Alternative therapies in patients with non-muscle invasive bladder cancer.

Bladder cancer (BC) is one of the leading causes of cancer-related deaths worldwide. Despite, the majority of the cases were diagnosed as non-muscle invasive bladder cancer (NMIBC) with favorable prognosis, it has tendency to recur or progress to a higher grade or stage. The first line treatment of patients with NMIBC is transurethral resection with adjuvant therapies primarily intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. However, in a portion of patients whose BCG treatment failed, alternative treatments may be required. Furthermore, intravesical BCG may be contraindicated in or untolerated by a group of patients. For these patients, some treatment options are readily available and a variety of them are currently under clinical investigation. In this review, these alternative therapies have been summarized.

Guideline of guidelines: non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) represents the vast majority of bladder cancer diagnoses, but this definition represents a spectrum of disease with a variable clinical course, notable for significant risk of recurrence and potential for progression. Management involves risk-adapted strategies of cystoscopic surveillance and intravesical therapy with the goal of bladder preservation when safe to do so. Multiple organizational guidelines exist to help practitioners manage this complicated disease process, but adherence to management principles among practising urologists is reportedly low. We review four major organizational guidelines on NMIBC: the American Urological Association (AUA)/Society of Urologic Oncology (SUO), European Association of Urology (EAU), National Comprehensive Cancer Network (NCCN), and National Institute for Health and Care Excellence (NICE) guidelines.

An initial negative round of targeted biopsies in men with highly suspicious multiparametric magnetic resonance findings does not exclude clinically significant prostate cancer-Preliminary experience.

BACKGROUND: Targeted prostate biopsies are changing the landscape of prostate cancer (PCa) diagnosis with the degree of suspicion on multiparametric magnetic resonance imaging (mpMRI) being a strong predictor of targeted biopsy outcome. Data regarding the rate and potential causes of false-negative magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion-targeted biopsy in patients with highly suspicious mpMRI findings are lacking. OBJECTIVES: To determine the rate of clinically significant PCa detection in repeat targeted biopsy or surgery in patients with highly suspicious mpMRI findings and in an initial negative MRI-TRUS fusion-targeted biopsy. MATERIALS AND METHODS: In this single-center, retrospective study of prospectively generated data, men with highly suspicious lesions (Likert 5 score) on mpMRI and an initial negative MRI-TRUS fusion-targeted biopsy were reviewed. The rate of PCa detection in a subsequent MRI-TRUS fusion-targeted biopsy or radical prostatectomy was determined. Tumors in the intermediate- and high-risk groups according to the National Comprehensive Cancer Network criteria were considered clinically significant. RESULTS: A total of 32 men with 38 Likert 5 lesions were identified. Repeat targeted biopsy or surgery detected cancer in 42% (16/38) of the Likert 5 lesions with initial negative targeted biopsy. Most of these cancers were intermediate- (69%; 11/16) or high-risk (25%; 4/16) tumors. CONCLUSION: A negative round of targeted biopsies does not exclude clinically significant PCa in men with highly suspicious mpMRI findings. Patients with imaging-pathology disagreement should be carefully reviewed and considered for repeat biopsy or for strict surveillance.

Comparison of prostate cancer detection at 3-T MRI with and without an endorectal coil: A prospective, paired-patient study.

OBJECTIVES: To compare the sensitivity of 2 different non-endorectal coil strategies vs. endorectal coil (ERC) magnetic resonance imaging (MRI) for detection of prostate cancer (PCa). METHODS: In this prospective, single-center, paired-patient, paired-reader study, 49 men with a clinical indication for MRI underwent non-ERC (phased-array coil only) T2-weighted imaging and diffusion-weighted imaging followed by the same sequences using both ERC and phased-array coils (ERC Protocol). Patients were randomized into 1 of 2 arms: standard non-ERC protocol and augmented non-ERC protocol. Lesions with Likert score≥3 were defined as suspicious for cancer. Radical prostatectomy specimen or combined systematic plus targeted biopsies served as the standard of reference. Cancers were stratified into risk groups according to the National Comprehensive Cancer Network guidelines. Generalized estimating equations with Bonferroni correction were used for comparisons. The level of reader confidence was inferred by the Likert scores assigned to index lesions. RESULTS: The ERC protocol provided sensitivity (78%) superior to MRI without ERC for PCa detection, both with a standard (43%) (P<0.0001) or augmented (60%) (P<0.01) protocol. The ERC MRI missed less-intermediate or high-risk index lesions (4%) than standard non-ERC (42%) (P = 0.02) and augmented non-ERC MRI (25%), although the latter did not reach significance (P = 0.09). The ERC improved radiologist confidence for the detection of PCa (average Likert score = 4.2±1.4) compared to standard (2.3±2.3) and augmented (2.9±2.1) non-ERC (P = 0.001). CONCLUSIONS: The use of combined ERC and pelvic phased-array coil for T2-weighted imaging and diffusion-weighted imaging provides superior sensitivity for the detection of PCa compared to an examination performed without the ERC.

