% and 74.5%, respectively (P < .05); and progression-free survival was 59.8% and 75.5%, respectively (P < .05). Patients with carcinoma-in-situ had worse oncologic outcomes compared to patients with papillary disease. In the multivariate analysis, multifocality, disease recurrence, and progression risk group were independently associated with device treatment failure. The 90-day RC-related overall complications rates were 63.9% in group A and 66.6% in group B (P = .63); grade 3 to 5 complications were 9.8% in group A and 9.8% in group B(P = .99). Complications within group A were comparable (P > .05).
Conclusion
Device-assisted treatment may a represent a valid second-line conservative tool in selected patients with recurrent high-risk non–muscle-invasive bladder cancer.
... A retrospective cohort study conducted by Di Gianfrancesco et al. 15 studied conservative device-assisted treatments with chemohyperthermia (CHT) and electromotive drug administration (EMDA) of MMC. In this study, 209 patients were analyzed. ...
... The second study by Di Gianfrancesco et al. 15 described the use of EMDA-MMC in 44 patients who were retrospectively analyzed. The median follow-up was 59 ± 5.3 months. ...
Introduction
Globally, urothelial bladder carcinoma is a disease which carries a poor prognosis. There are various treatment modalities for urothelial bladder carcinoma with intravesical Bacillus Calmette–Guérin immunotherapy being the most efficacious intravesical therapy and the treatment of choice for patients with carcinoma in situ. A number of chemotherapeutic drugs are also available for the management of Ta/T1 tumors such as mitomycin C and epirubicin. However, relapse and progression is quite common. The optimal management of patients with Bacillus Calmette–Guérin-unresponsive disease remains to be a challenge. The purpose of this study was to conduct a systematic review on the treatment modalities available for the management of Bacillus Calmette–Guérin-unresponsive carcinoma in situ and urothelial bladder carcinoma in patients who are ineligible or decline radical cystectomy.
Methods
Two authors independently searched three databases on the treatment modalities available for the management of Bacillus Calmette–Guérin-unresponsive carcinoma in situ and Bacillus Calmette–Guérin-unresponsive urothelial bladder carcinoma.
Results
The systematic search resulted in 15 studies. We recommend the use of intravesical CG0070 adenovirus or hyperthermic intravesical chemotherapy mitomycin C in patients with carcinoma in situ only disease. In patients with carcinoma in situ ± Ta/T1 disease, we recommend the use of intravesical radiofrequency-induced chemohyperthermia or electromotive drug administration of mitomycin C. In patients who have Ta/T1 disease, we recommend the use of either hyperthermic intravesical chemotherapy epirubicin or electromotive drug administration mitomycin C followed by chemohyperthermia mitomycin C. If any of these second line therapies fail, an alternative regimen would be a combination of gemcitabine, cabazitaxel, and cisplatin.
Conclusion
This recommendation is subject to the available resources and clinical expertise available in different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs with larger sample sizes and regular follow-up intervals should be performed to accurately assess the different medications and aid in designing guidelines to guide the management of Bacillus Calmette–Guérin-unresponsive non-muscle invasive intravesical bladder cancer.
Background
Devices that increase the penetration of intravesical chemotherapeutic agents have been developed as alternatives to the use of bacillus Calmette–Guérin, in short supply at a time of increasing global incidence of non-muscle invasive bladder cancer (NMIBC).
We performed a prospective observational study to compare 2 of these devices in the treatment of patients with high- and intermediate-risk NMIBC. The primary endpoint was the recurrence-free rate. Secondary endpoints were the rate of progression and adverse events.
Methods
After undergoing transurethral bladder resection, 98 patients were selected to receive 1 of 2 treatments: hyperthermic intravesical chemotherapy (HIVEC) treatment with 40 mg of mitomycin C (MMC) using Combat BRS System V2.0 at 43 ± 0.5°C and 200 ml/min for 60 minutes (56 patients) or electromotive drug administration (EMDA) with 40 mg of MMC at 20 mA for 30 minutes (42 patients). The treatment schemes were similar: 6 weekly instillations as induction and 6-monthly instillations as maintenance. The recurrence rates were evaluated at 6 and 12 months and the progression rates at 12 months.
Results
The recurrence-free rate at 12 months was 91,1% in the HIVEC group and 88.1% in the EMDA group (P ≥ 0.05). After the 12-month follow-up, only 1 progression occurred in each treatment group. In terms of adverse events, no significant differences were found between the treatments.
Conclusions
HIVEC and EMDA techniques are comparable in terms of recurrence, progression and adverse events at 12 months in the treatment of patients with high- and intermediate-risk NMIBC.
Background
Non-muscle invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence and progression, despite surgery and adjuvant therapies.
Objective
To analyze the published results on the effectiveness of mitomycin C (MMC) applied with an electromotive drug administration device (EMDA) in the treatment of patients with non-muscle invasive bladder tumors.
Method
A systematic review was conducted using the PubMed and Google Scholar search platforms. We selected the studies that included the recurrence and/or progression rates or complete response rate in patients diagnosed with NMIBC according to their treatment and included MMC applied with EMDA. The last search was performed in November 2021.
Results
The search yielded 64 articles; 11 articles met the selection criteria. In two of the 11 selected articles, mitomycin C was applied with an EMDA device (MMC-EMDA) as an ablative treatment, avoiding surgery in 50% of the patients. In 1 of the 11 studies, the application of MMC-EMDA was used as an induction treatment using a single preoperative instillation with promising results. In the remaining 8 studies, adjuvant MMC was applied with the EMDA device; in 3 of these 8 cases, treatment with MMC-EMDA alone was applied initially. In another3 cases the same treatment was applied after nonresponse to bacillus Calmette Guerin (BCG), and in the last 2 studies, MMC-EMDA was applied in combination with the classic therapy (BCG). All the studies selected supported the efficacy and safety of MMC-EMDA in patients with intermediate and high- risk bladder cancer. In 3 studies, adjuvant therapy with MMC-EMDA was performed in nonresponders to BCG, finding that adjuvant therapy with MMC-EMDA applied to BCG nonresponders without CIS avoided or delayed surgery.
Conclusions
The application of EMDA-enhanced MMC has been studied at different times of disease and with different administration protocols. It appears to delay bladder tumor recurrence and progression in certain populations. However, the methodological limitations of the published studies prevent definitive conclusions about its efficacy.
Purpose of review:
To critically analyze the oncological outcomes and safety profile of device-assisted intravesical chemotherapy studies reported in 2021. Studies were considered eligible if they included patients with nonmuscle invasive blood cancer (NMIBC), had a prospective or retrospective design, included at least 10 patients, were published in 2021, and assessed the oncological impact of device-assisted intravesical chemotherapy and/or reported standardized adverse effects (AEs).
