Cost-utility of Initial Management of High-grade T1 Bladder Cancer With Intravesical BCG vs Immediate Radical Cystectomy.

OBJECTIVE: To compare the cost-utility of initial management of high-grade T1 non-muscle invasive bladder cancer (HGT1 NMIBC) with intravesical BCG vs immediate radical cystectomy. High-risk NMIBC patients may climb a costly ladder of treatments, culminating in radical cystectomy for oncologic or symptomatic benefit in up to one-third. This high healthcare resource utilization presents a challenging dilemma in balancing sufficiently aggressive management with cost, toxicity, and quality-of-life. METHODS: Cost-utility of initially managing HGT1 with intravesical BCG and early radical cystectomy with ileal conduit urinary diversion was compared using decision-analytic Markov models. Five-year oncologic outcomes, adverse event rates, and published utility values were extracted from literature. Costs were calculated from a US Medicare perspective in 2021 US dollars. Sensitivity analysis identified drivers of cost and break-even points for recurrence and progression. RESULTS: Mean costs were $26,093 for intravesical BCG and $39,720 for immediate radical cystectomy, though cystectomy generated a gain of 2.2 quality-adjusted life years (QALYs) compared to intravesical BCG. Immediate cystectomy was a more cost-effective management strategy for HGT1 NMIBC with an incremental CE ratios (ICER) of $7120/QALY. The costs associated with cystectomy, TURBT, and BCG toxicity had the greatest impact on ICER. One-way sensitivity analysis demonstrated that intravesical BCG became a cost-effective management strategy if the 5-year recurrence rate of HG T1 was less than 56% or the 5-year progression rate to MIBC was less than 4%. CONCLUSION: At current prices, treatment of high-grade T1 NMIBC with early radical cystectomy is more cost-effective management strategy than initial treatment with intravesical BCG.

Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non-organ-confined Upper Tract Urothelial Carcinoma.

BACKGROUND: Optimal patient selection for neoadjuvant chemotherapy prior to surgical extirpation is limited by the inaccuracy of contemporary clinical staging methods in high-risk upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle-invasive (MI) and non-organ-confined (NOC) UTUC. DESIGN, SETTING, AND PARTICIPANTS: Plasma cell-free DNA was prospectively collected from chemotherapy-naïve, high-risk UTUC patients undergoing surgical extirpation and sequenced using a 152-gene panel and low-pass whole-genome sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To test for concordance, whole-exome sequencing was performed on matching tumor samples. The performance of ctDNA for predicting MI/NOC UTUC was summarized using the area under a receiver-operating curve, and a variant count threshold for predicting MI/NOC disease was determined by maximizing Youden's J statistic. Kaplan-Meier methods estimated survival, and Mantel-Cox log-rank testing assessed the association between preoperative ctDNA positivity and clinical outcomes. RESULTS AND LIMITATIONS: Of 30 patients enrolled prospectively, 14 were found to have MI/NOC UTUC. At least one ctDNA variant was detected from 21/30 (70%) patients, with 52% concordance with matching tumor samples. Detection of at least two panel-based molecular alterations yielded 71% sensitivity at 94% specificity to predict MI/NOC UTUC. Imposing this threshold in combination with a plasma copy number burden score of >6.5 increased sensitivity to 79% at 94% specificity. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (PFS; 1-yr PFS 69% vs 100%, p < 0.001) and cancer-specific survival (CSS; 1-yr CSS 56% vs 100%, p = 0.016). CONCLUSIONS: The detection of plasma ctDNA prior to extirpative surgery was highly predictive of MI/NOC UTUC and strongly prognostic of PFS and CSS. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy. PATIENT SUMMARY: Here, we show that DNA from upper tract urothelial tumors can be detected in the blood prior to surgical removal of the kidney or ureter. This circulating tumor DNA can be used to predict that upper tract urothelial carcinoma is invasive into the muscular lining of the urinary tract and may help identify those patients who could benefit from chemotherapy prior to surgery.

Short- and Long-Term Renal Function After Partial Nephrectomy: Comparison of Solitary and Multifocal Renal Masses.

INTRODUCTION: Multifocal partial nephrectomy (MPN) is a critical management strategy for extirpation of multiple distinct renal masses; however, its short- and long-term impact on renal function remains poorly described. Herein we compared absolute glomerular filtration rate (GFR) and change from baseline at multiple time points after MPN and standard partial nephrectomy (SPN). METHODS: Perioperative and pathologic characteristics of 1307 partial nephrectomies performed from 2009 to 2020 were identified. 3:1 propensity score methods were used to match MPN and SPN cohorts based on preoperative characteristics known to impact renal function. Differences in GFR, perioperative outcomes, and overall and recurrence-free survival were assessed. Absolute and relative change from baseline GFR was compared at 5 time points for 36 months after partial nephrectomy. RESULTS: After propensity score matching, 192 SPNs and 64 MPNs with a median GFR of 80.2 mL/min were compared. MPN was associated with a greater decline in GFR of between 11% and 18% for the first year compared to a decline of 7% to 10% for SPN. This difference stabilized after 24 months. However, no differences in overall survival or recurrence-free survival were observed. Median follow-up time was 46.7 months. CONCLUSIONS: Long-term renal function after MPN remains similar to SPN despite greater declines in the first year after excision of multifocal renal masses.

