High-grade T1 Urothelial Carcinoma: Where Do We Stand?

PURPOSE OF REVIEW: Bladder cancer is a deadly and common malignancy, with 24% of new cases presenting as T1 disease. High-grade T1 in particular represents a difficult entity to treat due to its clinical variability and known risks of recurrence, progression, and cancer-specific mortality. The differences in guidelines from major urologic organizations underscore this variability, and the past year has seen another BCG shortage, further complicating management. Advances have been made in the molecular and genomic characterization of high-grade T1, and new clinical trials are available to investigate alternative therapies. In this review, we summarize the variations in guidelines, alternatives to BCG, emerging molecular and genomic discoveries, and recent clinical trials. RECENT FINDINGS: Adherence to guidelines for non-muscle-invasive bladder cancer in the community among practicing urologists remains low, in part due to the variations in available guidelines. In the era of a BCG shortage, decreased dosing schedules and alternative intravesical options are increasingly being used. New biomarkers are being discovered to better risk-stratify patients, with future therapies aimed at targeting aggressive disease. HGT1 urothelial carcinoma remains a highly variable and aggressive disease, but we are making significant progress in better characterizing the clinical and molecular factors that influence recurrence and progression, to better guide management.

Urothelial carcinoma with villoglandular differentiation (UCVGD) with small cell neuroendocrine carcinoma of urinary bladder.

Urothelial carcinoma with villoglandular differentiation (UCVGD) is a rare aggressive variant of urothelial carcinoma. It is usually associated with high-grade urothelial carcinoma or rarely adenocarcinoma. There is only one other previous report of UCVGD associated with small cell neuroendocrine carcinoma of urinary bladder. We report the second case of UCVGD with small cell neuroendocrine carcinoma of urinary bladder in a 74-year-old non-smoker male patient. The mass was muscle invasive and also invaded the prostate. This entity needs to be confidently diagnosed due to its prognostic and therapeutic implications.

Recent advances in upper tract urothelial carcinomas: From bench to clinics.

Urothelial carcinoma in the upper tract is rare and often discussed separately. Many established risk factors were identified for the disease, including genetic and external risk factors. Radiographic survey, endoscopic examination and urine cytology remained the most important diagnostic modalities. In localized upper tract urothelial carcinomas, radical nephroureterectomy with bladder cuff excision are the gold standard for large, high-grade and suspected invasive tumors of the renal pelvis and proximal ureter, whereas kidney-sparing surgeries should be considered in patients with low-risk disease. Advances in technology have given endoscopic surgery an important role, not only in diagnosis, but also in treatment. Although platinum-based combination chemotherapy is efficacious in advanced or metastatic disease, current established chemotherapy regimens are toxic and lack a sustained response. Immune checkpoint inhibitors have led to a new era of treatment for advanced or metastatic urothelial carcinomas. The remarkable results achieved thus far show that immunotherapy will likely be the future treatment paradigm. The combination of immune checkpoint inhibitors and other agents is another inspiring avenue to explore that could benefit even more patients. With respect to the high incidence rate and different clinical appearance of upper tract urothelial carcinomas in Taiwan, a possible correlation exists between exposure to certain external risk factors, such as arsenic in drinking water and aristolochic acid in Chinese herbal medicine. As more gene sequencing differences between upper tract urothelial carcinomas and various disease causes are detailed, this has warranted the era of individualized screening and treatment for the disease.

ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer.

PURPOSE: To provide a summary of the Third International Consultation on Bladder Cancer recommendations for the management of non-muscle invasive bladder cancer (NMIBC). METHODS: A detailed review of the literature was performed focusing on original articles for the management of NMIBC. An international committee assessed and graded the articles based on the Oxford Centre for Evidence-based Medicine system. The entire spectrum of NMIBC was covered such as prognostic factors of recurrence and progression, risk stratification, staging, management of positive urine cytology with negative white light cystoscopy, indications of bladder and prostatic urethral biopsies, management of Ta low grade (LG) and high risk tumors (Ta high grade [HG], T1, carcinoma in situ [CIS]), impact of BCG strain and host on outcomes, management of complications of intravesical therapy, role of alternative therapies, indications for early cystectomy, surveillance strategies, and new treatments. The working group provides several recommendations on the management of NMIBC. RESULTS: Recommendations were summarized with regard to staging; management of primary and recurrent LG Ta and high risk disease, positive urine cytology with negative white light cystoscopy and prostatic urethral involvement; indications for timely cystectomy; and surveillance strategies. CONCLUSION: NMIBC remains a common and challenging malignancy to manage. Accurate staging, grading, and risk stratification are critical determinants of the management and outcomes of these patients. Current tools for risk stratification are limited but informative, and should be used in clinical practice when determining diagnosis, surveillance, and treatment of NMIBC.

