Browsing by Author "Inman, Brant A"

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    ItemOpen Access
    A lifestyle intervention of weight loss via a low-carbohydrate diet plus walking to reduce metabolic disturbances caused by androgen deprivation therapy among prostate cancer patients: carbohydrate and prostate study 1 (CAPS1) randomized controlled trial.
    (Prostate cancer and prostatic diseases, 2019-09) Freedland, Stephen J; Howard, Lauren; Allen, Jenifer; Smith, Jordan; Stout, Jennifer; Aronson, William; Inman, Brant A; Armstrong, Andrew J; George, Daniel; Westman, Eric; Lin, Pao-Hwa

    Purpose

    The objective of this study was to test a low-carbohydrate diet (LCD) plus walking to reduce androgen deprivation therapy (ADT)-induced metabolic disturbances.

    Materials and methods

    This randomized multi-center trial of prostate cancer (PCa) patients initiating ADT was designed to compare an LCD (≤20g carbohydrate/day) plus walking (≥30 min for ≥5 days/week) intervention vs. control advised to maintain usual diet and exercise patterns. Primary outcome was change in insulin resistance by homeostatic model assessment at 6 months. To detect 20% reduction in insulin resistance, 100 men were required. The study was stopped early after randomizing 42 men due to slow accrual. Secondary outcomes included weight, body composition, lipids, and prostate-specific antigen (PSA). Changes from baseline were compared between arms using rank-sum tests.

    Results

    At 6 months, LCD/walking reduced insulin resistance by 4% vs. 36% increase in control (p = 0.13). At 3 months, vs. control, LCD/walking arm significantly lost weight (7.8kg; p<0.001), improved insulin resistance (↑36%; p = 0.015), hemoglobin A1c (↓3.3%; p = 0.01), high-density lipoprotein (HDL) (↑13%; p = 0.004), and triglyceride (↓37%; p = 0.036). At 6 months, weight loss (10.6kg; p<0.001) and HDL (↑27%; p = 0.003) remained significant. LCD/walking preserved total body bone mineral count (p = 0.025), reduced fat mass (p = 0.002), lean mass (p = 0.036), and percent body fat (p = 0.004). There were no differences in PSA. Limitations include the effect of LCD, weight loss vs. walking instruction are indistinguishable, and small sample size.

    Conclusions

    In an underpowered study, LCD/walking did not improve insulin sensitivity at 6 months. Given most secondary outcomes were improved at 3 months with some remaining improved at 6 months and a secondary analysis showed that LCD/walking reduced insulin resistance over the study, supporting future larger studies of LCD/walking intervention to reduce ADT-induced disturbances.
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    Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC).
    (Cancer, 2021-07) Harrison, Michael R; Costello, Brian A; Bhavsar, Nrupen A; Vaishampayan, Ulka; Pal, Sumanta K; Zakharia, Yousef; Jim, Heather SL; Fishman, Mayer N; Molina, Ana M; Kyriakopoulos, Christos E; Tsao, Che-Kai; Appleman, Leonard J; Gartrell, Benjamin A; Hussain, Arif; Stadler, Walter M; Agarwal, Neeraj; Pachynski, Russell K; Hutson, Thomas E; Hammers, Hans J; Ryan, Christopher W; Inman, Brant A; Mardekian, Jack; Borham, Azah; George, Daniel J

    Background

    Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature.

    Methods

    This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival.

    Results

    Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST.

