Bladder Cancer Journal Vol. 7, Issue 3

Muscle-Invasive Bladder Cancer in Patients with Liver Cirrhosis: A Review of Pertinent Considerations

ABSTRACT:

The incidence of liver cirrhosis is increasing worldwide. Patients with cirrhosis are generally at a higher risk of harboring hepatic and non-hepatic malignancies, including bladder cancer, likely due to the presence of related risk factors such as smoking. Cirrhosis can complicate both the operative and non-surgical management of bladder cancer. For example, cirrhotic patients undergoing abdominal surgery generally demonstrate worse postoperative outcomes, and chemotherapy in patients with cirrhosis often requires dose reduction due to its direct hepatotoxic effects and reduced hepatic clearance. Multiple other considerations in the peri-operative management for cirrhosis patients with muscle-invasive bladder cancer must be taken into account to optimize outcomes in these patients. Unfortunately, the current literature specifically related to the treatment of cirrhotic bladder cancer patients remains sparse. We aim to review the literature on treatment considerations for this patient population with respect to perioperative, surgical, and adjuvant management.

Differences in Quality of Life Between Men and Women who Undergo Bladder Preservation with Trimodality Therapy

ABSTRACT:

PURPOSE: Sex-specific differences exist in muscle invasive bladder cancer (MIBC): men have a higher incidence; women present with more advanced disease; and surgical options differ between men and women. Health-related quality of life (HRQoL) for male versus female patients with MIBC is not well understood and limited data exist in patients who undergo bladder preservation with trimodality therapy (TMT). The purpose of this study was to compare long-term HRQoL between men and women who have undergone TMT.

METHODS AND MATERIALS: This was a secondary analysis of a prior study that reported long-term HRQoL differences for patients who underwent TMT. We analyzed patient-reported HRQoL data to assess differences in HRQoL between men and women.

RESULTS: Of the 64/74 (86%) TMT patients that completed questionnaires, 14 (22%) were women. The median age at diagnosis was 60 years for women and 66 years for men (p  = 0.007). From six HRQoL instruments, there were two responses with a statistically significant difference between women and men –incidence of diarrhea and degree of sexual activity. Fifty percent of women compared to 86%of men reported no diarrhea (p  = 0.02). A greater percentage of women reported some degree of sexual activity in the 4 weeks prior to questionnaire completion (p  = 0.04), and sexual interest following TMT declined significantly with age in men, but not in women.

CONCLUSIONS: In general, men and women report very good long-term HRQoL following TMT. There were, however, some differences between the sexes. Understanding this difference, especially related to sexual function, will allow more informed decision-making by patients when choosing between treatment modalities. 

A Randomized Feasibility Trial Comparing Surveillance Regimens for Patients with Low and Low-Intermediate Risk Non-Muscle Invasive Bladder Cancer

ABSTRACT:

BACKGROUND: Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown.

OBJECTIVES: To determine patient willingness to randomization to high frequency (HF) versus low frequency (LF) surveillance regimen for NMIBC and compare patient comfort and healthcare costs across regimens.

METHODS: A non-blinded, two-arm, randomized-controlled study of patients with low or low-intermediate risk NMIBC was conducted at two institutions where patients were offered randomization to HF vs. LF surveillance following initial tumor resection. The HF group underwent cystoscopy every three months for 2 years, then every 6 months for 2 years, then annually. The LF group underwent cystoscopy at 9 months following the 3-month cystoscopy, then annually. Assuming 75% of patients approached would agree to enrollment, a sample size of n  = 35 patients per arm provided a one-sided 95% exact Clopper-Pearson confidence lower-limit of 60%.

RESULTS: Of 70 patients approached, 45 (64.3%) agreed to participate and 25 (35.7%) declined enrollment due to preference for HF. Twelve biopsies were performed, including 4 (19%) of 21 patients in the HF group and 8 (33.3%) of 24 patients in the LF group. Disease recurrence (low grade Ta) was observed in 3 (14.3%) and 5 (20.8%) patients in the HF and LF groups, respectively. No patients experienced high grade recurrence or progression. Both groups had similar patient-reported procedure-related discomfort and quality of life measures over time. Patient out-of-pocket cost and healthcare systems costs were $383.80 more per patient annually in the HF group.

CONCLUSIONS: Randomization to variable frequency surveillance is challenging as over a third of patients declined participation. However, these data provide important preliminary insights into the potential effects of surveillance frequency on oncologic and economic outcomes in patients with low and low-intermediate risk bladder cancer.