Choline-phosphate cytidylyltransferase-α as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder.

OBJECTIVES: The aim of this study was to test choline-phosphate cytidylyltransferase-α (CCT-α) protein as a biomarker for neoadjuvant cisplatin chemotherapy response in a bladder tumor setting. MATERIALS AND METHODS: A total of 238 patients with T2-T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant cisplatin-based chemotherapy (NAC) plus cystectomy with cystectomy only (no-NAC) were used as discovery and validation cohorts. Protein expression was determined with immunohistochemistry and assessed with Histo (H)-scoring. RESULTS: In the discovery cohort, comprising 61 patients, the survival ratio after NAC treatment for CCT-α-negative patients was significantly increased (p = 0.001) while there was no survival advantage in the CCT-α-positive patient group. Similarly, in the validation cohort with 177 patients, NAC treatment improved survival only in the CCT-α-negative group (p = 0.006). Although there was a tendency for a good NAC response with negative CCT-α status, the interaction variable between biomarker and treatment was not significant (p = 0.24). In the cystectomy-only group, patients with positive CCT-α expression had a better survival than CCT-α-negative patients. This prognostic effect of CCT-α expression remained significant after adjusting for well-known prognostic factors in a multivariate analysis. In a pooled database of both patient data sets, multivariate analyses showed CCT-α status as an independent factor for overall survival (p = 0.018; hazard ratio = 1.80, 95% confidence interval 1.11-2.93). CONCLUSION: CCT-α status was not predictive of outcome of NAC response; however, in the control group with cystectomy only it was found to have prognostic value.

Can bladder preservation therapy come to the center stage?

Decision-making in urological cancer care requires a multidisciplinary approach for refinement, but its impact on urothelial carcinoma of the bladder has not been fully addressed for the past three decades, except for the latest immunological checkpoint inhibitor approved by the U.S. Food and Drug Administration for metastatic muscle-invasive bladder cancer that is resistant to platinum-based chemotherapy. For the time being, radical cystectomy is the gold standard of curative therapy for muscle-invasive bladder cancer. Trimodal therapy that combines chemotherapy for the purpose of radiation sensitization, external beam radiotherapy and transurethral resection of bladder tumor has emerged as a potential alternative treatment option that preserves the bladder. In lack of randomized studies for bladder preservation therapy compared with surgery, the principles of management of urothelial carcinoma of the bladder have evolved in recent times, with an emphasis on bladder preservation. A number of bladder preservation techniques are available to the surgeon; however, appropriately selected patients with muscle-invasive bladder cancer should be offered the opportunity to discuss various treatment options, including organ-sparing trimodal therapy. The aim of the present study was to compare the primary outcomes of the available treatment methods and identify the sources of variance among studies. A review of various bladder preservation techniques in vogue for the management of urothelial carcinoma of the bladder is discussed.

Cytological and histological changes in the urothelium produced by electromotive drug administration (EMDA) and by the combination of intravescical hyperthermia and chemotherapy (thermochemotherapy).