Circulating and urinary tumour DNA in urothelial carcinoma - upper tract, lower tract and metastatic disease.

Precision medicine has transformed the way urothelial carcinoma is managed. However, current practices are limited by the availability of tissue samples for genomic profiling and the spatial and temporal molecular heterogeneity observed in many studies. Among rapidly advancing genomic sequencing technologies, non-invasive liquid biopsy has emerged as a promising diagnostic tool to reproduce tumour genomics, and has shown potential to be integrated in several aspects of clinical care. In urothelial carcinoma, liquid biopsies such as plasma circulating tumour DNA (ctDNA) and urinary tumour DNA (utDNA) have been investigated as a surrogates for tumour biopsies and might bridge many shortfalls currently faced by clinicians. Both ctDNA and utDNA seem really promising in urothelial carcinoma diagnosis, staging and prognosis, response to therapy monitoring, detection of minimal residual disease and surveillance. The use of liquid biopsies in patients with urothelial carcinoma could further advance precision medicine in this population, facilitating personalized patient monitoring through non-invasive assays.

Concomitant vs Staged Therapeutic Inguinal Lymphadenectomy in Clinically Node Positive Penile Squamous Cell Carcinoma: Does It Make a Difference?

PURPOSE: Inguinal lymph node dissection within 3 months of primary tumor resection in penile cancer has been associated with longer recurrence-free and cancer-specific survival. However, the optimal timing and effect of lymphadenectomy performed concurrently at the time of primary lesion management on oncologic outcomes in clinically lymph node positive penile squamous cell carcinoma remains unknown. MATERIALS AND METHODS: An international, multicenter cohort of 966 penile cancer cases was queried for penile squamous cell carcinoma management after the year 2000, clinically lymph node positive status, and performance of penile surgery and inguinal lymph node dissection. Cohorts were stratified as concomitant if inguinal lymph node dissection and penile surgery occurred on the same date or staged when inguinal lymph node dissection was performed after penile resection. Rates and patterns of penile squamous cell carcinoma recurrence were reported. Distant recurrence-free, cancer-specific, and overall survival were estimated using Kaplan-Meier analyses and groups compared with log-rank testing. RESULTS: Of 253 contemporary men with clinically lymph node positive penile squamous cell carcinoma, 96 (38%) underwent concomitant inguinal lymph node dissection and 157 (62%) had inguinal lymph node dissection performed in a staged manner. Penile cancer was most likely to recur distantly (19%) followed by in the groin (14%) or pelvis (5%). There were no differences in distant recurrence-free, cancer-specific, or overall survival between management strategies. Multivariable analysis adjusting for stage, treatment center, and perioperative chemoradiation also demonstrated no recurrence-free, cancer-specific, or overall survival benefit between management strategies. CONCLUSIONS: Inguinal lymph node dissection performed concurrently with excision of the penile tumor for clinically node positive penile squamous cell carcinoma is not associated with differences in recurrence-free, cancer-specific, or overall survival compared to staged lymph node dissection.

Mobile Postoperative Symptom Intervention Tool and Biometric Monitoring After Radical Cystectomy: Pilot Study Evaluating Feasibility, Usability, and Potential Utility.

PURPOSE: Mobile health technology and integration of patient-reported outcome measures into clinical interventions have the potential to transform patient care. Though patient-reported outcome measure management has been shown to improve outcomes in ambulatory care settings, few studies have examined remote patient-reported outcome measure assessment after major cancer surgery. MATERIALS AND METHODS: A multiphased feasibility and usability study was designed. A mobile app-based postoperative symptom intervention tool was developed and evaluated by a focus group of bladder cancer patients and caregivers. Patients were prospectively accrued prior to cystectomy and asked to complete the daily mobile postoperative symptom intervention tool and wear biometric monitoring devices for 30 days post discharge. Retention, postoperative symptom intervention tool completion, and usability were assessed. Exploratory analysis of daily symptoms and patient-generated health information correlated signals with postsurgical complications and hospital readmission. RESULTS: Fifteen patients with a median age of 72 years completed 78% of daily surveys over the 30-day recovery period. Average time to complete the postoperative symptom intervention tool was 152 seconds. All patients agreed that the daily survey was easy to use, and most reported it would be a better way to communicate with the care team about symptoms than calling the clinic. Frequency and severity of patient-reported symptoms appeared to cluster prior to or at the time of complication or unplanned health care encounters on visual-analogue mapping. CONCLUSIONS: Using smartphone and wearable technology to capture patient-reported symptoms and biometric data is feasible and rated as highly usable by bladder cancer patients after cystectomy. Symptom scores may signal developing complications and help clinicians identify postsurgical patients who may benefit from intervention.