Quality of Life and Anxiety in Patients with First Diagnosed Non-Muscle Invasive Bladder Cancer Who Receive Adjuvant Bladder Therapy

ABSTRACT:

BACKGROUND: Bladder cancer (BC) is one of the most common malignancies (4.5%of all newly diagnosed cases worldwide). Most of the new BC cases are diagnosed as non-muscle-invasive BC (NMIBC), needing continuous follow-up after primary endoscopic therapy. Adjuvant bladder therapy with chemo- or immuno- agents, apart from the initial diagnosis, the strict surveillance program, and the risk of recurrence, may have a major impact on the patients’ physical and mental health. OBJECTIVE: We evaluated anxiety and quality of life (QoL) in patients who underwent surgery for NMIBC and followed a bladder instillation program.

METHODS: This is a prospective analysis of patients with histopathologically confirmed NMIBCs. Eligible were all adult patients with single or multiple NMIBCs who underwent transurethral tumor resection and followed a therapy with either BCG or Epirubicin instillations. The SF-36 questionnaire Physical and Mental health aspects were used for QoL assessment. Similarly, the STAI-Y was introduced for the state (STAI-Y1) and trait anxiety (STAI-Y2) evaluation.

RESULTS: 117 eligible patients were screened, with 108 entering finally the study; 9 patients were excluded due to disease recurrence. 17 patients (15.7%) received Epirubicin (Ta-T1, Low-Grade tumors), whereas 91 patients (84.3%) received BCG (T1, High Grade). Regarding SF-36 Physical a 6 months decrease was followed by an improvement at 12 months (p  = 0.008). Similarly, an increase of the SF-36 Mental health score was identified (p  = 0.03). In contrast to STAI-Y2 scores (p  = 0.945), a long-term reduction of the state anxiety was identified (p  = 0.001). Preoperative SF-36 Physical was inversely correlated with age (p  = 0.029), while the absence of alcohol was associated with lower mental health (p  = 0.003). Overall, patient characteristics, habits, and the administered treatment did not affect the postoperative QoL and anxiety.

CONCLUSION: Patient QoL and anxiety improved during follow-up. Still, further larger-scale studies are required to support our findings.

Alternating Cystoscopy with Bladder EpiCheck ^® in the Surveillance of Low-Grade Intermediate-Risk NMIBC: A Cost Comparison Model

ABSTRACT:

BACKGROUND: Bladder cancer surveillance is invasive, intensive, and costly. Patients with low-grade intermediate risk non-muscle invasive bladder cancer (NMIBC) are at high risk of recurrence.

OBJECTIVE: The objective of this model is to compare the cost of a strategy to alternate surveillance with cystoscopy and a urine marker, Bladder EpiCheck, to standard surveillance.

METHODS: A decision tree model was built using TreeAge Pro Healthcare to compare standard surveillance (Standard) with modified surveillance incorporating Bladder EpiCheck. The model was based on 2 years of surveillance. Outcomes were obtained from the literature. Costs were obtained from the US and 9 European countries. Sensitivity analyses were performed.

RESULTS: The efficacy of the model was equivalent in terms of recurrence for each arm with a median recurrence rate of 22%. When setting marker price at 200 local currency, the marker arm was less expensive in the USA, Netherlands, Switzerland, Belgium, Italy, Austria, and UK by 154€ to 329£ per patient, for a 2-year period. The cost was higher in France, Spain, and Germany by 33–103€. Cost parity was achieved with marker price between 148€ and $421. Marker cost and specificity have the greatest impact on the overall model cost.

CONCLUSIONS: A strategy alternating the urine marker Bladder EpiCheck with cystoscopy in the surveillance of patients with low-grade intermediate-risk bladder cancer is cost equivalent in the US and European countries when the marker is priced 148€ –$421, as a result of the marker’s high specificity (86%). Prospective studies will be necessary to validate these findings.

Basal and Luminal Molecular Subtypes in Naturally-Occurring Canine Urothelial Carcinoma are Associated with Tumor Immune Signatures and Dog Breed

ABSTRACT:

BACKGROUND: Improved therapies are needed for patients with invasive urothelial carcinoma (InvUC). Tailoring treatment to molecular subtypes holds promise but requires further study, including studies in pre-clinical animal models. Naturally-occurring canine InvUC harbors luminal and basal subtypes, mimicking those observed in humans, and could offer a relevant model for the disease in people.

OBJECTIVE: To further validate the canine InvUC model, clinical and tumor characteristics associated with luminal and basal subtypes in dogs were determined, with comparison to findings from humans.

METHODS: RNA sequencing (RNA-seq) analyses were performed on 56 canine InvUC tissues and bladder mucosa from four normal dogs. Data were aligned to CanFam 3.1, and differentially expressed genes were identified. Data were interrogated with panels of genes defining luminal and basal subtypes, immune signatures, and other tumor features. Subject and tumor characteristics and outcome data were obtained from medical records.