The treatment of non muscle-invasive bladder cancer (NMIBC) encompasses a range of different procedures. Electromotive drug administration (EMDA) and chemo-hyperthermia (C-HT; Synergo) represent a minimally-invasive methods of intravesical instillation of therapeutic agents as mitomycin C (MMC). We selected patients with high grade NMIBC, BCG non responder, treated with EMDA/MMC and C-HT/MMC and we also examined the morphological changes in urine cytology samples. During the period from 2012 to 2014, 110 patients with high grade NMIBC, BCG refractory were selected. All cases examined were classified according to The Paris System Classification as negative for high urothelial carcinoma (NHGUC) or atypical urothelial cells (AUC) with a mean of follow-up of 15 months and the cytological diagnosis were confirmed by histological biopsies. In particular 50 patients were treated with EMDA/MMC and 60 patients underwent to C-HT/MMC. The morphological changes were evaluated in urine samples processed by Thin Prep method. In the 50 patients treated with EMDA/MMC, 35 samples were classified as NHGUC and 15 cases were classified as AUC, while in the 60 patients treated with C-HT/MMC, 43 samples were NHGUC and 17 cases were classified AUC. The increase of cellularity and nuclear size with the alteration of nuclear/cytoplasmatic ratio (N/C) were common in patients treated with EMDA/MMC and C-HT/MMC without clinical and histological evidence of recurrence of neoplasia. The hyperchromasia and irregular nuclear chromatin were rarely observed. The irregular nuclear membrane rarely identified in urine cytology after EMDA/MMC treatment, is a feature present in patients C-HT/MMC treated.

Intravesical Bacillus Calmette Guerin Combined with a Cancer Vaccine Increases Local T-Cell Responses in Non-muscle-Invasive Bladder Cancer Patients.

PURPOSE: Treatments with cancer vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T cells in the bladder and tumor-regression in murine bladder cancer models. Here, we determined whether an adjuvanted cancer vaccine can be safely administered with concomitant standard intravesical Bacillus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle-invasive bladder cancer (NMIBC). EXPERIMENTAL DESIGN: In a nonrandomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine injections or BCG instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG instillations. RESULTS: The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AEs were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T cells were induced in blood, irrespective of BCG treatment. Interestingly, such T cells were only detected in urine upon BCG-induced T-cell infiltration. CONCLUSIONS: Cancer vaccines, including strong adjuvants, can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T cells in the bladder upon BCG provides proof-of-principle evidence that cancer vaccines with local immunostimulation may be beneficial. Clin Cancer Res; 23(3); 717-25. ©2016 AACR.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study.

PURPOSE: We report for the first time the activity and safety of Unithermia(®) (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette-Guerin (BCG). METHODS: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I-II prospective single-arm study. Six weekly instillations with Unithermia(®) were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan-Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. RESULTS: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59%). Among the 14/34 (41%) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18% progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5%, respectively. Toxicity did not go beyond grade 2 except in five cases. CONCLUSIONS: Initial experience with MMC-HT with Unithermia(®) showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.

Clinical response to induction chemotherapy predicts improved survival outcome in urothelial carcinoma with clinical lymph nodal metastasis treated by consolidative surgery.

BACKGROUND: To determine the indications for post-chemotherapy consolidative surgery in patients with clinical lymph node (LN) metastatic (cN+) urothelial carcinoma (UC). METHODS: Sixty UC patients with measurable cN+ but without detectable systemic visceral/bone dissemination received induction platinum-based chemotherapy. Consolidative surgery was offered to all patients except for those with progressive disease. We retrospectively analyzed the clinicopathological response to induction chemotherapy and identified prognostic factors for overall survival (OS). RESULTS: The primary cancer site was the urinary bladder in 31 patients (52 %) and upper urinary tract in 29 (48 %). The median number of chemotherapy courses was 4. Forty-five patients (75 %) showed a clinically objective response to the induction chemotherapy. Fifty-one patients (85 %) underwent subsequent consolidative surgery. Histopathological analysis indicated pT0 status in 10 (20 %) and pN0 in 17 (33 %). When all 60 patients were considered, clinical tumor response was found to be significantly correlated with achievement of pathological complete response. At the median follow-up of 22 months, the median progression-free survival and OS periods were excellent: 18.6 and 31.6 months, respectively. In the multivariate analysis, clinical tumor response was found to be an independent pre-surgical prognostic factor for OS, and pathologically negative lymph node, negative resection margin, more LNs removed, and negative lymphovascular invasion were found to be independent post-surgical prognostic parameters for OS. CONCLUSIONS: The median OS in induction chemotherapy followed by consolidative surgery was very encouraging. Our results suggest that achieving a good clinical response to pre-surgical induction chemotherapy is a good indication for subsequent consolidative surgery in UC patients with cN+ to improve OS through a good pathological response.