Recent findings:
Eight new studies reported oncological outcomes after hyperthermic intravesical chemotherapy (HIVEC). In Bacillus Calmette-Guérin (BCG) naive patients, the reported 2-yr. recurrence-free survival (RFS) ranged from 70.7% to 82.4%, with one study reporting 2 yr. progression free survival (PFS) of 92%. In both BCG naive and BCG refractory patients, the reported 1-yr. RFS ranged from 60.5% to 70% and PFS was 94% in one study. For radiofrequency-induced HIVEC, the reported 5-yr. estimates were 38%for RFS and 91.5%for PFS. Regarding AEs, 10.2% of patients had severe AEs. Six studies reported AEs after HIVEC; the majorities were grade 1-2 AEs.
Summary:
Data coming from the studies published in the last years provides support for a consolidating role of device-assisted intravesical chemotherapy as a safe and effective alternative first- or second-line adjuvant treatment of patients with NMIBC.
Context
Currently, there is no standard of care for patients with non–muscle-invasive bladder cancer (NMIBC) who recur despite bacillus Calmette-Guerin (BCG) therapy. Although radical cystectomy is recommended, many patients decline to undergo or are ineligible to receive it. Multiple agents are being investigated for use in this patient population.
Objective
To systematically synthesize and describe the efficacy and safety of current and emerging treatments for NMIBC patients after treatment with BCG.
Evidence acquisition
A systematic literature search of MEDLINE, Embase, and the Cochrane Controlled Register of Trials (period limited to January 2007–June 2019) was performed. Abstracts and presentations from major conference proceedings were also reviewed. Randomized controlled trials were assessed using the Cochrane risk of bias tool. Data for single-arm trials were pooled using a random-effect meta-analysis with the proportions approach. Trials were grouped based on the minimum number of prior BCG courses required before enrollment and further stratified based on the proportion of patients with carcinoma in situ (CIS).
Evidence synthesis
Thirty publications were identified with data from 23 trials for meta-analysis, of which 17 were single arm. Efficacy and safety outcomes varied widely across studies. Heterogeneity across trials was reduced in subgroup analyses. The pooled 12-mo response rates were 24% (95% confidence interval [CI]: 16–32%) for trials with two or more prior BCG courses and 36% (95% CI: 25–47%) for those with one or more prior BCG courses. In a subgroup analysis, inclusion of ≥50% of patients with CIS was associated with a lower response.
Conclusions
The variability in efficacy and safety outcomes highlights the need for consistent endpoint reporting and patient population definitions. With promising emerging treatments currently in development, efficacious and safe therapeutic options are urgently needed for this difficult-to-treat patient population.
Patient summary
We examined the efficacy and safety outcomes of treatments for non–muscle-invasive bladder cancer after bacillus Calmette-Guerin therapy. Outcomes varied across studies and patient populations, but emerging treatments currently in development show promising efficacy.
Context:
This overview presents the updated European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ (CIS).
Objective:
To provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation and recommendations.
Evidence acquisition:
A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines has been performed annually since the last published version in 2017. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned.
Evidence synthesis:
Tumours staged as Ta, T1, and/or CIS are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of the tissue obtained by transurethral resection (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system. Stratification of patients into low-, intermediate-, and high-risk groups is pivotal to the recommendation of adjuvant treatment. In patients with tumours presumed to be at a low risk and in those presumed to be at an intermediate risk with a low previous recurrence rate and an expected EORTC recurrence score of <5, one immediate chemotherapy instillation is recommended. Patients with intermediate-risk tumours should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at the highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-unresponsive tumours. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.
Conclusions:
These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.
Patient summary:
The European Association of Urology Non-muscle-invasive Bladder Cancer (NMIBC) Panel has released an updated version of their guidelines, which contains information on classification, risk factors, diagnosis, prognostic factors, and treatment of NMIBC. The recommendations are based on the current literature (until the end of 2018), with emphasis on high-level data from randomised clinical trials and meta-analyses. Stratification of patients into low-, intermediate-, and high-risk groups is essential for deciding appropriate use of adjuvant intravesical chemotherapy or bacillus Calmette-Guérin (BCG) instillations. Surgical removal of the bladder should be considered in case of BCG-unresponsive tumours or in NMIBCs with the highest risk of progression.
Background
Urothelial bladder cancer (UBC) is the ninth most common cancer worldwide. In Italy, the prevalence of the disease is approximately 10%, making it the fourth most prevalent cancer in the country. The increase in prevalence requires continuous surveillance and care, resulting in a significant burden on Italian National Health Service, making any improvement to the strategy for diagnosing and treating this disease important to the medical and scientific community. The aim of this study was to evaluate the UBC cost of illness in the Italian context, collecting the total costs of the disease.
Methods
An economic analysis was carried out in the context of the National Health Service, using data collected from six centers, in order to evaluate direct costs in terms of outpatient, inpatient, and emergency care; pharmaceuticals and follow-up procedures; and indirect costs in terms of productivity losses. Data were collected through aggregated form reports, focusing on patients with an existing diagnosis of UBC who were treated in the last year. The Italian Association of Medical Oncology (AIOM) guidelines were used to identify diagnostic and therapeutic procedures. Statistical analysis was conducted to explore variations among centers.
Results
The weighted mean total annual cost per patient was € 3,591, where the cost for superficial disease was € 3,252 and that for metastatic disease was € 606. The analysis confirmed a proportional relation between disease severity and disability grade. The UBC cost of illness, considering prevalence and incidence data coming from the 2016 AIOM/Italian Association of Cancer Registries report, was € 1,187,036,344. Indirect costs accounted to 44%, represented by estimated productivity losses.
Conclusion
Our analysis represents the first economic study of UBC in the Italian context, as well as the first real-life evidence of the current therapeutic algorithm. This study opens the possibility for further analysis on the indirect cost components that represent a great burden for the society, especially for those in the severest stages of the disease with high disability grades.
Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.
Patients with high-grade muscle invasive bladder cancer (NMIBC) receive intravesical therapy with bacillus Calmette-Guérin (BCG) as the well-established standard-of-care. However, even with prompt induction of intravesical therapy, approximately 40 % of patients will recur within 2 years. For patients who fail BCG, options include radical cystectomy, repeat BCG therapy, or alternative intravesical salvage therapy. In this review, we will discuss the most recent published evidence on salvage intravesical therapy with an emphasis on a more in-depth report of our therapeutic strategy with sequential gemcitabine and docetaxel intravesical therapy for this treatment-refractory population. In addition, we will provide practical advice on our approach to this challenging patient population including the use of operative staging to aid early identification of treatment failures.