RESULTS: Twenty-nine tumors were classified as luminal and 27 tumors as a basal subtype. Basal tumors were strongly associated with immune infiltration (OR 52.22, 95%CI 4.68–582.38, P  = 0.001) and cancer progression signatures in RNA-seq analyses, more advanced clinical stage, and earlier onset of distant metastases in exploratory analyses (P  = 0.0113). Luminal tumors were strongly associated with breeds at high risk for InvUC (OR 0.06, 95%CI 0.01 –0.37, P  = 0.002), non-immune infiltrative signatures, and less advanced clinical stage.

CONCLUSIONS: Dogs with InvUC could provide a valuable model for testing new treatment strategies in the context of molecular subtype and immune status, and the search for germline variants impacting InvUC onset and subtype. 

Efficacy of EGFR Inhibitors and NSAIDs Against Basal Bladder Cancers in a Rat Model: Daily vs. Weekly Dosing, Combining EGFR Inhibitors with Naproxen, and Effects on RNA Expression

ABSTRACT:

BACKGROUND: There are few effective treatments specifically aimed at basal bladder cancer.

OBJECTIVE: Female F344 rats administered N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) develop large invasive bladder cancers. We determined the efficacy of daily vs weekly dosing of EGFR inhibitors, determined the efficacy of naproxen combined with an EGFR inhibitor, and performed RNA analysis of bladder tumors treated for 5 days with EGFR inhibitors or NO-naproxen to identify pharmacodynamic biomarkers.

METHODS: Erlotinib (6 mg/Kg BW daily or 21 or 42 mg/Kg BW weekly), lapatinib (25 or 75 mg/Kg BW daily or 263 or 525 mg/Kg BW weekly), and/or naproxen (30 mg/Kg BW daily) were administered to OH-BBN-treated rats beginning 2–12 weeks post-OH-BBN. Rats were sacrificed 28 weeks after the final OH-BBN treatment to determine the effects of the EGFR inhibitors + naproxen on bladder weights and tumor development. In a separate study, rats were treated with OH-BBN. When palpable tumors developed, rats were treated with erlotinib, lapatinib, gefitinib, or the NSAID NO-naproxen for 5 days. RNA analysis was performed on the tumors.

RESULTS: Daily or weekly dosing of erlotinib or lapatinib and daily dosing of naproxen reduced large tumor formation up to 70%, while combining daily lapatinib and naproxen reduced tumors 100%. RNA Analysis: All EGFR inhibitors strongly reduced cell proliferation and chromosome replication pathways, while NO-naproxen altered the G protein receptor, oxygen homeostasis, and immune function pathways.

CONCLUSIONS: While daily and weekly dosing with EGFR inhibitors and naproxen were effective, combining lapatinib and naproxen yielded no tumors. This might encourage its clinical use in an adjuvant setting with superficial basal tumors, and perhaps even in a more advanced setting. Furthermore, RNA analysis identified specific pathways that might be potential pharmacodynamic biomarkers in clinical trials.

Lung Metastases Versus Second Primary Lung Cancers in Patients with Primary Urothelial Carcinoma of the Bladder: A National Population-Based Assessment

ABSTRACT:

BACKGROUND: The work-up and diagnosis of indeterminate lung nodules at the time of bladder cancer diagnosis may delay or change treatment.

OBJECTIVE: To quantify the incidence of synchronous and metachronous lung cancers in adults with bladder cancer and compare these rates to the incidence of bladder cancer metastases in the lung.

METHODS: We retrospectively analyzed all adults diagnosed with bladder cancer in the Surveillance, Epidemiology and End Results (SEER) registry (2010– 2015) and identified second primary lung cancers defined as being either synchronous (diagnosed within 6 months of bladder cancer diagnosis) or metachronous (more than 6 months following index bladder cancer diagnosis). The risk of second primary lung cancers was reported as a standardized incidence ratio (SIR) reflecting observed and expected case ratios.

RESULTS: A total of 88,335 patients diagnosed with bladder cancer were included. Among adults with NMIBC (n  = 66,071) and MIBC (n  = 18,879), 0.3% and 3.9% had bladder cancer metastatic to the lungs at diagnosis. Synchronous second primary lung cancers were diagnosed in 0.4% and 0.7% of patients with NMIBC and MIBC, respectively. Compared to the general population, the SIR for synchronous lung cancers among adults with NMIBC was 2.5 (95% CI 2.3– 2.9) and was 4.7 (95% CI 4.0– 5.6) for adults with MIBC.

CONCLUSIONS: Bladder cancer metastatic to the lung is more common in adults with MIBC compared to NMIBC. There are similar frequencies of synchronous second primary lung cancers regardless of the initial bladder cancer stage. 

The Impact of Physical Activity on Risk and Health-Related Quality of Life in Bladder Cancer

ABSTRACT:

BACKGROUND: Sedentarism is an important modifiable risk factor in the struggle against cancer. In the last decades, the relationship between physical activity and different types of cancer has been investigated in depth.