Impact of perioperative chemotherapy on survival in patients with advanced primary urethral cancer: results of the international collaboration on primary urethral carcinoma.

BACKGROUND: To investigate the impact of perioperative chemo(radio)therapy in advanced primary urethral carcinoma (PUC). PATIENTS AND METHODS: A series of 124 patients (86 men, 38 women) were diagnosed with and underwent surgery for PUC in 10 referral centers between 1993 and 2012. Kaplan-Meier analysis with log-rank testing was used to investigate the impact of perioperative chemo(radio)therapy on overall survival (OS). The median follow-up was 21 months (mean: 32 months; interquartile range: 5-48). RESULTS: Neoadjuvant chemotherapy (NAC), neoadjuvant chemoradiotherapy (N-CRT) plus adjuvant chemotherapy (ACH), and ACH was delivered in 12 (31%), 6 (15%) and 21 (54%) of these patients, respectively. Receipt of NAC/N-CRT was associated with clinically node-positive disease (cN+; P = 0.033) and lower utilization of cystectomy at surgery (P = 0.015). The objective response rate to NAC and N-CRT was 25% and 33%, respectively. The 3-year OS for patients with objective response to neoadjuvant treatment (complete/partial response) was 100% and 58.3% for those with stable or progressive disease (P = 0.30). Of the 26 patients staged ≥cT3 and/or cN+ disease, 16 (62%) received perioperative chemo(radio)therapy and 10 upfront surgery without perioperative chemotherapy (38%). The 3-year OS for this locally advanced subset of patients (≥cT3 and/or cN+) who received NAC (N = 5), N-CRT (N = 3), surgery-only (N = 10) and surgery plus ACH (N = 8) was 100%, 100%, 50% and 20%, respectively (P = 0.016). Among these 26 patients, receipt of neoadjuvant treatment was significantly associated with improved 3-year relapse-free survival (RFS) (P = 0.022) and OS (P = 0.022). Proximal tumor location correlated with inferior 3-year RFS and OS (P = 0.056/0.005). CONCLUSION: In this series, patients who received NAC/N-CRT for cT3 and/or cN+ PUC appeared to demonstrate improved survival compared with those who underwent upfront surgery with or without ACH.

Results of Intravesical Chemo-Hyperthermia in High-risk Non-muscle Invasive Bladder Cancer.

PURPOSE: To examine the effectiveness of mitomycin-C and chemo-hyperthermia in combination for patients with high-risk non-muscle-invasive bladder cancer. MATERIALS AND METHODS: Between November 2011-September 2013, 43 patients with high-risk non-muscle-invasive bladder cancer undergoing adjuvant chemo-hyperthermia in two centers were evaluated retrospectively. Treatment consisted of 6 weekly sessions, followed by 6 sessions. Recurrence and progression rate, recurrence-free interval and side effects were examined. Analyzed factors included age, gender, smoking status, AB0 blood group, body mass index, T stage and grade, concominant CIS assets. The associations between predictors and recurrence were assessed using multivariate Cox proportional hazard analyses. RESULTS: A total of 40 patients completed induction therapy. Thirteen (32.5%) were diagnosed with tumor recurrence. Median follow-up was 30 months (range 9-39). Median recurrence-free survival was 23 months (range 6-36). The Kaplan-Meier-estimated recurrence-free rates for the entire group at 12 and 24 months were 82% and 61%. There was no statistically significant difference between patient subgroups. Cox hazard analyses showed that an A blood type (OR=6.23, p=0.031) was an independent predictor of recurrence- free. Adverse effects were seen in 53% of patients and these were frequently grades 1 and 2. CONCLUSIONS: Intravesical therapy with combination of mitomycin-C and chemohyperthermia seems to be appropriate in high-risk patients with non-muscle-invasive bladder cancer who cannot tolerate or have contraindications for standard BCG therapy.