Background: Bacillus Calmette-Guerin (BCG) is the most effective intravesical therapy for non-muscle invasive bladder cancer
(NMIBC), but patients can fail or supply shortages can develop. For BCG failures, radical cystectomy is recommended. However,
in patients who desire bladder preservation or are poor surgical candidates, alternative salvage intravesical therapies should be
explored.
Objective: To determine whether dual sequential intravesical gemcitabine and docetaxel is effective in treating NMIBC.
Methods: We evaluated our initial experience with 45 patients treated with intravesical gemcitabine and docetaxel between
June 2009 and May 2014. Patients were treated with 6 weekly instillations of gemcitabine (1 gram of gemcitabine in 50 ml of
sterile water) followed immediately by docetaxel (37.5 mg of docetaxel in 50 mL of saline). Treatment success was defined as
no bladder cancer recurrence and no cystectomy. Intention-to-treat analysis was performed using the Kaplan Meier method.
Results: Forty-five patients received treatment with a median overall follow-up of 15 months. Median follow up for treatment
success was 6 months in all patients and 13 months for responders. Five patients were unable to tolerate a full induction course.
Treatment success was 66% at first surveillance, 54% at 1 year, and 34% at 2 years after initiating induction. Ten patients received
cystectomy (median of 5.6 months from starting induction) with no positive margins or lymph nodes on final pathology.
Conclusions: Sequential dual intravesical gemcitabine and docetaxel can salvage some patients in a challenging NMIBC cohort
Objectives:
The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of valrubicin.
Methods:
Patients ≥ 18 years with NMIBC who received had one or more instillations of valrubicin (October 2009- September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed.
Results:
The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed valrubicin treatment. The median age was 75 years (range 42-95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9-61.3%), 30.4% (20.4-41.1%), and 16.4% (7.9-27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5-4.0) months after the first valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued valrubicin because of adverse events or LARs.
Conclusions:
Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate valrubicin safety and efficacy in the broader patient population with NMIBC.
Radical cystectomy (RC) is a morbid procedure associated with high costs. Limited population-based data exist on the complication profile and costs of robot-assisted RC (RARC) compared with open RC (ORC).
To evaluate morbidity and cost differences between ORC and RARC.
We conducted a population-based, retrospective cohort study of patients who underwent RC at 279 hospitals across the United States between 2004 and 2010.
Multivariable logistic and median regression was performed to evaluate 90-d mortality, postoperative complications (Clavien classification), readmission rates, length of stay (LOS), and direct costs. To reduce selection bias, we used propensity weighting with survey weighting to obtain nationally representative estimates.
The final weighted cohort included 34 672 ORC and 2101 RARC patients. RARC use increased from 0.6% in 2004 to 12.8% in 2010. Major complication rates (Clavien grade ≥3; 17.0% vs 19.8%, p=0.2) were similar between ORC and RARC (odds ratio [OR]: 1.32; p=0.42). RARC had 46% decreased odds of minor complications (Clavien grade 1-2; OR: 0.54; p=0.03). RARC had $4326 higher adjusted 90-d median direct costs (p=0.004). Although RARC had a significantly shorter LOS (11.8 d vs 10.2 d; p=0.008), no significant differences in room and board costs existed (p=0.20). Supply costs for RARC were significantly higher ($6041 vs $3638; p<0.0001). Morbidity and cost differences were not present among the highest-volume surgeons (≥7 cases per year) and hospitals (≥19 cases per year). Limitations include use of an administrative database and lack of oncologic characteristics.
The use of RARC has increased between 2004 and 2010. Compared with ORC, RARC was associated with decreased odds of minor but not major complications and with increased expenditures attributed primarily to higher supply costs. Centralization of ORC and RARC to high-volume providers may minimize these morbidity and cost differences.
Using a US population-based cohort, we found that robotic surgery for bladder cancer decreased minor complications, had no impact on major complications and was more costly than open surgery.
Purpose:
Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated, but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon. We performed a multi-institutional phase II study within the SWOG (Southwest Oncology Group) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting.
Materials and methods:
Eligible patients had recurrent nonmuscle invasive bladder cancer, stage Tis (carcinoma in situ), T1, Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin. Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months. Cystoscopy and cytology were performed every 3 months, with biopsy at 3 months and then as clinically indicated. Initial complete response was defined as negative cystoscopy, cytology and biopsy at 3 months.
Results:
A total of 58 patients were enrolled in the study and 47 were evaluable for response. Median patient age was 70 years (range 50 to 88). Of the evaluable patients 42 (89%) had high risk disease, including high grade Ta in 12 (26%), high grade T1 in 2 (4%) and carcinoma in situ in 28 (60%) with or without papillary lesions. At the initial 3-month evaluation 47% of patients were free of disease. At 1 year disease had not recurred in 28% of the 47 patients, all except 2 from the high risk group, and at 2 years disease had not recurred in 21%.
Conclusions:
Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy. However, less than 30% of patients had a durable response at 12 months even with maintenance therapy.
To study the results of chemotherapy combined with intravesical hyperthermia in patients with mainly BCG-failing carcinoma in situ (CIS).
Patients with histologically confirmed CIS were included retrospectively. Outpatient thermochemotherapy treatment was done with mitomycin-C (MMC) and the Synergo system SB-TS 101 (temperature range between 41 and 44 degrees C), weekly for 6-8 weeks, followed by 4-6 sessions every 6-8 weeks.
Fifty-one patients were treated between 1997 and 2005 from 15 European centers. Thirty-four were pre-treated with BCG. Mean age was 69.9 years. Twenty-four patients had concomitant papillary tumors. The mean number of hyperthermia/MMC treatments per patient was 10.0. Of the 49 evaluable patients 45 had a biopsy and cytology proven complete response. In two patients CIS disappeared, but they had persistent papillary tumors. Follow-up of 45 complete responders showed 22 recurrences after a mean of 27 months (median 22): T2 (4), T1 (4), T1/CIS (1), CIS (5), Ta/CIS (2), Ta (5) and Tx (1). Side effects (bladder complaints) were generally mild and transient.
In patients with primary or BCG-failing CIS, treatment with intravesical hyperthermia and MMC appears a safe and effective treatment. The initial complete response rate is 92%, which remains approximately 50% after 2 years.
