A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Nonmuscle-Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: Combination intravesical gemcitabine and docetaxel (GemDoce) has demonstrated efficacy as second-line therapy for patients with bacillus Calmette-Guérin (BCG)‒unresponsive nonmuscle-invasive urothelial carcinoma of the bladder (NMIBC). In the context of widespread BCG shortages, we performed a phase 2 prospective trial to assess GemDoce for BCG-naïve NMIBC. MATERIALS AND METHODS: This study is a prospective, single-arm, open-label phase 2 trial for patients with BCG-naïve high-risk NMIBC. Intravesical GemDoce was given weekly for 6 weeks as induction followed by monthly maintenance therapy for 2 years among responders. The primary end point was 3-month complete response, and key secondary end points included adverse events (AEs) and 12-month recurrence-free survival. RESULTS: Twenty-five patients were enrolled between August 2020 and August 2022 with median follow-up of 19.6 months. The pretreatment pathologic stages were high-grade (HG) T1 with carcinoma in situ (CIS; n = 7), HGT1 without CIS (n = 6), HGTa (n = 9), and CIS alone (n = 3). The 3-month complete response rate was 100% and recurrence-free survival at 12 months was 92%. Two patients with pretreatment HGT1 had HGT1 recurrences at 9 and 12 months. No patients progressed to T2 disease, underwent radical cystectomy, or had any radiographic evidence of progressive disease. Grade 1 AEs were common (23/25 patients) including hematuria, urinary frequency, urgency, and fatigue. Five patients (20%) experienced a grade 3 AE including hematuria and UTI. CONCLUSIONS: In this single-arm phase 2 trial, GemDoce was well tolerated with promising efficacy for patients with BCG-naïve high-risk NMIBC.

Interruptions in bladder cancer care during the COVID-19 public health emergency.

BACKGROUND: Academic and community urology centers participating in a pragmatic clinical trial in non-muscle-invasive bladder cancer completed monthly surveys assessing restrictions in aspects of bladder cancer care due to the COVID-19 Public Health Emergency. Our objective was to describe pandemic-related restrictions on bladder cancer care. METHODS: We invited 32 sites participating in a multicenter pragmatic bladder cancer trial to complete monthly surveys distributed through REDCap beginning in May 2020. These surveys queried sites on whether they were experiencing restrictions in the use of elective surgery, transurethral resection of bladder tumors (TURBT), radical cystectomy, office cystoscopy, and intravesical bacillus Calmette-Guerin (BCG) availability. Responses were collated with descriptive statistics. RESULTS: Of 32 eligible sites, 21 sites had at least a 50% monthly response rate over the study period and were included in the analysis. Elective surgery was paused at 76% of sites in May 2020, 48% of sites in January 2021, and 52% of sites in January 2022. Over those same periods, coinciding with COVID-19 incidence waves, TURBT was restricted at 10%, 14%, and 14% of sites, respectively, radical cystectomy was restricted at 10%, 14%, and 19% of sites, respectively, and cystoscopy was restricted at 33%, 0%, and 10% of sites, respectively. CONCLUSIONS: Bladder cancer care was minimally restricted compared with more pronounced restrictions seen in general elective surgeries during the COVID-19 pandemic.

A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

BACKGROUND: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. OBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites. INTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. RESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. CONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. PATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Differential changes in self-reported quality of life in elderly populations after diagnosis of a genitourinary malignancy.