Efficacy and safety of systemic chemotherapy and intra-arterial chemotherapy with/without radiotherapy for bladder preservation or as neo-adjuvant therapy in patients with muscle-invasive bladder cancer: a single-centre study of 163 patients.

INTRODUCTION: Patients with muscle-invasive bladder cancer (MIBC) often undergo various preoperative treatments to improve survival; however, their efficacy and safety remain unclear. MATERIALS AND METHODS: The anti-tumour effects and adverse events were evaluated in 163 MIBC patients who received systemic chemotherapy (SC, n = 34), intra-arterial chemotherapy (IAC, n = 50), or combined IAC and radiotherapy (IAC + R, n = 79). RESULTS: Pathological complete responses were observed in 17.6%, 22.0%, and 43.0% of patients in the SC, IAC, and IAC + R groups, respectively, with respective 5-year overall survival rates of 42.0%, 46.7%, and 50.3%. Multivariate analysis showed that successful IAC + R protocol administration was a significant predictor for survival (hazard ratio = 0.16, p = 0.028). The incidence of severe adverse events was higher in the IAC + R group (36.7%) than in the SC (9.8%) and IAC groups (16.0%). CONCLUSIONS: IAC + R was useful for patients with MIBC. Successful completion and optimal patient selection were important for this treatment strategy.

Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia.

OBJECTIVES: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders. METHODS: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis. RESULTS: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders. CONCLUSION: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Influence of hyperthermia on efficacy and uptake of carbon nanohorn-cisplatin conjugates.

Single-walled carbon nanohorns (SWNHs) have significant potential for use in photothermal therapies due to their capability to absorb near infrared light and deposit heat. Additionally, their extensive relative surface area and volume makes them ideal drug delivery vehicles. Novel multimodal treatments are envisioned in which laser excitation can be utilized in combination with chemotherapeutic-SWNH conjugates to thermally enhance the therapeutic efficacy of the transported drug. Although mild hyperthermia (41-43 °C) has been shown to increase cellular uptake of drugs such as cisplatin (CDDP) leading to thermal enhancement, studies on the effects of hyperthermia on cisplatin loaded nanoparticles are currently limited. After using a carbodiimide chemical reaction to attach CDDP to the exterior surface of SWNHs and nitric acid to incorporate CDDP in the interior volume, we determined the effects of mild hyperthermia on the efficacy of the CDDP-SWNH conjugates. Rat bladder transitional carcinoma cells were exposed to free CDDP or one of two CDDP-SWNH conjugates in vitro at 37 °C and 42 °C with the half maximal inhibitory concentration (IC50) for each treatment. The in vitro results demonstrate that unlike free CDDP, CDDP-SWNH conjugates do not exhibit thermal enhancement at 42 °C. An increase in viability of 16% and 7% was measured when cells were exposed at 42 deg compared to 37 deg for the surface attached and volume loaded CDDP-SWNH conjugates, respectively. Flow cytometry and confocal microscopy showed a decreased uptake of CDDP-SWNH conjugates at 42 °C compared to 37 °C, revealing the importance of nanoparticle uptake on the CDDP-SWNH conjugate's efficacy, particularly when hyperthermia is used as an adjuvant, and demonstrates the effect of particle size on uptake during mild hyperthermia. The uptake and drug release studies elucidated the difference in viability seen in the drug efficacy studies at different temperatures. We speculate that the disparity in thermal enhancement efficacy observed for free drug compared to the drug SWNH conjugates is due to their intrinsic size differences and, therefore, their mode of cellular uptake: diffusion or endocytosis. These experiments indicate the importance of tuning properties of nanoparticle-drug conjugates to maximize cellular uptake to ensure thermal enhancement in nanoparticle mediated photothermal-chemotherapy treatments.

Intravesical thermo-chemotherapy based on conductive heat: a first pharmacokinetic study with mitomycin C in superficial transitional cell carcinoma patients.