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Background: The PD-1 inhibitor pembro has durable antitumor activity in pts with metastatic urothelial carcinoma. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting pembro may benefit. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study; updated results for pts with carcinoma in situ (CIS) with or without papillary tumor (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary disease, who received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts with HR NMIBC or progressive disease during treatment were required to discontinue. Primary end point: complete response rate (CRR); key secondary end points: duration of response and safety. Results: 103 pts (median age 73 years; CIS alone 71.8%; median number of prior BCG instillations 12) have enrolled in cohort A. 3-mo CRR rate was 38.8% (95% CI 29.4%-48.9%) by central assessment. Among 40 pts who achieved CR at 3 mo, 72.5% maintained CR at last follow-up (median 14.0 mo; range 4.0-26.3) and median CR duration has not been reached (range 0+ to 14.1+ mo). 80.2% of pts had a CR duration of ≥6 mo (Kaplan-Meier method). 10 (25.0%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle invasive or metastatic disease. Treatment-related adverse events (AEs) occurred in 65 (63.1%) pts; most frequent were pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.6%) pts; 1 death was considered treatment-related (colitis in patient inadequately treated with steroids). Immune-mediated AEs occurred in 19 (18.4%) pts. Conclusions: Pembro had encouraging activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial. Clinical trial information: NCT02625961.
Background:
There is no effective intravesical second-line therapy for non-muscle-invasive bladder cancer (NMIBC) when bacillus Calmette-Guérin (BCG) fails.
Objective:
To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/maintenance BCG.
Design, settings, and participants:
Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 (HYMN [ClinicalTrials.gov: NCT01094964]).
Intervention:
Patients were randomly assigned (1:1) to RITE (60min, 40mg mitomycin-C, 42±2°C) or control following stratification for carcinoma in situ (CIS) status (present/absent), therapy history (failure of previous induction/maintenance BCG), and treatment centre.
Outcome measurements and statistical analysis:
Primary outcome measures were DFS and complete response (CR) at 3 mo for the CIS at randomisation subgroup. Analysis was based on intention-to-treat.
Results and limitations:
A total of 104 patients were randomised (48 RITE: 56 control). Median follow-up for the 31 patients without a DFS event was 36 mo. There was no significant difference in DFS between treatment arms (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.84-2.10, p=0.23) or in 3-mo CR rate in CIS patients (n=71; RITE: 30% vs control: 47%, p=0.15). There was no significant difference in DFS between treatment arms in non-CIS patients (n=33; RITE: 53% vs control: 24% at 24 mo, HR 0.50, 95% CI 0.22-1.17, p=0.11). DFS was significantly lower in RITE than in control in CIS with/without papillary patients (n=71; HR 2.06, 95% CI 1.17-3.62, p=0.01; treatment-subgroup interaction p=0.007). Disease progression was observed in four patients in each treatment arm. Adverse events and health-related quality of life between treatment arms were comparable.
Conclusions:
DFS was similar between RITE and control. RITE may be a second-line therapy for non-CIS recurrence following BCG failure; however, confirmatory trials are needed. RITE patients with CIS with/without papillary had lower DFS than control. HYMN highlights the importance of the control arm when evaluating novel therapies.
Patient summary:
This study did not show a difference in bladder cancer outcomes between microwave-heated chemotherapy and standard of care treatment. Papillary bladder lesions may benefit from microwave-heated chemotherapy treatment; however, more research is needed. Both treatments are similarly well tolerated.
Non-muscle-invasive bladder cancer (NMIBC), the most prevalent type of bladder cancer, accounts for ~75% of bladder cancer diagnoses. This disease has a 50% risk of recurrence and 20% risk of progression within 5 years, despite the use of intravesical adjuvant treatments (such as BCG or mitomycin C) that are recommended by clinical guidelines. Intravesical device-assisted therapies, such as radiofrequency-induced thermochemotherapeutic effect (RITE), conductive hyperthermic chemotherapy, and electromotive drug administration (EMDA), have shown promising efficacy. These device-assisted treatments are an attractive alternative to BCG, as issues with supply have been a problem in some countries. RITE might be an effective treatment option for some patients who have experienced BCG failure and are not candidates for radical cystectomy. Data from trials using EMDA suggest that it is effective in high-risk disease but requires further validation, and results of randomized trials are eagerly awaited for conductive hyperthermic chemotherapy. Considerable heterogeneity in patient cohorts, treatment sessions, use of maintenance regimens, and single-arm study design makes it difficult to draw solid conclusions, although randomized controlled trials have been reported for RITE and EMDA.
Purpose
Many patients with high-risk non–muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd–IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC.
Methods
In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd–IFNα/Syn3 (randomly assigned 1:1 to 1 × 10 ¹¹ viral particles (vp)/mL or 3 × 10 ¹¹ vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses.
Results
Forty patients received rAd–IFNα/Syn3 (1 × 10 ¹¹ vp/mL, n = 21; 3 × 10 ¹¹ vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd–IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%).
Conclusion
rAd—IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.
Patients with recurrent superficial bladder tumors have been treated by vesical and intradermal administration of Bacillus Calmette-Guerin. The pattern of recurrence in 9 patients has been altered favorably. Although the findings are still preliminary they appear to hold promise of a new therapeutic approach to the treatment of a group of neoplasms for which effective therapy is still lacking.
Patients with recurrent superficial bladder tumors have been treated by vesical and intradermal administration of Bacillus Calmette-Guerin. The pattern of recurrence in 9 patients has been altered favorably. Although the findings are still preliminary they appear to hold promise of a new therapeutic approach to the treatment of a group of neoplasms for which effective therapy is still lacking.
Purpose:
To provide recommendations on appropriate clinical trial designs in non-muscle-invasive bladder cancer (NMIBC) based on current literature and expert consensus of the International Bladder Cancer Group.
Methods:
We reviewed published trials, guidelines, meta-analyses, and reviews and provided recommendations on eligibility criteria, baseline evaluations, end points, study designs, comparators, clinically meaningful magnitude of effect, and sample size.
Results:
NMIBC trials must be designed to provide the most clinically relevant data for the specific risk category of interest (low, intermediate, or high). Specific eligibility criteria and baseline evaluations depend on the risk category being studied. For the population of patients for whom bacillus Calmette-Guérin (BCG) has failed, the type of failure (BCG unresponsive, refractory, relapsing, or intolerant) should be clearly defined to make comparisons across trials feasible. Single-arm designs may be relevant for the BCG-unresponsive population. Here, a clinically meaningful initial complete response rate (for carcinoma in situ) or recurrence-free rate (for papillary tumors) of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months is recommended. For other risk levels, randomized superiority trial designs are recommended; noninferiority trials are to be used sparingly given the large sample size required. Placebo control is considered unethical for all intermediate- and high-risk strata; therefore, control arms should comprise the current guideline-recommended standard of care for the respective risk level. In general, trials should use time to recurrence or recurrence-free survival as the primary end point and time to progression, toxicity, disease-specific survival, and overall survival as potential secondary end points. Realistic efficacy thresholds should be set to ensure that novel therapies receive due review by regulatory bodies.