    Conclusions

    AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.
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    Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.
    (European urology, 2021-12-18) Mitra, Anirban P; Narayan, Vikram M; Mokkapati, Sharada; Miest, Tanner; Boorjian, Stephen A; Alemozaffar, Mehrdad; Konety, Badrinath R; Shore, Neal D; Gomella, Leonard G; Kamat, Ashish M; Bivalacqua, Trinity J; Montgomery, Jeffrey S; Lerner, Seth P; Busby, J Erik; Poch, Michael; Crispen, Paul L; Steinberg, Gary D; Schuckman, Anne K; Downs, Tracy M; Svatek, Robert S; Mashni, Joseph; Lane, Brian R; Guzzo, Thomas J; Bratslavsky, Gennady; Karsh, Lawrence I; Woods, Michael E; Brown, Gordon A; Canter, Daniel; Luchey, Adam; Lotan, Yair; Krupski, Tracey; Inman, Brant A; Williams, Michael B; Cookson, Michael S; Keegan, Kirk A; Andriole, Gerald L; Sankin, Alexander I; Boyd, Alan; O'Donnell, Michael A; Philipson, Richard; Ylä-Herttuala, Seppo; Sawutz, David; Parker, Nigel R; McConkey, David J; Dinney, Colin PN
    A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.
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    Assessments of frailty in bladder cancer.
    (Urologic oncology, 2020-05-22) Grimberg, Dominic C; Shah, Ankeet; Molinger, Jeroen; Whittle, John; Gupta, Rajan T; Wischmeyer, Paul E; McDonald, Shelley R; Inman, Brant A
    BACKGROUND AND AIMS:The incidence of frailty is increasing as the population ages, which has important clinical implications given the associations between frailty and poor outcomes in the bladder cancer population. Due to a multi-organ system decline and decreased physiologic reserve, frail patients are vulnerable to stressors of disease and have poorer mortality and morbidity rates than their nonfrail peers. The association between frailty and poor outcomes has been documented across multiple populations, including radical cystectomy, creating a need for frailty assessments to be used preoperatively for risk stratification. We aim to provide a review of the common frailty assessments and their relevance to radical cystectomy patients. FINDINGS:A variety of assessments for frailty exist, from short screening items to comprehensive geriatric assessments. The syndrome spans multiple organ systems, as do the potential diagnostic instruments. Some instruments are less practical for use in clinical practice by urologists, such as the Canadian Study of Health and Aging Frailty Index and Comprehensive Geriatric Assessment. The tool most studied in radical cystectomy is the modified Frailty Index, associated with high grade complications and 30-days mortality. Frailty often coexists with malnutrition and sarcopenia, stressing the importance of screening for and addressing these syndromes to improve patient's perioperative outcomes. CONCLUSIONS:There is no universally agreed upon frailty assessment, but the most studied in radical cystectomy is the modified Frailty Index, providing valuable data with which to counsel patients preoperatively. Alterations in immune phenotypes provide potential future diagnostic biomarkers for frailty.
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    Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.
    (Prostate cancer and prostatic diseases, 2021-10-13) Patierno, Brendon M; Foo, Wen-Chi; Allen, Tyler; Somarelli, Jason A; Ware, Kathryn E; Gupta, Santosh; Wise, Sandra; Wise, John P; Qin, Xiaodi; Zhang, Dadong; Xu, Lingfan; Li, Yanjing; Chen, Xufeng; Inman, Brant A; McCall, Shannon J; Huang, Jiaoti; Kittles, Rick A; Owzar, Kouros; Gregory, Simon; Armstrong, Andrew J; George, Daniel J; Patierno, Steven R; Hsu, David S; Freedman, Jennifer A

    Background

    Prostate cancer is a clinically and molecularly heterogeneous disease, with highest incidence and mortality among men of African ancestry. To date, prostate cancer patient-derived xenograft (PCPDX) models to study this disease have been difficult to establish because of limited specimen availability and poor uptake rates in immunodeficient mice. Ancestrally diverse PCPDXs are even more rare, and only six PCPDXs from self-identified African American patients from one institution were recently made available.

    Methods

    In the present study, we established a PCPDX from prostate cancer tissue from a patient of estimated 90% West African ancestry with metastatic castration resistant disease, and characterized this model's pathology, karyotype, hotspot mutations, copy number, gene fusions, gene expression, growth rate in normal and castrated mice, therapeutic response, and experimental metastasis.

    Results

    This PCPDX has a mutation in TP53 and loss of PTEN and RB1. We have documented a 100% take rate in mice after thawing the PCPDX tumor from frozen stock. The PCPDX is castrate- and docetaxel-resistant and cisplatin-sensitive, and has gene expression patterns associated with such drug responses. After tail vein injection, the PCPDX tumor cells can colonize the lungs of mice.

    Conclusion

    This PCPDX, along with others that are established and characterized, will be useful pre-clinically for studying the heterogeneity of prostate cancer biology and testing new therapeutics in models expected to be reflective of the clinical setting.
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    ItemOpen Access
    Clinical trial of high dose hyperthermic intravesical mitomycin C for intermediate and high-risk non-muscle invasive bladder cancer during BCG shortage.
    (Urologic oncology, 2021-08) Grimberg, Dominic C; Dudinec, John; Shah, Ankeet; Inman, Brant A

    Purpose

    Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC), but availability is limited by global shortages. We present the first North American clinical experience using intravesical hyperthermia (HIVEC) with high-dose mitomycin C (MMC) during BCG shortage.