Impact of peri-operative blood transfusion on the outcomes of patients undergoing radical cystectomy for urothelial carcinoma of the bladder.

OBJECTIVE: To determine the association between peri-operative blood transfusion (PBT) and oncological outcomes in a large multi-institutional cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS: We conducted a retrospective analysis of 2895 patients treated with RC for UCB. Univariable and multivariable Cox regression models were used to analyse the effect of PBT administration on disease recurrence, cancer-specific mortality, and any-cause mortality. RESULTS: Patients' median (interquartile range [IQR]) age was 67 (60, 73) years and the median (IQR) follow-up was 36.1 (15, 84) months. Patients who received PBT were more likely to have advanced disease (P < 0.001), high grade tumours (P = 0.047) and nodal metastasis (P = 0.004). PBT was associated with a higher risk of disease recurrence (P = 0.003), cancer-specific mortality (P = 0.017), and any-cause mortality (P = 0.010) in univariable, but not multivariable, analyses (P > 0.05). In multivariable analyses, pathological tumour stage, pathological nodal stage, soft tissue surgical margin, lymphovascular invasion and administration of adjuvant chemotherapy were independent predictors of disease recurrence, cancer-specific mortality and any-cause mortality (all P values <0.002). CONCLUSIONS: Patients with UCB who underwent RC and received PBT had a greater risk of disease recurrence, cancer-specific mortality and any-cause mortality in univariable, but not multivariable, analysis. Although the greater need for PBT with more advanced disease is probably caused by a number of factors, including surgical and cancer-related factors, the present analysis showed that the disease characteristics rather than need for PBT led to worse outcomes.

Evaluation of vitamin E and selenium supplementation for the prevention of bladder cancer in SWOG coordinated SELECT.

PURPOSE: Epidemiological and biological evidence suggests a preventive effect of selenium and vitamin E on bladder cancer. We assessed the effect of selenium and/or vitamin E on bladder cancer development. MATERIALS AND METHODS: This was a secondary analysis of the randomized, placebo controlled SELECT (Selenium and Vitamin E Cancer Prevention Trial), which included 34,887 men randomly assigned to 4 groups (selenium, vitamin E, selenium plus vitamin E and placebo) in double-blind fashion between August 22, 2001 and June 24, 2004. The primary end point was bladder cancer incidence, as determined by routine clinical management. RESULTS: During a median followup of 7.1 years (IQR 6.4-8.0) 224 bladder cancer cases were recorded. Patients with bladder cancer were older, and more likely to be white and have a smoking history than those without bladder cancer. Most cancers were urothelial and nonmuscle invasive. There was no significant difference in the bladder cancer incidence between the 53 men in the placebo group and the 56 in the vitamin E group (HR 1.05, IQR 0.64-1.73, p=0.79), the 60 in the selenium group (HR 1.13, 0.70-1.84, p=0.52) or the 55 in the vitamin E plus selenium group (HR 1.05, 0.63-1.70, p=0.86). CONCLUSIONS: This secondary analysis showed no preventive effect of selenium or vitamin E alone or combined on bladder cancer in this population of men. Further studies are needed to assess the effect in women, and at different doses and formulations.

Select screening in a specific high-risk population of patients suggests a stage migration toward detection of non-muscle-invasive bladder cancer.

BACKGROUND: More than 25% of bladder cancer (BC) cases are still muscle-invasive at first diagnosis. Screening is unproven to enable the detection of more non-muscle-invasive tumors. BC association with aristolochic acid nephropathy (AAN) was reported after intake of slimming pills containing Chinese herbs. OBJECTIVE: We evaluated whether a BC screening protocol in a high-risk and unique patient population had an impact on the stage of tumor presentation. DESIGN, SETTING, AND PARTICIPANTS: Forty-eight AAN-affected patients were enrolled in a screening program, establishing BC incidence during prospective screening cystoscopies and biopsies biannually for up to 10 yr. Two patients were lost to follow-up, and three refused screening after consenting. MEASUREMENTS: Patients were evaluated for presence of BC and tumor stage at diagnosis. RESULTS AND LIMITATIONS: BC was diagnosed in 25 patients (52%). Among 43 patients who underwent screening cystoscopies (median follow-up: 94 mo), 22 were first diagnosed with non-muscle-invasive BC but none with muscle-invasive tumors and none died of BC. Three women who declined follow-up were diagnosed and died with advanced metastatic disease. The limitations of our findings include the small sample size of this case series, the absence of a real control group, and the particular risk factor in these patients that differs from the usual risk factors, such as smoking or industrial chemicals. CONCLUSIONS: BC screening in high-risk groups may allow identification of tumors before muscle invasion. The optimal screening schedule and the relevance of the present findings in smoking-related BC remain to be defined.