Conclusion:
The International Bladder Cancer Group has developed formal recommendations regarding definitions, end points, and clinical trial designs for NMIBC to encourage uniformity among studies in this disease.
Hyperthermic mitomycin (HM) is a novel treatment modality for selected patients with high-risk non-muscle invasive bladder cancer (NMIBC). We sought to determine predictors of response to this therapy.
A longitudinal, cohort study of 97 patients with high-risk NMIBC treated with ≥4 HM instillations on a prophylactic schedule was conducted. The primary outcome was time-to-progression survival; secondary outcomes were overall survival, cancer-specific survival, and adverse events. Descriptive statistics, Kaplan-Meier survival analyses, Cox proportional hazards modelling, and univariate and multivariable regression were performed.
The presence of initial complete response (CR; no evidence of disease at first check video-cystoscopy and urine cytology) post-HM treatment was an independent predictor of good response to HM. Female patients and those without carcinoma in situ (CIS) also appeared to respond better to the intervention. The overall bladder preservation rate at a median of 27 months was 81.4%; 17/97 (17.5%) patients died during the course of the study.
High-risk NMIBC patients can be safely treated with HM and have good oncological outcome. However, those without an initial CR have a poor prognosis and should be counselled towards adopting other treatment methodologies such as cystectomy. Female gender and lack of CIS may be good prognostic indicators for response to HM. © 2015 S. Karger AG, Basel.
Bladder cancer (BC) is the fifth most commonly diagnosed cancer in the nation. Radical cystectomy (RC) is the most effective treatment for locally advanced bladder cancer and is a formidable operation. The perioperative mortality in high-volume centers ranges from 0.7 to 5.6%. Thus, when faced with this diagnosis, there is a desire to pursue a bladder-preserving strategy and avoid RC. One treatment for HG Ta/T1 and carcinoma in situ (CIS) is intravesical bacillus Calmette-Guérin (BCG) therapy. Many studies have confirmed its value in reducing tumor recurrence following transurethral resection of bladder tumors (TURBT). After reviewing the various guidelines, we summarize our recommendations for defining BCG failure.
Purpose
Patients with high-risk recurrences after BCG failure have limited options. We performed an open-label study to evaluate the efficacy and safety of intravesical MCNA in this setting.
Materials and Methods
Patients were treated intravesically with 8 mg MCNA weekly for 6 weeks followed by 3 weekly instillations at months 3, 6, 12, 18 and 24. Cystoscopy and cytology were performed every 3 months for 2 years, with mandatory biopsy at 6 months and then as clinically indicated. The primary efficacy endpoint was the DFS rate at 1 year.
Results
A total of 129 patients enrolled in the study; 91 had CIS, with or without papillary disease, and 38 had papillary only tumors. Most patients had high-risk disease: 107 were BCG-refractory, 68 received ≥2 prior BCG induction courses. Median duration of follow-up for all patients was 34.7 months. Overall DFS rate was 25.0% at 1 year and 19.0% at 2 years; for patients with papillary only tumors, DFS rate was 35.1% and 32.2% at 1 and 2 years, respectively. Median disease-free duration for the 30 responders was 32.7 months. PFS rate was 87.3%, 79.8% and 77.7% at 1, 2 and 3 years, respectively, with 28 patients experiencing a progression event. MCNA was very well tolerated and few AEs lead to treatment discontinuation.
Conclusions
Intravesical MCNA achieved significant activity in high-risk NMIBC patients who failed BCG treatment, especially in patients with papillary only tumors and in BCG-relapsing patients. Durable response is seen particularly in patients with a response at 1 year. MCNA offers an option for patients who are not candidates for or who refuse cystectomy.
Purpose
Nonmuscle invasive bladder cancer is characterized by a high recurrence rate. New adjuvant treatments are needed to decrease this high number of recurrences. We present the results of more than 10 years of experience with chemohyperthermia in patients with nonmuscle invasive bladder cancer.
Materials and Methods
Using standardized medical record forms we prospectively collected patient and tumor characteristics of patients treated with chemohyperthermia between 2002 and 2013. Median followup was 75.6 months. Recurrence-free survival was the primary objective. The secondary objective was to observe recurrence-free survival differences in 1) the epirubicin group vs the mitomycin group and 2) the highly recurrent (greater than 2 recurrences in 24 months) nonmuscle invasive bladder cancer group vs the other groups.
Results
A total of 160 patients with nonmuscle invasive bladder cancer were included in study, including 20 (13%) treated with epirubicin and 129 (81%) previously treated with bacillus Calmette-Guérin. One and 2-year recurrence-free survival was 60% and 47%, respectively. Muscle invasive progression was seen in 4% of cases. Two-year recurrence-free survival in the epirubicin and mitomycin groups was 55% and 46%, respectively (p = 0.30). The highly recurrent nonmuscle invasive bladder cancer group had significant decreased recurrence-free survival compared to other groups (p <0.01). Patients treated with 2 or fewer vs greater than 2 transurethral bladder tumor resections before chemohyperthermia had higher recurrence-free survival (p = 0.01). On multivariable analysis the highly recurrent cancer criteria remained independently associated with decreased recurrence-free survival (HR 2.40, 95% CI 1.30–4.43, p = 0.01).
Conclusions
Chemohyperthermia is an effective approach to nonmuscle invasive bladder cancer for which standard intravesical treatments fail. Patients with highly recurrent disease before chemohyperthermia have lower recurrence-free survival. Furthermore, recurrence-free survival appears to improve with earlier chemohyperthermia. No significant differences were observed between the 2 chemotherapy agents.
Purpose:
Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy.
Materials and methods:
This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months.
Results:
A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2.
Conclusions:
Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population.