    Materials and methods

    Single arm intermediate size expanded access protocol for high dose HIVEC MMC in patients with intermediate and high-risk NMIBC during BCG shortage. Patients received 120 mg intravesical MMC using the Combat BRS to achieve 43°C HIVEC. Primary outcome was a safety assessment of adverse events, with recurrence-free survival and a descriptive analysis of hematologic impacts as secondary outcomes.

    Results

    Fourteen patients were treated from May 2019 to June 2020, 4 (29%) intermediate and 10 (71%) high risk. The cohort is heavily pretreated, only 2 (14%) BCG naïve and median 6 BCG instillations (IQR 5.25, 8.25), with median 3.5 recurrences per patient (IQR 1.00, 5.25) 67% with >1 per year. Patients underwent a median 6 instillations (IQR 3.25, 9.25) which were well tolerated in 11/14 (79%). Seven patients (50%) experienced 10 adverse events, all grades 1 or 2. Most common was MMC allergy (4/14, 29%), followed by bladder spasm (3/14, 21%). Two had recurrences at median 11 months follow up, but both discontinued HIVEC after only 2 treatments.

    Conclusions

    High dose MMC HIVEC is a safe and well-tolerated substitute for BCG during global shortages. The higher rate of systemic effects implies increased drug delivery, which may improve efficacy.
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    Diet and Exercise Are not Associated with Skeletal Muscle Mass and Sarcopenia in Patients with Bladder Cancer.
    (European urology oncology, 2021-04) Wang, Yingqi; Chang, Andrew; Tan, Wei Phin; Fantony, Joseph J; Gopalakrishna, Ajay; Barton, Gregory J; Wischmeyer, Paul E; Gupta, Rajan T; Inman, Brant A

    Background

    There is limited understanding about why sarcopenia is happening in bladder cancer, and which modifiable and nonmodifiable patient-level factors affect its occurrence.

    Objective

    The objective is to determine the extent to which nonmodifiable risk factors, modifiable lifestyle risk factors, or cancer-related factors are determining body composition changes and sarcopenia in bladder cancer survivors.

    Design, setting, and participants

    Patients above 18 yr of age with a histologically confirmed diagnosis of bladder cancer and a history of receiving care at Duke University Medical Center between January 1, 1996 and June 30, 2017 were included in this study.

    Outcome measurements and statistical analysis

    Bladder cancer survivors from our institution were assessed for their dietary intake patterns utilizing the Diet History Questionnaire II (DHQ-II) and physical activity utilizing the International Physical Activity Questionnaire long form (IPAQ-L) tools. Healthy Eating Index 2010 (HEI2010) scores were calculated from DHQ-II results. Body composition was evaluated using Slice-O-Matic computed tomography scan image analysis at L3 level and the skeletal muscle index (SMI) calculated by three independent raters.

    Results and limitations

    A total of 285 patients were evaluated in the study, and the intraclass correlation for smooth muscle area was 0.97 (95% confidence interval: 0.94-0.98) between raters. The proportions of patients who met the definition of sarcopenia were 72% for men and 55% of women. Univariate linear regression analysis demonstrated that older age, male gender, and black race were highly significant predictors of SMI, whereas tumor stage and grade, chemotherapy, and surgical procedures were not predictors of SMI. Multivariate linear regression analysis demonstrated that modifiable lifestyle factors, including total physical activity (p=0.830), strenuousness (high, moderate, and low) of physical activity (p=0.874), individual nutritional components (daily calories, p=0.739; fat, p=0.259; carbohydrates, p=0.983; and protein, p=0.341), and HEI2010 diet quality (p=0.822) were not associated with SMI.

    Conclusions

    Lifestyle factors including diet quality and physical activity are not associated with SMI and therefore appear to have limited impact on sarcopenia. Sarcopenia may largely be affected by nonmodifiable risk factors.