Phase I dose-escalation study of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer.

PURPOSE: To evaluate the tolerability of escalating doses of stereotactic body radiation therapy in the treatment of localized prostate cancer. PATIENTS AND METHODS: Eligible patients included those with Gleason score 2 to 6 with prostate-specific antigen (PSA) ≤ 20, Gleason score 7 with PSA ≤ 15, ≤ T2b, prostate size ≤ 60 cm(3), and American Urological Association (AUA) score ≤ 15. Pretreatment preparation required an enema and placement of a rectal balloon. Dose-limiting toxicity (DLT) was defined as grade 3 or worse GI/genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 3). Patients completed quality-of-life questionnaires at defined intervals. RESULTS: Groups of 15 patients received 45 Gy, 47.5 Gy, and 50 Gy in five fractions (45 total patients). The median follow-up is 30 months (range, 3 to 36 months), 18 months (range, 0 to 30 months), and 12 months (range, 3 to 18 months) for the 45 Gy, 47.5 Gy, and 50 Gy groups, respectively. For all patients, GI grade ≥ 2 and grade ≥ 3 toxicity occurred in 18% and 2%, respectively, and GU grade ≥ 2 and grade ≥ 3 toxicity occurred in 31% and 4%, respectively. Mean AUA scores increased significantly from baseline in the 47.5-Gy dose level (P = .002) as compared with the other dose levels, where mean values returned to baseline. Rectal quality-of-life scores (Expanded Prostate Cancer Index Composite) fell from baseline up to 12 months but trended back at 18 months. In all patients, PSA control is 100% by the nadir + 2 ng/mL failure definition. CONCLUSION: Dose escalation to 50 Gy has been completed without DLT. A multicenter phase II trial is underway treating patients to 50 Gy in five fractions to further evaluate this experimental therapy.

In vitro assessment of the efficacy of thermal therapy in human renal cell carcinoma.

OBJECTIVES: To define the temperature-time points that result in cell death in a human renal cell carcinoma cell (RCC) line in vitro. METHODS: Cellular viability and clonogenic cell survival were determined for human A498 RCC cells after thermal treatment. Various temperature (45 degrees C to 70 degrees C) and time (1 to 30 minutes) combinations were used. Cell viability was assessed by vital dye uptake and clonogenic cell survival. Mathematical Arrhenius modeling was performed to construct a graphic display of A498 cell thermal sensitivity. RESULTS: Temperature-time points at which 99% or greater cell death occurred according to the vital dye assay were 55 degrees C for 30 minutes, 60 degrees C for 10 minutes, and 65 degrees C for 8 minutes. Clonogenic survival studies confirmed that cells treated at these temperature-time points failed to grow even after 10 days. CONCLUSIONS: These in vitro results show that short exposure to temperatures higher than 70 degrees C is lethal in the A498 RCC cell line. Lower temperatures in the 60 degrees C range require more prolonged heating to cause cell death. Knowledge of these temperatures will be useful to better plan and monitor complex radiofrequency ablations.

Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy.

PURPOSE: We hypothesized that bladder cancer patients with associated lymphovascular invasion (LVI) are at increased risk of occult metastases. METHODS: A multi-institutional group (University of Texas Southwestern [Dallas, TX], Baylor College of Medicine [Houston, TX], Johns Hopkins University [Baltimore, MD]) carried out a retrospective study of 958 patients who underwent cystectomy for bladder cancer between 1984 and 2003. Of patients with transitional-cell carcinoma (n = 776), LVI status was available for 750. LVI was defined as the presence of tumor cells within an endothelium-lined space. RESULTS: LVI was present in 36.4% (273 of 750) overall, involving 26% (151 of 581) and 72% (122 of 169) of node-negative and node-positive patients, respectively. Prevalence of LVI increased with higher pathologic stage (9.0%, 23%, 60%, and 78%, for T1, T2, T3, and T4, respectively; P < .001). Using multivariate Cox regression analyses including age, stage, grade, and number of pelvic lymph nodes removed, LVI was an independent predictor of local (HR = 2.03, P = .049), distant (HR = 2.60, P = .0011), and overall (HR = 2.02, P = .0003) recurrence in node-negative patients. LVI was an independent predictor of overall (HR = 1.84, P = .0002) and cause-specific (HR = 2.07, P = .0012) survival in node-negative patients. LVI maintained its independent predictor status in competing risks regression models (P = .013), where other-cause mortality was considered as a competing risk. LVI was not a predictor of recurrence or survival in node-positive patients. CONCLUSION: LVI is an independent predictor of recurrence and decreased cause-specific and overall survival in patients who undergo cystectomy for invasive bladder cancer and are node-negative. These patients represent a high risk group that may benefit from integrated therapy with cystectomy and perioperative systemic chemotherapy.