PURPOSE: To evaluate, for the first time, the mitomycin C (MMC) pharmacokinetics during intravesical hyperthermia treatment based on conductive heat and the stability and recovery of the drug at the end of the instillation period. METHODS: Eleven patients with recurrent intermediate-risk superficial transitional cell carcinoma of the bladder were treated weekly for six cycles with intravesical MMC (40 mg MMC in 50 ml) in local hyperthermia (45 °C) with Unithermia(®) system. Each instillation lasted 45 min, with the solution being replaced after the first 22 min. The MMC recovery at the end of the two instillation period and the plasmatic pharmacokinetics of MMC were evaluated by high-pressure liquid chromatography. RESULTS: Nine patients completed all the six planned cycles, whereas two patients missed the last cycle because of allergic reactions. No other systemic toxicity was observed, and the local toxicities were mild. Median MMC concentration in the instillation residual solution decreases from the initial 0.8 to 0.22 mg/ml for the 0-22-min instillation period and to 0.38 mg/ml for the 22-45-min instillation period; the median percentage of MMC recovered after instillation was 66.2 and 99.6, respectively. In all patients, MMC plasmatic C max resulted considerably lower than the toxic threshold (400 ng/ml). CONCLUSIONS: The MMC is stable during the instillation, and its absorption occurs mainly during the first minutes of the treatment. The plasmatic MMC concentration is always well below the threshold level for myelosuppression, as confirmed by the total lack of hematological toxicity evidenced by the patients. In order to evaluate the efficacy of the treatment performed with UniThermia(®) in reducing the disease recurrence rate in short- and long-term follow-up, we are currently carrying out a clinical multicentric study involving a larger number of patients.

The predictive value of GSTT1 polymorphisms in predicting the early response to induction BCG therapy in patients with non-muscle invasive bladder cancer.

INTRODUCTION: We evaluated the predictive value of glutathione S transferase mu (GSTM1) and theta (GSTT1) polymorphisms in early response to bacillus Calmette-Guérin (BCG) induction therapy in patients with primary non-muscle invasive bladder cancer. METHODS: GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction using blood genomic DNA from 135 patients with primary non-muscle invasive bladder cancer who were being treated with a single induction course of BCG. BCG nonresponsiveness (early BCG failure) was defined as a tumor recurrence or progression within 12 months after BCG induction therapy. The predictive value of GST polymorphisms was evaluated by Kaplan-Meier analysis and multivariate logistic regression models. RESULTS: Patients carrying a GSTT1-positive genotype demonstrated a higher likelihood of early BCG failure regardless of cigarette smoking. After stratification based on the tumor stage and grade, the high-risk group (T1G3) with a GSTT1-positive genotype showed a 14-fold higher risk of early BCG failure compared with those with a GSTT1-null genotype. In a combined analysis of 2 genes, the GSTT1-positive/GSTM1-null genotype had a higher risk of BCG nonresponsiveness compared with the GSTT1-null/GSTM1-null genotype (odds ratio = 4.17, 95% CI: 1.54-11.26). By multivariate logistic regression analysis, the GSTT1-positive genotype was an independent predictor of early BCG failure (odds ratio = 3.67, 95% CI: 1.61-8.38). Kaplan-Meier estimates revealed a significant difference in disease-free survival depending on the GSTT1 genotype (log rank test, P = 0.038). CONCLUSIONS: The results of this study suggest that the GSTT1-positive genotype is an independent predictor of early BCG failure. These results can help determine whether patients would benefit from adjuvant BCG treatment or may require more aggressive alternative therapies.

Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial.