    Patient summary

    In this report, we aim to determine whether lifestyle factors such as diet and physical activity were the primary drivers of body composition changes and sarcopenia in bladder cancer survivors. We found that lifestyle factors including dietary habits, individual nutritional components, and physical activity do not demonstrate an association with skeletal muscle mass, and therefore may have limited impact on sarcopenia.
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    ItemOpen Access
    Editorial Comment.
    (The Journal of urology, 2020-11-30) Campbell, Scott P; Inman, Brant A
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    En Bloc Resection of Bladder Tumors: Style or Substance?
    (European Urology, 2020-06) Grimberg, Dominic C; Shah, Ankeet; Inman, Brant A
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    Evaluation of the Fluorescence In Situ Hybridization Test to Predict Recurrence and/or Progression of Disease after bacillus Calmette-Guérin for Primary High Grade Nonmuscle Invasive Bladder Cancer: Results from a Prospective Multicenter Trial.
    (The Journal of urology, 2019-11) Lotan, Yair; Inman, Brant A; Davis, Leah Gerber; Kassouf, Wassim; Messing, Edward; Daneshmand, Siamak; Canter, Daniel; Marble, H Tony; Joseph, Ajith M; Jewell, Susan; Boorjian, Stephen A
    PURPOSE:Single center studies have shown that positive UroVysion® fluorescence in situ hybridization results were associated with recurrence of nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. Our goal was to validate these findings. MATERIALS AND METHODS:We performed a prospective, multicenter diagnostic trial to determine whether the fluorescence in situ hybridization test could predict recurrence or progression in patients with primary high grade nonmuscle invasive bladder cancer who were scheduled to receive bacillus Calmette-Guérin. Fluorescence in situ hybridization testing was performed prior to the first bacillus Calmette-Guérin instillation, prior to the sixth instillation and at 3-month cystoscopy. The performance of fluorescence in situ hybridization was evaluated. RESULTS:A total of 150 patients were enrolled in analysis, including 68 with Ta disease, 41 with T1 disease, 26 with carcinoma in situ alone and 15 with papillary carcinoma plus carcinoma in situ. At 9 months of followup there were 46 events, including 37 recurrences and 9 progressions. For events with positive fluorescence in situ hybridization findings the HR was 2.59 (95% CI 1.42-4.73) for the baseline test, 1.94 (95% CI 1.04-3.59) for the 6-week test and 3.22 (95% CI 1.65-6.27) at 3 months. Patients with positive results at baseline, 6 weeks and 3 months had events 55% of the time and patients with negative results at each time point had no event 76% of the time. CONCLUSIONS:The study validated that a positive UroVysion fluorescence in situ hybridization test was associated with a 3.3-fold increased risk of recurrence. The test may be useful to risk stratify patients entering clinical trials in whom induction therapy fails. However, using the test to change management decisions is limited due to the discordance between results and outcomes as well as the variance of tests results with time.
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    Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non-muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis.
    (European urology oncology, 2020-06) Kamat, Ashish M; Lerner, Seth P; O'Donnell, Michael; Georgieva, Mihaela V; Yang, Min; Inman, Brant A; Kassouf, Wassim; Boorjian, Stephen A; Tyson, Mark D; Kulkarni, Girish S; Chang, Sam S; Konety, Badrinath R; Svatek, Robert S; Balar, Arjun; Witjes, J Alfred

    Context

    Currently, there is no standard of care for patients with non-muscle-invasive bladder cancer (NMIBC) who recur despite bacillus Calmette-Guerin (BCG) therapy. Although radical cystectomy is recommended, many patients decline to undergo or are ineligible to receive it. Multiple agents are being investigated for use in this patient population.

    Objective

    To systematically synthesize and describe the efficacy and safety of current and emerging treatments for NMIBC patients after treatment with BCG.

    Evidence acquisition

    A systematic literature search of MEDLINE, Embase, and the Cochrane Controlled Register of Trials (period limited to January 2007-June 2019) was performed. Abstracts and presentations from major conference proceedings were also reviewed. Randomized controlled trials were assessed using the Cochrane risk of bias tool. Data for single-arm trials were pooled using a random-effect meta-analysis with the proportions approach. Trials were grouped based on the minimum number of prior BCG courses required before enrollment and further stratified based on the proportion of patients with carcinoma in situ (CIS).

    Evidence synthesis

    Thirty publications were identified with data from 23 trials for meta-analysis, of which 17 were single arm. Efficacy and safety outcomes varied widely across studies. Heterogeneity across trials was reduced in subgroup analyses. The pooled 12-mo response rates were 24% (95% confidence interval [CI]: 16-32%) for trials with two or more prior BCG courses and 36% (95% CI: 25-47%) for those with one or more prior BCG courses. In a subgroup analysis, inclusion of ≥50% of patients with CIS was associated with a lower response.

    Conclusions

    The variability in efficacy and safety outcomes highlights the need for consistent endpoint reporting and patient population definitions. With promising emerging treatments currently in development, efficacious and safe therapeutic options are urgently needed for this difficult-to-treat patient population.