BACKGROUND: The time of cancer diagnosis is a major event during which quality of life (QOL) can be affected and represents a crucial time to identify patients at high risk of decline. We sought to compare the differential effects of the diagnosis of 3 major urologic malignancies on QOL. METHODS: The Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey database was queried for patients who completed a QOL questionnaire (SF-36 or VR-12) before and after a diagnosis of bladder, kidney, or prostate cancer. Primary outcome measures were the mental component summary (MCS), and physical component summary (PCS) scores. Mixed effects linear regression was performed with cancer diagnosis as the primary variable of interest, with race and cardiovascular comorbidity status included as potentially confounding independent variables. RESULTS: There were 3,258 patients with urologic cancers. Both MCS and PCS scores dropped after diagnosis in all disease states. Bladder and kidney cancer patients demonstrated the greatest decline in MCS score (-1.762 points, 95% CI-2.571 to -0.952, P < 0.001) and PCS score (-3.769 points, 95% CI-5.042 to -2.496, P < 0.001), respectively, after adjustment for potential confounders. By contrast, prostate cancer patients demonstrated the smallest decline in both domains. Race and cardiovascular comorbidity status were independently associated with QOL, with an association 2 to 3 times greater than that of cancer diagnosis. CONCLUSIONS: Diagnosis of a urologic cancer was associated with a decline in patient-reported QOL, particularly in those with bladder or kidney cancer. Changes in physical health were more prominent than in mental health. Race and cardiovascular comorbidity status influenced QOL domains to a greater extent than specific urologic cancer diagnosis.

Circulating Tumor Cell and Circulating Tumor DNA Assays Reveal Complementary Information for Patients with Metastatic Urothelial Cancer.

Despite considerable advances in the management of urothelial carcinoma (UC), better risk stratification and enhanced detection of minimal residual disease are still urgent priorities to prolong survival while avoiding the morbidity of overtreatment. Circulating tumor cells and DNA (CTCs, ctDNA) are two biologically distinct "liquid biopsies" that may potentially address this need, although they have been understudied in UC to date and their relative utility is unknown. To this end, matched CTC and ctDNA samples were collected for a head-to-head comparison in a pilot study of 16 patients with metastatic UC. CTCs were defined as cytokeratin- and/or EpCAM-positive using the RareCyte direct imaging platform. ctDNA was assayed using the PlasmaSelect64 probe-capture assay. 75% of patients had detectable CTCs, and 73% had detectable somatic mutations, with no correlation between CTC count and ctDNA. 91% of patients had tissue confirmation of at least one plasma mutation and, importantly, several clinically actionable mutations were detected in plasma that were not found in the matching tumor. A ctDNA fraction of >2% was significantly associated with worse overall survival (p=0.039) whereas CTC detection was not (p=0.46). Notably, using a predefined gene panel for ctDNA detection had a high but not complete detection rate in metastatic UC, similar to what has been described for a custom tissue-personalized assay approach. In sum, both liquid biopsies show promise in UC and deserve further investigation. PATIENT SUMMARY: New "liquid biopsy" blood tests are emerging for urothelial cancer aimed at early detection and avoiding overtreatment. Our results suggest that two such tests provide complementary information: circulating tumor cells may be best for studying the biological features of a person's cancer, whereas circulating tumor DNA may be better for early detection.

Site of metastatic recurrence impacts prognosis in patients with high-grade upper tract urothelial carcinoma.