PurposeWe report the 5-year followup of a randomized comparison of mitomycin C and bacillus Calmette-Guerin (BCG) in patients with superficial bladder carcinoma. Recurrence, progression and survival rates, crossover results, prognostic factors and long-term side effects were analyzed.Materials and MethodsA total of 261 patients were enrolled in the study, and the inclusion criteria were primary Tis, dysplasia G2, T1 G3 and multiple recurrent Ta/T1 G1-2 disease. Intravesical instillations of 40 mg. mitomycin C and 120 mg. Pasteur BCG, Danish strain 1331, were given for 2 years.ResultsAfter a median followup of 64 months 101 of the 250 evaluable patients (42%) were disease-free. A significant difference was noted in disease-free survival with BCG (p = 0.04), which was most pronounced for stage Tis disease. No difference in tumor progression, or crude or corrected survival was found between the 2 arms. Crossover treatment was successful in 39% of patients with second line BCG and 19% with second line mitomycin C. Independent risk factors for progression were initial p53 status and stage. Only the completion of treatment was predictive of outcome of patients treated with BCG. Bladder shrinkage occurred in 2.4% of patients.Conclusions
Therapy with BCG was superior to mitomycin C for recurrence prophylaxis but no difference was found for progression and survival.
Objective:
Apart from cystectomy, few treatment options exist for the management of bacillus Calmette-Guerin refractory non-muscle invasive bladder cancer (NMIBC). We report a multi-institutional experience with sequential intravesical combination chemotherapy using gemcitabine and mitomycin C (MMC) for NMIBC in the treatment of high-risk patients.
Methods:
We performed a retrospective review of patients who received 6 weekly treatments with sequential intravesical gemcitabine (1g) and MMC (40 mg) chemotherapy for NMIBC. Gemcitabine was administered first and retained for 90 minutes and then drained. MMC was then administered directly after and retained for an additional 90 minutes. Forty-seven patients received treatment from 3 academic tertiary referral centers between 2000 and 2010.
Results:
Forty-seven patients (median age 70, range 32-85; 36 males, 11 females) who previously failed a median of 2 intravesical treatments were reviewed. Complete response, 1-year, and 2-year recurrence-free survival rates for all patients were 68%, 48%, and 38%, respectively. Median recurrence-free survival for all patients was 9 months (range 1-80). Fourteen of 47 patients (30%) remained free of recurrence with a median time to follow-up of 26 months (range 6-80 mo). Ten patients required cystectomy.
Conclusion:
Sequential intravesical combination chemotherapy using gemcitabine and MMC appears to be a useful treatment for patients with high-grade NMIBC as well as those with prior bacillus Calmette-Guerin failure. Further prospective studies are warranted.
Purpose:
Docetaxel is a safe agent for intravesical therapy. Adding monthly maintenance treatments can extend response durability. We report our cumulative experience with intravesical docetaxel in a larger cohort with extended followup.
Materials and methods:
A total of 54 patients received salvage intravesical docetaxel for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer between 2003 and 2012, including 18 treated during the original phase I trial. All patients received 6 weekly instillations of intravesical docetaxel. After the phase I trial, those with a complete response to induction treatment were offered single dose monthly maintenance treatments for a total of up to 12 months of docetaxel therapy. Recurrence was defined as positive biopsy or urine cytology. Recurrence-free, disease specific and overall survival was determined by Kaplan-Meier analysis.
Results:
Median followup was 39.1 months. Of the 54 patients 32 (59%) had a complete initial response after induction therapy, including 18 who received additional monthly maintenance treatments. Median time to recurrence in initial responders treated with vs without docetaxel maintenance was 39.3 vs 19.0 months. One and 3-year recurrence-free survival rates for the entire cohort were 40% and 25%, respectively. Of the 54 patients 17 (24%) underwent radical cystectomy at a median of 24 months of followup. Five-year disease specific and overall survival rates were 85% and 71%, respectively.
Conclusions:
Intravesical docetaxel appears to be a promising agent with significant efficacy and durability for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. Adding maintenance treatments may increase the duration of recurrence-free survival.
The unpredictable behavior of carcinoma in situ and its high potential for recurrence and progression make identifying patient characteristics predicting a poor prognosis a priority. We assessed which factors affect the response to bacillus Calmette-Guérin plus interferon-α therapy in patients with urothelial carcinoma in situ.
We analyzed data on a subset of 231 patients with carcinoma in situ enrolled in a multicenter, phase II trial of bacillus Calmette-Guérin plus interferon-α therapy for nonmuscle invasive bladder cancer. Analysis included patients who were bacillus Calmette-Guérin naïve and those with previous exposure to failed bacillus Calmette-Guérin therapy. We evaluated factors potentially affecting the bacillus Calmette-Guérin plus interferon-α response, including patient age, gender, tumor stage, multifocality, prior tumor stage, the previous bacillus Calmette-Guérin failure pattern, courses and maintenance, and prior chemotherapy.
The complete response rate at 3 and 6 months in naïve vs previously failed bacillus Calmette-Guérin cases was 76% and 70% vs 76% and 66%, respectively. The 24-month disease-free rate was decreased in the 53 patients with a history of 2 or more failed bacillus Calmette-Guérin courses vs that in the 71 with a history of 1 failed course and bacillus Calmette-Guérin naïve patients (23% vs 57% and 60%, respectively). The 22 patients with refractory carcinoma in situ had the worst outcome of a 23% disease-free rate at 24 months while the 59 with relapse within 1 year had an intermediate outcome of 42% vs 59% in the 33 with relapse after 1 year. Patients with a history of papillary disease did better than those without such a history (p=0.019).
Factors associated with a poor response to bacillus Calmette-Guérin plus interferon-α therapy in patients with carcinoma in situ are prior tumor stage, 2 or more prior bacillus Calmette-Guérin failures and a bacillus Calmette-Guérin failure pattern.
Twelve patients with superficial bladder cancer who had failed one or two 6-week courses of intravesical bacillus Calmette-Guérin (BCG) therapy were treated with recombinant interferon-alfa-2b (rIFN-alfa-2b). Patients received 12 weekly instillations of rIFN-alfa-2b (100 MU) in 50 cc of normal saline. Those with an initial tumor-free response at the 3-month follow-up received maintenance rIFN-alfa-2b instillations (100 MU) monthly for an additional 9 months. Prior to rIFN-alfa-2b treatment, 6 patients had carcinoma in situ (CIS) with concurrent papillary tumor (pTa or pT I), and 6 had grades I or 2 pTa tumors. Patients were monitored every 3 months with urinary cytologies, cystoscopies, and biopsies when indicated. Median follow-up was 18 months (range 12 to 26 months). At the 3-month follow-up tumor recurrence was noted in 8 (66%) of 12 patients. An additional 3 (25%) patients had tumor recurrence at the 6-month follow-up period, and 3 (25%) patients also developed upper tract tumors during follow-up. Only 1 (8%) patient has maintained a continuous tumor-free response for 24 months. We are unable to demonstrate that rIFN-alfa-2b is likely to induce a tumor-free response in superficial bladder tumor patients who have failed intravesical BCG therapy, including those with CIS.