    Patient summary

    We examined the efficacy and safety outcomes of treatments for non-muscle-invasive bladder cancer after bacillus Calmette-Guerin therapy. Outcomes varied across studies and patient populations, but emerging treatments currently in development show promising efficacy.
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    Follicle-Stimulating Hormone (FSH) Levels During Androgen Deprivation Therapy Are Not Associated With Survival or Development of Castration-Resistant Prostate Cancer
    (Soc Int Urol J) Atchia, Kaleem; Joncas, France-Helene; Trasiewicz, Lily Summers; Tan, Wei Phin; Ding, Keyue; Inman, Brant A; Toren, Paul
    Background Follicle-stimulating hormone (FSH) dysregulation plays a potential role in prostate cancer progression. The objective of this study was to evaluate whether higher FSH levels during androgen deprivation therapy (ADT) for recurrent prostate cancer could predict the development of castration-resistant prostate cancer (CRPC), prostate cancer-specific survival (CSS), and overall survival (OS). Methods Serum FSH levels were measured in cryopreserved samples of the continuous ADT arm of the PR.7 trial, supplemented with analogous samples from a large contemporaneous biobank. Univariate and multivariate analyses assessed the relationship between FSH tertiles and time to CRPC, as well as CSS, and OS. Results A total of 172 patients were included in our analysis. Of these, 54 patients (31%) developed CRPC during the 9-year follow-up. Median FSH for the tertiles was 4.35, 6.13, and 11.32 mIU/mL. FSH tertiles were not significantly associated with the time to CRPC, or with CSS or OS. FSH levels were not a significant prognostic factor for these oncologic outcomes. Conclusion As previously reported, the use of gonadotropin-releasing hormone (GnRH) antagonists for ADT has significantly more suppression of FSH levels than GnRH agonists. Our results do not suggest that differences in circulating FSH 1 year following ADT initiation influence long-term oncologic outcomes or development of CRPC.
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    From Dog's Breakfast to Michelin Guide: Post-bacillus Calmette-Guérin Trials in Non-muscle-invasive Bladder Cancer.
    (European urology, 2020-04-14) Shah, Ankeet; Grimberg, Dominic C; Inman, Brant A
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    Heated Intravesical Chemotherapy: Biology and Clinical Utility.
    (The Urologic clinics of North America, 2020-02) Tan, Wei Phin; Longo, Thomas A; Inman, Brant A
    Non-muscle-invasive bladder cancer can be a challenging disease to manage. In recent years, hyperthermia therapy in conjunction with intravesical therapy has been gaining traction as a treatment option for bladder cancer, especially if Bacillus Calmette-Guerin might not be available. Trials of intravesical chemotherapy with heat are few and there has been considerable heterogeneity between studies. However, multiple new trials have accrued and high-quality data are forthcoming. In this review, we discuss the role of combined intravesical hyperthermia and chemotherapy as a novel approach for the treatment of bladder cancer.
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    Impact of an enhanced recovery pathway on length of stay and complications in elective radical cystectomy: a before and after cohort study
    (Perioperative Medicine, 2019-12) Dunkman, W Jonathan; Manning, Michael W; Whittle, John; Hunting, John; Rampersaud, Edward N; Inman, Brant A; Thacker, Julie K; Miller, Timothy E
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    Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
    (The Lancet. Oncology, 2020-11-27) Boorjian, Stephen A; Alemozaffar, Mehrdad; Konety, Badrinath R; Shore, Neal D; Gomella, Leonard G; Kamat, Ashish M; Bivalacqua, Trinity J; Montgomery, Jeffrey S; Lerner, Seth P; Busby, Joseph E; Poch, Michael; Crispen, Paul L; Steinberg, Gary D; Schuckman, Anne K; Downs, Tracy M; Svatek, Robert S; Mashni, Joseph; Lane, Brian R; Guzzo, Thomas J; Bratslavsky, Gennady; Karsh, Lawrence I; Woods, Michael E; Brown, Gordon; Canter, Daniel; Luchey, Adam; Lotan, Yair; Krupski, Tracey; Inman, Brant A; Williams, Michael B; Cookson, Michael S; Keegan, Kirk A; Andriole, Gerald L; Sankin, Alexander I; Boyd, Alan; O'Donnell, Michael A; Sawutz, David; Philipson, Richard; Coll, Ruth; Narayan, Vikram M; Treasure, F Peter; Yla-Herttuala, Seppo; Parker, Nigel R; Dinney, Colin PN

    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

    In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 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

    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

    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

    FKD Therapies Oy.
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    Longitudinal patterns of cost and utilization of medicare beneficiaries with bladder cancer.
    (Urologic oncology, 2020-02) Sloan, Frank A; Yashkin, Arseniy P; Akushevich, Igor; Inman, Brant A

    Background

    Bladder cancer (BC) is highly prevalent and costly. This study documented cost and use of services for BC care and for other (non-BC) care received over a 15-year follow-up period by a cohort of Medicare beneficiaries diagnosed with BC in 1998.

