Faculty Bibliography

AIM/OBJECTIVE:This review article summarizes the current clinical practice guidelines around disease definitions and risk stratifications, and the treatment of non-muscle-invasive bladder cancer (NMIBC). Recently completed and ongoing clinical trials of novel and investigational therapies in Bacillus Calmette-Guérin (BCG)-naïve, BCG-recurrent, and BCG-unresponsive patient populations are also described, e.g., those involving immune checkpoint inhibitors, targeted therapies, other chemotherapy regimens, vaccines, and viral- or bacterial-based treatments. Finally, a brief overview of enhanced cystoscopy and drug delivery systems for the diagnosis and treatment of NMIBC is provided. BACKGROUND:A global shortage of access to BCG is affecting the management of BCG-naïve and BCG-recurrent/unresponsive NMIBC; hence, there is an urgent need to assist patients and urologists to enhance the treatment of this disease. METHODS:Searches of ClinicalTrials.gov, PubMed, and Google Scholar were conducted. Published guidance and conference proceedings from major congresses were reviewed. CONCLUSION/CONCLUSIONS:Treatment strategies for NMIBC are generally consistent across guidelines. Several novel therapies have demonstrated promising antitumor activity in clinical trials, including in high-risk or BCG-unresponsive disease. The detection, diagnosis, surveillance, and treatment of NMIBC have also been improved through enhanced disease detection.

Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). Clinical trial registration: NCT03924856 & NCT03924895 (ClinicalTrials.gov).

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

BACKGROUND: The work-up and diagnosis of indeterminate lung nodules at 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 were 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 initial bladder cancer stage.

BACKGROUND:BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS:viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS/RESULTS:Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION/CONCLUSIONS:Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING/BACKGROUND:FKD Therapies Oy.

Dissemination of misinformation through social media is a major societal issue. Bladder cancer is the second most common urological cancer in the world, but there are limited data on the quality of bladder cancer information on social networks. Our objective was to characterize the quality of information and presence of misinformation about bladder cancer on YouTube, the most commonly used social media platform. We reviewed the first 150 YouTube videos about "bladder cancer" using two validated instruments for consumer health information and assessed the videos for the presence of misinformation. The videos had a median of 2288 views (range, 14-511 342), but the overall quality of information was moderate to poor in 67%, based on scores of 1-3 out of 5 on the validated DISCERN instrument. A moderate to high amount of misinformation was present in 21% of videos and reached 1 289 314 viewers. Commercial bias was apparent in 17% of videos, which reached 324 287 viewers. From a networking perspective, comments sections in the videos were sometimes used to request medical advice (20%), provide medical advice to others (9%), or give support (19%). In conclusion, YouTube is a widely used source of information and advice about bladder cancer, but much of the content is of poor quality. PATIENT SUMMARY: A large quantity of content about bladder cancer is available on YouTube. Unfortunately, much of the content is of moderate to poor quality and presents a risk of exposure to misinformation.