Radical cystectomy remains associated with significant morbidity. Most series report outcomes with relatively short-term followup that may underestimate the true magnitude of the procedure and many report length of hospital stay but ignore readmission rates. We analyzed the predictors of early (30 days or less), late (31 to 90 days) and cumulative 90-day hospital readmissions, as well as morbidity and mortality rates.
We reviewed our prospectively collected database of 753 patients who underwent radical cystectomy for urothelial cancer between January 2001 and December 2007. We examined the relationship between clinical variables and readmission rates during the early, late and 90-day postoperative period, and reviewed mortality and perioperative morbidity rates.
There were 200 (26.6%) patients readmitted in the first 90 days following radical cystectomy. Of these patients 148 (19.7%) were readmitted early, 81 (10.8%) were readmitted late, and 29 (3.9%) had an early and late readmission. Logistical regression revealed gender (OR 1.50, 95% CI 1.00-2.27, p = 0.05), age adjusted Charlson comorbidity index (OR 1.19, 95% CI 1.06-1.34, p = 0.003) and any postoperative complications before discharge home (OR 1.84, 95% CI 1.19-2.83, p = 0.006) as independent predictors of 90-day readmission. The 30 and 90-day mortality rates were 2.1% (16) and 6.9% (52), respectively.
Readmission rates after radical cystectomy are significant, approaching 27% within the first 90 days. Gender and age adjusted Charlson comorbidity index were independent predictors providing preoperative information identifying patients more likely to require readmission or possibly to benefit from a longer initial hospital stay.
Despite an initial adequate response many patients with nonmuscle invasive urothelial cell carcinoma of the bladder eventually have recurrence after intravesical bacillus Calmette-Guerin treatments. We evaluated the efficacy of combined bladder wall hyperthermia and intravesical mitomycin C instillation (thermo-chemotherapy) in cases of recurrence after bacillus Calmette-Guerin.
A total of 111 patients with recurrent papillary nonmuscle invasive urothelial cell carcinoma of the bladder after previous bacillus Calmette-Guerin treatment underwent complete bladder tumor resection and were referred for prophylactic adjuvant treatment with thermo-chemotherapy. Treatment was received on an outpatient basis weekly for 6 weeks, followed by 6 maintenance sessions at 4 to 6-week intervals. Each treatment included 2, 30-minute cycles of 20 mg mitomycin C and bladder wall hyperthermia to 42C +/- 2C. Cystoscopy and urine cytology were performed after the completion of induction treatment and every 3 months thereafter.
The Kaplan-Meier estimated disease-free survival rate was 85% and 56% after 1 and 2 years, respectively. No maintenance treatment was associated with decreased efficacy, that is the recurrence rate was 61% at 2 years vs 39% in those with maintenance treatments (p = 0.01). The progression rate was 3%.
Thermo-chemotherapy may be effective for papillary nonmuscle invasive urothelial cell carcinoma of the bladder that recurs after BCG treatment without increasing the risk of tumor progression. Maintenance therapy is important and improves the outcome.
We performed intravesical electromotive drug administration (EMDA) for various bladder disorders during a 3-year period and assessed the technique, possible applications, complications and outcomes of this procedure.
Intravesical EMDA was performed with local anesthetics for transurethral surgery and in combination with dexamethasone for the treatment of noninfectious chronic cystitis (interstitial/radiation cystitis), with mitomycin C for recurrence prophylaxis of high risk superficial bladder cancer and with oxybutynin/bethanechol for the hyperreflexive/acontractile detrusor. A standardized power source and electrode catheter were used for 215 treatments in 84 patients.
Transurethral bladder tumor resections were pain-free in 10 of 12 patients. Of the 25 patients with chronic noninfectious cystitis 15 were free of symptoms for a mean of 6.6 months, and there was a 73% increase in mean bladder capacity from 244 before to 421 cc after EMDA. Of the 16 patients with superficial bladder cancer 9 were free of recurrence for a mean of 14.1 months. In 10 of 14 patients with acontractile detrusors urodynamic examination showed detrusor contraction during EMDA of bethanechol. There were no contractions without electric current. EMDA of oxybutynin reduced detrusor hyperreflexia. A bladder ulcer was the single severe local complication and 4.6% of patients, mainly those with chronic cystitis, reported significant post-EMDA bladder/urethral pain. Minor side effects accounted for 23% of all treatments. No systemic side effects occurred.
Intravesical EMDA is effective and innocuous. The therapeutic concept combines the advantages of increased drug administration without systemic side effects.
We assess the efficacy and safety of intravesical valrubicin for the treatment of carcinoma in situ in patients with failure or recurrence after bacillus Calmette-Guerin (BCG) and who otherwise would have undergone cystectomy. Total anthracycline recovery in urine samples obtained within 24 hours of valrubicin administration was assessed in a subset of patients.
A total of 90 patients with recurrent carcinoma in situ after failed multiple prior courses of intravesical therapy, including at least 1 course of BCG, participated in this open label, noncomparative study. Each patient received 6 weekly instillations of 800 mg. intravesical valrubicin. Disease evaluations were made at baseline and 3-month intervals following treatment. Evaluations included cystoscopy with biopsy and urine cytology. Toxicity was noted throughout treatment and followup. No evidence of disease recurrence for 6 months or greater was considered a complete response.
Of 90 patients 19 (21%) had a complete response, including 7 who remained disease-free at the last evaluation, with a median followup of 30 months. Additionally, 14 patients who did not meet the strict protocol definition of complete response had superficial Ta disease only. Median time to failure and/or last followup for complete responders was greater than 18 months. Recurrence has been noted in 79 patients to date, including only 2 with clinically advanced disease (stage T2). Of these 79 patients 44 (56%, 4 responders and 40 nonresponders) underwent radical cystectomy. Of the 41 patients with known pathological stage 6 (15%) had stage pT3 or greater at cystectomy. Four patients died of bladder cancer during the median followup of 30 months, none of whom was a complete responder or underwent cystectomy following valrubicin. The main side effects of valrubicin therapy were reversible local bladder symptoms.
Valrubicin was effective and well tolerated in patients with carcinoma in situ of the bladder refractory to BCG therapy. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an undue risk to most patients.
We determined whether photodynamic therapy after the oral administration of 5-aminolevulinic acid in patients with superficial bladder cancer that cannot be controlled by transurethral resection and intravesical bacillus Calmette-Guerin (BCG) immunotherapy would preserve the bladder, while stopping tumor progression. Side effects of treatment were also assessed.
We performed photodynamic therapy after the oral administration of 5-aminolevulinic acid in 24 patients with rapidly recurring, multifocal, BCG refractory superficial pTa-pT1 transitional cell carcinoma of the bladder and carcinoma in situ.