    Methods

    Data came from the Surveillance, Epidemiology and End Results Program linked to Medicare claims. Medicare claims provided data on diagnoses, services provided, and Medicare Parts A and B payments. Cost was actual Medicare payments to providers inflated to 2018 US$. Cost and utilization were BC-related if the claim contained a BC diagnosis code. Otherwise, costs were for "other care." For utilization, we grouped Part B-covered services into 6 mutually-exclusive categories. Utilization rates were ratios of the count of claims in a particular category during a follow-up year divided by the number of beneficiaries with BC surviving to year-end.

    Results

    Cumulatively over 15-years, for all stages combined, total BC-related cost per BC beneficiary was $42,011 (95% Confidence Interval (CI): $42,405-$43,417); other care cost was about twice this number. Cumulative total BC-related cost of 15-year BC survivors for all stages was $43,770 (CI: $39,068-$48,522), intensity of BC-related care was highest during the first year following BC diagnosis, falling substantially thereafter. After follow-up year 5, there were few statistically significant changes in BC-related utilization. Utilization of other care remained constant during follow-up or increased.

    Conclusions

    Substantial costs were incurred for non-BC care. While increasing BC survivorship is an important objective, non-BC care would remain a burden to Medicare.
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    Managing Prostate Cancer Surgical Patients during the COVID-19 Pandemic: A Brief Report of the Duke Cancer Institute's Initial Experience.
    (Oncology (Williston Park, N.Y.), 2020-05) Moul, Judd W; Chang, Andrew; Inman, Brant A
    The coronavirus disease 2019 pandemic has rapidly placed tremendous stress on health systems around the world. In response, multiple health systems have postponed elective surgeries in order to conserve hospital beds and personal protective equipment, minimize patient traffic, and prevent unnecessary utilization and exposure of healthcare workers. The American College of Surgeons released the following statement on March 13, 2020: "Each hospital, health system and surgeon should thoughtfully review all scheduled elective procedures with a plan to minimize, postpone, or cancel electively scheduled operations, endoscopes, or other invasive procedures until we have passed the predicted inflection point in the exposure graph and can be confident that our health care infrastructure can support a potentially rapid and overwhelming uptick in critical patient care needs." In our state, North Carolina, Governor Roy Cooper requested that all hospitals postpone elective and non-urgent procedures and surgeries effective March 23, 2020.
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    Metastatic Urothelial Carcinoma from Transplanted Kidney with Complete Response to an Immune Checkpoint Inhibitor.
    (Case reports in urology, 2020-01) Chiang, Ryan S; Connor, Ashton A; Inman, Brant A; Foo, Wen-Chi; Howell, David N; Madden, John F; Ellis, Matthew J; Rege, Aparna S; Harrison, Michael R

    Background

    Donor-derived malignancy is a rare complication in patients who undergo organ transplant. Approaches to treatment have largely been individualized based on clinical circumstances given the lack of evidence-based guidelines, with therapeutic options ranging from discontinuation of immunosuppression and transplantectomy to the addition of chemotherapy or radiotherapy. Case Presentation. Herein, we describe a 60-year-old woman with metastatic donor-derived upper tract urothelial carcinoma (UTUC) discovered nine years postrenal transplant. Molecular diagnostic studies using polymerase chain reaction amplification of short tandem repeat alleles and HLA tissue typing proved that the urothelial carcinoma originated from donor tissue. She achieved sustained complete remission with transplant nephroureterectomy, retroperitoneal lymphadenectomy, immunosuppression withdrawal, and immunotherapy with pembrolizumab. Routine radiologic surveillance has demonstrated 15-month progression-free survival to date off pembrolizumab, and she is now under consideration for retransplantation.

    Conclusions

    Immunotherapy using checkpoint inhibitors can serve as a novel treatment option for patients in the clinical predicament of having a solid organ transplant and simultaneous metastatic malignancy. In this report, we also discuss the oncogenic potential of BK virus, the use of checkpoint inhibitors in urothelial carcinoma, and the feasibility of retransplant for this patient population.
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