PURPOSE: Metastatic recurrence occurs in over 25% of upper tract urothelial carcinoma patients treated with radical nephroureterectomy. While metastatic recurrence suggests poor prognosis, the impact of the specific site of recurrence on prognosis is not well documented. MATERIALS AND METHODS: We retrospectively analyzed 188 patients who underwent radical nephroureterectomy for high-grade, node-negative upper tract urothelial carcinoma at our institution from 2003 to 2018 without receiving neoadjuvant or adjuvant chemotherapy. Competing-risks survival analysis was performed to evaluate the cumulative incidence and predictors of metastatic recurrence. The Kaplan-Meier method and log-rank test were used to estimate and compare recurrence site-specific survival probabilities following metastatic recurrence. Cox regression analyses were performed to assess site-specific prognoses. RESULTS: Of the 188 patients, 47 (25%) developed metastatic recurrence over a median follow-up of 30 months (interquartile range: 10.5-58.5 months). The 1- and 2-year cumulative incidences of metastatic recurrence were 13.6% and 23.6%, respectively. On multivariable analysis, lymphovascular invasion was significantly predictive of metastatic recurrence (subhazard ratio: 2.6, P = 0.01). Of the 47 patients who developed recurrence, 38 (80.9%) died over a median follow-up of 10 months (interquartile range: 5-20 months). Metastatic recurrence was most common in the lungs (n= 13, 28%) and at multiple sites (n= 14, 30%). Median time to recurrence was shorter for recurrences at multiple sites (6.5 months) and those in the liver (13 months) and bone (18 months) compared to other sites. Patients who recurred in the liver (hazard ratio: 6.3, P = 0.007), bone (hazard ratio: 4.9, P = 0.02), and multiple sites (hazard ratio: 4.6, P = 0.01) had significantly worse prognosis compared to those who recurred in lymph nodes. Statistical significance persisted after adjusting for treatment with salvage therapy. CONCLUSIONS: A significant proportion of high-grade upper tract urothelial carcinoma patients recur systemically after radical nephroureterectomy. Lymphovascular invasion is a predictor of metastatic recurrence and may inform decisions regarding perioperative chemotherapy. Hepatic and osseous recurrences have relatively quicker onset and less favorable prognosis compared to other sites. These findings may benefit future efforts to develop recurrence site-specific treatment plans and highlight the necessity of subsequent endeavors to explore the genetic associations of recurrence in upper tract urothelial carcinoma.

Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer.

BACKGROUND: Standard of care for patients with muscle-invasive bladder cancer (MIBC) includes neoadjuvant cisplatin-based chemotherapy (NAC) followed by consolidative therapy with either chemoradiation or radical cystectomy (RC). Some patients experience robust pathologic responses to NAC, and these have been reported to associate with somatic mutations in specific gene pathways including DNA damage response genes. OBJECTIVE: To evaluate the ability of post-NAC clinical restaging, with or without tumor sequencing, to predict final RC pathologic staging. DESIGN, SETTING, AND PARTICIPANTS: We reviewed our institutional review board-approved institutional database to identify patients with MIBC who underwent NAC followed by RC from 2003 to 2016. Following NAC prior to RC, cystoscopy was performed routinely, with resection of residual visible tumor and/or tumor base (transurethral resection [TUR]). For patients with pre-NAC tumor tissue available, tumor sequencing was performed. Outcome measurements and statistical analysis: Clinical restaging and tumor sequencing were evaluated for their ability to predict the final pathologic stage accurately at RC using chi-square or Fisher's exact test. RESULTS AND LIMITATIONS: A total of 114 patients underwent restaging TUR following NAC and prior to RC. The diagnostic accuracy of post-NAC clinical restaging including TUR was poor, with 32% of patients being downstaged falsely when compared with their final RC pathology. Forty-nine patients had sequencing of pre-NAC tumor tissue, of whom 32 showed at least one mutation of interest. However, NAC responses and rates of false downstaging did not differ significantly according to tumor mutation status. CONCLUSIONS: This study highlights the inaccuracy of post-NAC clinical restaging TUR with or without adjunctive tumor mutation analysis, to assess pathologic residual disease accurately. Caution must be taken when performing post-NAC restaging, especially when considering conservative management strategies such as active surveillance on this basis. Patient summary: Several groups are evaluating whether certain patients, whose bladder cancer responds well to upfront chemotherapy, may be able to forego cystectomy safely. We demonstrate that currently available staging tools and tumor DNA sequencing cannot identify such patients reliably and accurately.

Identification of Candidates for Salvage Therapy: The Past, Present, and Future of Defining Bacillus Calmette-Guérin Failure.

Disease progression and recurrence are common among patients on Bacillus Calmette-Guérin (BCG) therapy, and options for bladder-preserving subsequent therapy remain limited. Ongoing efforts to develop better second-line bladder-sparing therapies rely on clinical trials of patients deemed to have failed management with BCG. This article describes historical definitions of BCG failure, as well as recent efforts to better delineate and refine the clinical criteria for identifying individual patients who will not benefit from further intravesical BCG therapy. It also reviews guidance from the most recent expert consensus panels and professional association guidelines regarding which patients should not receive additional BCG therapy.