At a median followup of 36 months (range 12 to 51) 3 of the 5 patients with carcinoma in situ and 4 of the 19 with papillary tumors were free of recurrence. Three patients were rendered disease-free by repeat photodynamic therapy with 5-aminolevulinic acid and 3 underwent cystectomy. Tumor progression was stopped in 20 of our 24 cases. Immediately after the oral administration of 5-aminolevulinic acid hypotension and tachycardia occurred in 19 and 10 patients, respectively, with previously known severe cardiovascular disease. No phototoxic skin reaction or decreased bladder capacity was observed.
These initial clinical results suggest that photodynamic therapy with orally administered 5-aminolevulinic acid is effective as an organ preserving procedure for treating superficial bladder cancer even in patients with bacillus Calmette-Guerin refractory carcinoma. One should be aware of hemodynamic instability after the oral administration of 5-aminolevulinic acid, particularly in patients with cardiovascular co-morbidity.
In laboratory studies electromotive mitomycin C (MMC) demonstrated markedly increased transport rates compared with passive transport. We performed a prospective study in patients with high risk superficial bladder cancer to assess the efficacy of intravesical electromotive vs passive MMC using bacillus Calmette-Guerin (BCG) as a comparative treatment.
Following transurethral resection and multiple biopsies 108 patients with multifocal Tis, including 98 with T1 tumors, were randomized into 3 equal groups of 36 each who underwent 40 mg electromotive MMC instillation with 20 mA electric current for 30 minutes, 40 mg passive MMC with a dwell time of 60 minutes or 81 mg BCG with a dwell time of 120 minutes. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders and a followup 10 monthly treatments for responders. Primary end points were the complete response rate at 3 and 6 months. MMC pharmacokinetics were assessed.
The complete response for electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p = 0.036) and 58% versus 31% (p = 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p = 0.013) and for BCG it was 26 months. Peak plasma MMC was significantly higher following electromotive MMC than after MMC (43 vs 8 ng/ml), consistent with bladder content absorption.
Intravesical electromotive administration increases bladder uptake of MMC, resulting in an improved response rate in cases of high risk superficial bladder cancer.
The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer.
After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website .
Median follow-up was 88 months (IQR 63-110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months [95% CI 55-86] vs 21 months [15-54]; difference between groups 48 months [42-54], log-rank p=0.0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41.9% [32.7-51.5] vs 57.9% [48.7-67.5]; difference between groups 16.0% [2.7-29.3], log-rank p=0.0012); progression (9.3% [3.8-14.8] vs 21.9% [17.9-25.9]; difference between groups 12.6% [3.0-22.2], log-rank p=0.004); overall mortality (21.5% [13.5-29.5] vs 32.4% [23.4-41.4], difference between groups 10.9% [0.6-21.2], log-rank p=0.045); and disease-specific mortality (5.6% [1.2-10.0] vs 16.2% [6.1-23.3], difference between groups 10.6% [2.5-18.7], log-rank p=0.01). Side-effects were mainly localised to the bladder.
BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.
We present the characteristics and outcomes of a large, contemporary, consecutive series of patients treated with radical cystectomy and pelvic lymphadenectomy for transitional cell carcinoma of the bladder.
We developed a multi-institutional database and collected retrospective and prospective data on 888 consecutive patients with bladder transitional cell carcinoma who were treated with radical cystectomy and pelvic lymphadenectomy at 3 academic centers in the United States between 1984 and 2003.
Of the patients 25% had extravesical tumor extension with negative lymph nodes and 23% had lymph node metastasis. The rate of lymph node involvement increased with advancing pathological stage. Mean recurrence-free and bladder cancer specific survival +/- SE was 58% +/- 2% and 66% +/- 2% at 5 years, respectively. On preoperative multivariate analysis clinical tumor stage and neoadjuvant systemic chemotherapy were associated with cancer recurrence, while more advanced age, clinical tumor stage and preoperative carcinoma in situ were associated with bladder cancer specific mortality. On postoperative multivariate analysis pathological tumor stage, lymph node metastasis, lymphovascular invasion, adjuvant radiotherapy and adjuvant chemotherapy were associated with cancer recurrence, while higher pathological tumor stage, more advanced age, lymph node metastasis, lymphovascular invasion and adjuvant radiotherapy were associated with disease specific survival. Patients with metastasis to regional lymph nodes (pT any N1-3) were at significantly higher risk for bladder cancer recurrence and death than patients with extravesical tumor extension (pT3N0), who in turn were at significantly higher risk than patients with organ confined disease (pT2 N0 or less).
The results of this large, contemporary, multi-institutional series show that radical cystectomy and pelvic lymphadenectomy provide durable local control and disease specific survival in patients with localized invasive transitional cell carcinoma.
Historically patients with recurrent T1 bladder tumors after bacillus Calmette-Guerin have been treated with bladder sparing approaches. Recently a paradigm shift has occurred since patients are increasingly offered radical cystectomy before disease progression to muscle invasion. In this study we explored the effect of this paradigm shift on progression rates and disease specific survival.
The historical cohort consisted of 307 patients from 3 prospective intravesical bacillus Calmette-Guerin protocols from 1980 to 1989. An institutional review board approved review identified 589 patients treated with bacillus Calmette-Guerin in a contemporary cohort from 1992 to 2004.
In the historical cohort the 85 patients with documented T1 recurrence were initially treated with repeat transurethral resection and intravesical bacillus Calmette-Guerin. Of these 85 patients 60 had progression to muscle invasive disease. At 5 years after T1 recurrence, the cumulative incidence of progression to T2 disease was 71% (95% CI 61%, 81%) and the cumulative incidence of death from disease was 48% (95% CI 39%, 60%). In the contemporary cohort 129 patients had documented T1 recurrence. In this cohort 65 of the 129 patients with recurrent T1 underwent immediate radical cystectomy. At 5 years after T1 recurrence, the cumulative incidence of progression to muscle invasive disease was 28% (95% CI 20%, 38%) and the cumulative incidence of death from disease was 31% (95% CI 22%, 42%).
Preemptive radical cystectomy performed for recurrent T1 disease following intravesical bacillus Calmette-Guerin therapy may be associated with better disease specific survival.
Electro-motive drug administration (EMDA) of intravesical mitomycin-C in patients with high-risk non-invasive bladder cancer and failure of BCG immunotherapy
- Sockett
Tumours of the urinary system: non-invasive urothelial neoplasias.
- Sauter G.
- Algaba F.
- Amin M.
Tumours of the urinary system: non-invasive urothelial neoplasias
- Sauter