Antibody-Drug Conjugates in Bladder Cancer

Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC. Several new targets are identified and utilized for novel or existing ADC testing. The most promising ones include human epidermal growth factor receptor 2 (HER2) and members of the fibroblast growth factor receptor axis (FGF/FGFR). Positive preclinical and early clinical results are reported in many cases, thus the next step involves further improving efficacy and reducing toxicity as well as testing combination strategies with approved agents.

Systematic Review: An Update on the Spectrum of Urological Malignancies in Lynch Syndrome

Lynch syndrome is an autosomal dominant disorder that predisposes individuals affected to certain malignancies. Colon and endometrial cancers are the malignancies most highly associated with Lynch syndrome. However, growing body of evidence links Lynch syndrome to urological cancers. Objective: This review aims to clarify the type of urological malignancies that fall under the Lynch-associated cancer spectrum. Methods: Using PRISMA guidelines, a systematic search between January 1990 to February 2018, was conducted using the MEDLINE database with the application of the following MESH terms: colorectal neoplasms, hereditary nonpolyposis; DNA mismatch repair; urologic neoplasms; kidney pelvis; ureteral neoplasms; urinary bladder; carcinoma, transitional cell; prostatic neoplasms; testicular neoplasms. Results: Upper tract urothelial cancers are well established under the Lynch spectrum. Increasing evidence supports its association with prostate cancer. However, there is, inconclusive and limited evidence for an association with bladder and testicular cancer. Conclusions: The evidence underpinning certain urological malignancies associated with Lynch syndrome has expanded in recent years. Our review may assist in providing a summary of the current standing in literature. However, we recommend further investigations to better clarify associations, particularly with prostate, bladder and testicular cancer.

Fatty Acid Patterns Detected By Ambient Ionization Mass Spectrometry in Canine Invasive Urothelial Carcinoma From Dogs of Different Breeds

In early work ambient ionization mass spectrometry (MS) revealed lipid patterns distinguishing muscle invasive bladder cancer (invasive urothelial carcinoma, InvUC) from normal urothelium. A new ambient ionization MS approach, touch spray MS (TS-MS) can rapidly generate mass spectra in real time, potentially in a point-of-care setting. A tissue sample removed from a patient is touched by a probe, and mass spectra generated within seconds. Objective: To validate TS-MS methods using specimens from naturally-occurring InvUC in dogs where the cancer closely mimics the human condition, and to demonstrate proof-of-concept that TS-MS can elucidate lipid patterns distinguishing InvUC from normal urothelium. Methods: Samples of normal urothelium and InvUC from dogs of several breeds were analyzed by TS-MS with correlative histopathology across each sample. Results were compared to those obtained with desorption electrospray ionization mass spectrometry (DESI-MS), a more traditional method. Data were analyzed by Principal Component Analysis and Linear Discriminant Analysis. Results: Lipid patterns identified by TS-MS, as well as by DESI-MS, differed between InvUC and normal urothelium with m/z 281.5 (oleic acid) and m/z 563.5 (oleic acid dimer) substantially contributing to the differences. Using histologic diagnosis as the gold standard, TS-MS had a global prediction rate of 93%. Conclusions: TS-MS can be used to identify lipid patterns that differentiate canine InvUC from normal urothelium. Optimization of TS-MS could lead to a point-of-care approach to distinguish cancer from normal in ex vivo tissues in real time, and to define biochemical processes leading to cancer development and progression.

Double-Blind, Randomized, Placebo-controlled Studies Evaluating Apaziquone (E09, Qapzola™) Intravesical Instillation Post Transurethral Resection of Bladder Tumors for the Treatment of Low-risk Non-Muscle Invasive Bladder Cancer