BACKGROUND: We assessed effectiveness, safety, and tolerability of paclitaxel or fluorouracil when added to radiation plus cisplatin followed by adjuvant chemotherapy in a programme of selected bladder preservation for patients with muscle invasive bladder cancer. METHODS: In our randomised phase 2 trial, we enrolled patients with T2-4a transitional cell carcinoma of the bladder at 24 medical centres in the USA. We randomly allocated patients to receive paclitaxel plus cisplatin (paclitaxel group) or fluorouracil plus cisplatin (fluorouracil group) with twice-daily radiation in random block sizes per site on the basis of clinical T-stage (T2 vs T3-4). Patients and physicians were aware of treatment assignment. All patients had transurethral resection of bladder tumour and twice-daily radiotherapy to 40·3 Gy, along with allocated chemotherapy, followed by cystoscopic and biopsy assessment of response. Patients who had a tumour response with downstaging to T0, Tcis, or Ta received consolidation chemoradiotherapy to 64·3 Gy, with the same chemotherapy regimen as in the induction phase. Patients received adjuvant cisplatin-gemcitabine-paclitaxel after the end of chemoradiotherapy. If, after induction, persistent disease was graded as T1 or worse, we recommended patients undergo cystectomy and adjuvant chemotherapy. We assessed the primary endpoints of rates of treatment completion and toxic effects in all randomly allocated patients. This study is registered with ClinicalTrials.gov, number NCT00055601. FINDINGS: Between Dec 13, 2002, and Jan 11, 2008, we enrolled 97 patients, of whom 93 were eligible for analysis. Median follow-up was 5·0 years (IQR 5·0-6·2). Of 46 patients in the paclitaxel group, 45 (98%) completed induction (16 [35%] with grade 3-4 toxicity), 39 (85%) completed induction and consolidation (11 [24%] with grade 3-4 toxicity due to consolidation), and 31 (67%) completed the entire protocol with adjuvant chemotherapy. 34 (85%) of 40 assessable patients in the paclitaxel group had grade 3-4 toxicity during adjuvant chemotherapy. Of 47 patients in the fluorouracil group, 45 (96%) completed induction (nine [19%] with grade 3-4 toxicity), 39 (83%) completed induction and consolidation (12 [26%] had grade 3-4 toxicity due to consolidation), and 25 (53%) completed the entire protocol with adjuvant chemotherapy. 31 (76%) of 41 assessable patients in the fluorouracil group had grade 3-4 toxicity during adjuvant chemotherapy. Five (11%) patients treated with the paclitaxel regimen and three (6%) patients treated with the fluorouracil regimen developed late grade 3-4 radiotherapy toxicities. 11 (24%) patients treated with the paclitaxel regimen and 16 (34%) patients treated with the fluorouracil regimen developed late grade 3-4 toxicities unrelated to radiotherapy. One patient (in the fluorouracil group) died during follow-up. Six (13%) patients in the paclitaxel group and in three (6%) patients in the fluorouracil group discontinued due to treatment-related toxicity. INTERPRETATION: In the absence of phase 3 data, our findings could inform selection of a bladder-sparing trimodality chemotherapy regimen for patients with muscle invasive bladder cancer. FUNDING: US National Cancer Institute.

Spatially controlled photothermal heating of bladder tissue through single-walled carbon nanohorns delivered with a fiberoptic microneedle device.

Laser-based photothermal therapies for urothelial cell carcinoma (UCC) are limited to thermal ablation of superficial tumors, as treatment of invasive lesions is hampered by shallow light penetration in bladder tissue at commonly used therapeutic wavelengths. This study evaluates the utilization of sharp, silica, fiberoptic microneedle devices (FMDs) to deliver single-walled carbon nanohorns (SWNHs) serving as exogenous chromophores in conjunction with a 1,064-nm laser to amplify thermal treatment doses in a spatially controlled manner. Experiments were conducted to determine the lateral and depth dispersal of SWNHs in aqueous solution (0.05 mg/mL) infused through FMDs into the wall of healthy, inflated, ex vivo porcine bladders. SWNH-perfused bladder regions were irradiated with a free-space, CW, 1,064-nm laser in order to determine the SWNH efficacy as exogenous chromophores within the organ. SWNHs infused at a rate of 50 µL/min resulted in an average lateral expansion rate of 0.36 ± 0.08 cm(2)/min. Infused SWNHs dispersal depth was limited to the urothelium and muscular propria for 50 µL/min infusions of 10 min or less, but dispersed through the entire thickness after a 15-min infusion period. Irradiation of SWNH-perfused bladder tissue with 1,064 nm laser light at 0.95 W/cm(2) over 40 s exhibited a maximum increase of approximately 19 °C compared with an increase of approximately 3 °C in a non-perfused control. The results indicate that these silica FMDs can successfully penetrate into the bladder wall to rapidly distribute SWNHs with some degree of lateral and depth control and that SWNHs may be a viable exogenous chromophore for photothermal amplification of laser-based UCC treatments.