OBJECTIVE: To provide an overview of the literature on the effectiveness of physical activity in reducing the risk to develop bladder cancer and improving health-related quality of life in patients.

METHODS: A systematic review was conducted through a search of the Embase, Cochrane, PubMed, Scopus, and Web of Science (WOS) databases to seek information and PRISMA system to delimitate the research. Outcomes included in searches were physical activity, tobacco consumption, obesity, body mass index, and metabolic syndrome, associated with bladder cancer and quality of life.

RESULTS: Database searches identified 394 records, of which 75 were duplicated. A total of 280 articles were excluded based on abstract screening. An additional 16 full-text articles were excluded because they did not meet the eligibility criteria. Overall, 21 of the 23 studies included in the review reported beneficial effects of physical activity in bladder cancer. The majority of papers found that physical activity is a significant factor in reducing the risk of bladder cancer. Moreover, physical activity improves health-related quality of life in bladder cancer survivors and diminishes both recurrence and mortality in those who engage in regular activity. Lastly, physical inactivity is associated with increased body mass index, obesity, metabolic syndrome, type 2 diabetes, and unfavorable energy balance, which led to a greater probability of suffering from bladder cancer.

CONCLUSIONS: These data reinforce the importance of promoting a healthy lifestyle to reduce the risk of bladder cancer and to improve survivorship and health-related quality of life of patients.

Impact of Intestinal Urinary Diversion on the Risk of Fracture and Loss of Bone Mass: A Systematic Review

ABSTRACT:

BACKGROUND: Patients undergoing intestinal urinary diversion (IUD) may have a higher risk of osteoporosis and risk of fractures due to metabolic acidosis and a decrease of intestinal absorption surface.

OBJECTIVE: We performed a systematic review of the available literature on the impact of IUD on bone demineralization.

METHODS: We systematically searched PubMed® , for original articles published before April 2020. Primary endpoints were the risk of fracture and loss of bone density. Secondary outcomes were the metabolic changes in biochemical and urine parameters related to calcium metabolism and histological changes.

RESULTS: Our electronic search identified a total of 2417 articles. After a detailed review, we selected 11 studies that addressed the impact of IUD on bone health in 10369 patients. The risk of bone fracture was studied in 3 articles, showing a higher risk in the IUD population. Of the 9 articles evaluating the relation between intestinal urinary diversion and bone density, 5 did find a positive association. One article evaluated the bone metabolism at a cellular level after IUD showing a decrease in bone turnover in this population. Three of the eight studies reporting data on serum parameters related to calcium and phosphate metabolism showed differences. Finally, a correlation between the concentration of pyridolines in urine and loss of bone density was found in two of the three studies.

CONCLUSIONS: Although published data on BMD are contradictory, patients undergoing IUD seem to be at higher risk of bone fractures. Our findings support the need to implement accessible strategies on osteoporosis screening and prevention in IUD patients.

Challenging Cases in Urothelial Cancer: Case 21

This is a 65-year-old current and longtime cigarette smoker who presented to me with an 8-month history of intermittent gross hematuria and a diagnosis of muscle-invasive urothelial cancer of the bladder. He has type 2 diabetes mellitus. He had symptomatic coronary artery disease and coronary artery stents were placed in 2015. He currently has a good performance status.

He was initially evaluated by another urologist who identified a papillary and sessile tumor on the right side of the bladder located above the right ureteral orifice. The tumor appeared to be arising from a bladder diverticulum.

Clinical Trials Corner Issue 7(3)

In this issue, we highlight several trials evaluating bladder preservation. While exciting, these trials do raise the question of comparability across studies given the use of different regimens of radiotherapy and different endpoints. 

Iatrogenic Causes of Urothelial Cancer of the Upper Urinary Tract and Bladder

The bladder and the upper urinary tract (UUT) are both lined by urothelium and have cancer characteristics that are histologically and molecularly similar. Aside from inherited (e.g. Lynch family tumor syndrome) [1] or unusual exposures (e.g. phenacetin or herbal remedies with Aristolochia fanchi) [2, 3], upper tract urothelial cancer (UTUC) represents 5–10%of all UCs [4] (Sountoulides) and presents with concomitant UC of the bladder (BC) in 20%of cases [5]. Moreover, about 30%of patients with UTUC have prior histories of BC [6, 7], and as many a 30% of patients with newly diagnosed UTUC without prior BCs will experience a recurrence in the bladder over the 12 months following radical nephron-ureterostomy (RNU) and bladder cuff excision [8]. Clearly, finding ways to prevent both UTUC and BC is worthwhile. Thus, it is of interest that two articles recently published in the Journal of Urology look at ways to reduce recurrences that are potentially iatrogenically induced.