Guidelines recommend a single postoperative instillation of intravesical chemotherapy within 24 hours of transurethral resection of bladder tumors (TURBT) in patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC) to reduce recurrence risk. Objective: To evaluate the 2-year recurrence rate (2-YRR) of bladder cancer in randomized patients with Ta, G1-G2 histology who receive TURBT plus apaziquone versus TURBT plus placebo. Methods: Two nearly identical Phase 3, multinational, randomized, double-blind, placebo-controlled trials were conducted in patients with histologically confirmed Ta, G1-G2 NMIBC (Target Population) to evaluate the efficacy/safety of a single instillation of apaziquone post-TURBT. A single intravesical instillation of apaziquone (4 mg/40 mL) or placebo was administered within 6 hours post-TURBT. The primary and secondary efficacy endpoints were 2-YRR and time to recurrence (TTR) respectively. Results: Overall, 1614 patients were enrolled, including 1146 patients in the Target Population. Individually, the two studies did not meet statistical significance for 2-YRR (38.0% vs 44.6% ; 39.7% vs. 46.3%). Because apaziquone is rapidly metabolized in blood, a post hoc subgroup analysis was performed by time window of drug instillation post-TURBT. Patients who had drug instilled in the time window 60±30 minutes post-TURBT demonstrated 20.3% and 20.8% reduction in 2-YRR and 56% (HR = 0.44) and 45% (HR = 0.55) reduction in hazards for TTR in two studies respectively. Apaziquone was well tolerated with minimal toxicity. Conclusions: Two identical Phase 3 studies supported the safety of apaziquone (4 mg/40 mL) administered as a single intravesical instillation post-TURBT and identified efficacy when instilled within 60±30-minutes time interval which requires further study.

Total Fluid Intake and the Risk of Recurrence in Patients With Non-Muscle Invasive Bladder Cancer: A Prospective Cohort Study

Objectives: To investigate the role of fluid intake from beverages before and after a diagnosis of bladder cancer in relation to the risk of developing bladder cancer recurrence. Study Design: Prospective cohort study. Methods: 716 patients with non-muscle invasive bladder cancer (NMIBC), who received transurethral resection of a primary bladder tumour (TURBT) and completed self-administrated questionnaires on usual fluid intake from beverages at time of diagnosis (over the year before diagnosis) and during follow-up (over the year after diagnosis), were included. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals of developingrecurrent bladder cancer in relation to the intake of total fluid, total alcohol, and individual beverages. Results: During 2,025 person-years of follow-up, 238 (33%) of the included 716 NMIBC patients developed one or more recurrences of bladder cancer. Total fluid intake before diagnosis was not associated with a first recurrence of bladder cancer when comparing the highest and lowest intake group (HR = 0.98, 95% C.I. 0.70–1.38, p = 0.91). Comparable results were obtained for total fluid intake pre-diagnosis and the risk of developing multiple recurrences of bladder cancer (HR = 1.01, 95% C.I. 0.87–1.19, p = 0.85). A total of 379 of the 716 patients reported on usual fluid intake within 1 year of diagnosis. No significant associations between total fluid intake 1 year after diagnosis and a first recurrence of bladder cancer were found when comparing the highest and lowest intake group (HR = 0.91; 95% C.I. 0.60–1.37, p = 0.65) or with multiple recurrences of bladder cancer (HR = 1.06; 95% C.I. 0.89–1.26, p = 0.54). In addition, total alcohol intake and individual beverages were not associated with bladder cancer recurrence. Conclusions: The results indicate that an individual’s fluid intake from beverages is unlikely to have an important role in bladder cancer recurrence.

Radiation Therapy as Definitive Local Treatment in Patients with Limited-Stage Small Cell Carcinoma of the Bladder: Does total dose matter?

Purpose: To determine whether total radiation dose affects survival outcomes for patients with small cell carcinoma of the bladder (SCCB). Methods: We queried the National Cancer Database (NCDB) for patients with limited stage SCCB undergoing multimodality treatment and retrospectively analyzed survival outcomes according to total radiation dose received. Results: Patients aged 41–79 receiving a total radiation dose of 54 Gy or greater had a significant improvement in overall survival compared to those receiving less than 54 Gy, with a median overall survival of 58.9 months (95% confidence interval [CI] 37.2–80.6 months) compared to 21.5 months (95% CI 15.2 –27.8 months) (p < 0.05). There was no difference in outcomes for patients receiving between 54 and 60 Gy compared to those receiving 60 Gy or higher. There was also no difference in outcomes based on total radiation dose for patients 80 years and older. Conclusions: For patients aged 79 or younger with limited stage SCCB, total radiation dose of 54 Gy or greater is associated with better overall survival.

Systematic Review: Depression and Anxiety Prevalence in Bladder Cancer Patients

Depression affects more than 300 million people of all ages worldwide. In patients with cancer the reported prevalence is up to 24%. Objective: To systematically review the literature to report the prevalence of depression and anxiety among patients with bladder cancer (BC). Methods: Web of Science, MEDLINE/PubMed, and The Cochrane Library were searched between January and March 2018 using the terms “bladder carcinoma OR bladder cancer AND depression OR anxiety”. Results: Thirteen studies encompassing 1659 patients with BC were included. Six studies assessed depression prior and after treatment at 1, 6 and 12 

Low Frequency of Intratumor Heterogeneity in Bladder Cancer Tissue Microarrays

Intratumoral heterogeneity (ITH) is associated with clinical challenges such as possible differences in response to treatment and difficulties in classifying the tumor. Previously, ITH has been described in bladder cancer using detailed genetic analyses. However, in this disease, it is not known to what extent ITH actually occurs, or if it involves molecular subtyping, when assessment is achieved by immunohistochemistry (IHC) on the protein level using tissue microarrays (TMAs), the method most widely applied when analyzing large sample numbers. Objective: We aimed to investigate ITH by IHC in bladder cancer TMAs. Methods: Staining for eleven immunohistochemical markers (CK5, Cyclin D1, E-Cadherin, EGFR, FGFR, GATA3, HER2, p16, p63, P-Cadherin and RB1) was performed, and differences in staining patterns were assessed both within 1981 individual tissue-cores and by comparing two cores from the same tumor in 948 cases according to our pre-specified criteria. Presence of ITH was associated with clinicopathological data such as stage, grade, molecular subtype and survival. Results: Intracore ITH in one or several markers was associated with grade 3, stage T1 and the genomically unstable molecular subtype. ITH in three or more markers was found in 5% between cores (intercore heterogeneity) and in 2% within cores (intracore heterogeneity). No association with survival was found for any of the ITH groups. Conclusions: We observed ITH in a small proportion of the tumors, suggesting that ITH has only a limited impact on TMA bladder cancer studies.

New Horizons in Bladder Cancer Research: Report of the 15th Meeting of the International Bladder Cancer Network (IBCN) in Lisbon, Portugal, October 21–23, 2017

Fueled by recent progress of modern immunotherapy, bladder cancer has regained the interest of the scientific community and stimulated research exceeding the field of checkpoint inhibitors. The 15th meeting of the International Bladder Cancer Network (IBCN) took place at the Fundacao Champalimaud in Lisbon, Portugal, from October 21–23, 2017, 20 years after the first meeting in Barcelona. Once again, participants from different countries and with different scientific background discussed a broad spectrum of bladder cancer research spanning from basic research related topics (e.g. cancer models, biomarkers, molecular subtyping, molecular background of cancer progression and novel targets) to clinical aspects including tumor immunology [1]. A separate session tried to define “room to improvement” in clinical trial design.

Clinical Trials Corner

The American Society of Clinical Oncology (ASCO) just completed its annual meeting in Chicago this year and early clinical trial data were presented with new mechanisms of action. In addition, we are presenting ongoing trials other than immunotherapy trials against metastatic disease. Some of the trials have data and other advanced urothelial cancer trials are ongoing. We will also highlight the results for the English POUT trial in upper tract tumors, presented at the ASCO GU, EAU, and AUA annual meetings.

Financial Toxicity of Having Bladder Cancer

Bladder cancer is the most expensive malignancy to treat over the lifetime of patients. What is not often recognized, particularly by treating physicians, is that these costs are frequently a source of great concern and anxiety among patients with the disease and their families – a condition termed “financial toxicity“ (FT). This was emphasized in a recent article by a team at the University of North Carolina’s Lineberger Comprehensive Cancer Center. In it, researchers identified patients with a diagnosis of bladder cancer from Cancer Center rosters and asked them to reply via a computer assisted telephone survey to questions about demographics, healthcare access, comorbid conditions and treatments for those conditions and their bladder cancer.

Challenging Cases in Urothelial Cancer

MG is a 75 year old man who presented with a single episode of gross hematuria in October 2017. He is overweight and has insulin dependent diabetes mellitus. He has some lower urinary tract voiding symptoms. These consist of nocturia twice and some daytime frequency. His urinary stream is slow…