Contemporary Management of Chylous Ascites after Retroperitoneal Surgery: Development of an Evidence-Based Treatment Algorithm.

PURPOSE: Chylous ascites (CA) is an uncommon complication that occurs from traumatic disruption of lymphatic channels after retroperitoneal surgery. The purpose of this study was to generate an evidence-based management strategy for CA by reviewing the current literature and available treatment modalities. MATERIALS AND METHODS: A MEDLINE® literature review was performed for "chylous ascites." Individual patient data were extracted from case series and reports to create an efficacy analysis. Treatment modality, drain output, time to escalation of care and time to resolution were recorded. The efficacy analysis was utilized to generate a data-driven treatment algorithm. RESULTS: The literature review yielded 1,953 articles, from which 146 studies contributed data for 523 patients. The efficacy analysis included 245 patients, 168 (69%) of whom were managed successfully with conservative management (CM), at a median time to resolution of 11 days. Forty-eight patients underwent lymphangiography±embolization after CM, with a success rate of 85%. Thirty-one (12%) patients underwent surgical exploration. When treating CA, the patients who underwent stepwise management with CM followed by lymphangiography if CM failed experienced a resolution rate of 96.7%. An evidence-based treatment algorithm was created to guide treatment selection and duration of therapy before escalating to additional forms of therapy. CONCLUSIONS: In this report, we describe the largest conglomeration of iatrogenic CA cases from a literature review (523 cases) and efficacy analysis (245 cases), and created the first evidence-based treatment algorithm for this condition. Treatment success is substantial when using a stepwise combination of CM followed by lymphangiography±embolization.

Sexual function outcomes of radiation and androgen deprivation therapy for localized prostate cancer in men with good baseline function.

BACKGROUND: Sexual dysfunction, including erectile dysfunction and loss of libido, are common among men undergoing treatment for localized prostate cancer. Both local treatments and systemic androgen deprivation therapy may contribute to these outcomes and are differentially indicated based on disease characteristics. We sought to compare sexual function through 5 years after radiation treatment with and without androgen deprivation therapy in men with good baseline sexual function to better understand long-term effects in this understudied subset of patients. METHODS: We retrospectively reviewed a prospectively assembled population-based cohort of men who underwent radiation with and without androgen deprivation therapy for intermediate or high-risk localized prostate cancer. Sexual function was assessed longitudinally over 5 years. Men with erections sufficient for intercourse at baseline were selected for inclusion. RESULTS: Out of 167 patients included, 73 underwent radiation alone and 94 received androgen deprivation therapy plus radiation (51 with intermediate and 43 with high-risk disease). Androgen deprivation therapy use was associated with worse sexual function through 1 year regardless of disease risk. This difference was no longer statistically significant at 3 years in the intermediate-risk group. Compared to radiation alone, androgen deprivation therapy in high-risk disease was associated with worse sexual function at 3 years (effect: -20.3 points, CI [-31.8, -8.8], p < 0.001) but not at 5 years (effect: -3.4, CI [-17.2, 10.5], p = 0.63). CONCLUSIONS: Androgen deprivation therapy plus radiation is associated with worse sexual function through 3-years follow-up in men with high-risk prostate cancer compared to radiation alone. The addition of androgen deprivation therapy in the treatment of intermediate-risk disease does not appear to result in worse sexual function at 3 or 5-year follow-up compared to radiation alone.

Assessment of gender representation in clinical trials leading to FDA approval for oncology therapeutics between 2014 and 2019: A systematic review-based cohort study.

BACKGROUND: Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. METHODS: An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. RESULTS: There were 149 clinical trials with 59,988 participants-60.3% and 39.7% were male and female, respectively-leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, -26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). CONCLUSIONS: For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. LAY SUMMARY: This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.

Obesity is Associated with Longer Survival Independent of Sarcopenia and Myosteatosis in Metastatic and/or Castrate-Resistant Prostate Cancer.

PURPOSE: Obesity (body mass index 30 kg/m2 or greater) is associated with better overall survival in metastatic prostate cancer. Conversely, low muscle mass (sarcopenia) and low muscle radiodensity (myosteatosis) are associated with worse overall survival in many cancers. This study seeks to evaluate the relationship of sarcopenia, myosteatosis and obesity with overall survival in men with metastatic or castrate-resistant prostate cancer. MATERIALS AND METHODS: Retrospective analysis of men with metastatic or castrate-resistant prostate cancer and computerized tomography of abdomen/pelvis presenting to the Vanderbilt Comprehensive Prostate Cancer Clinic from 2012 to 2017 was performed. Demographic, pathological and survival data were described, with sarcopenia and myosteatosis determined from abdominal skeletal muscle area and skeletal muscle radiodensity, respectively. Kaplan-Meier curves and log-rank tests estimated the effect of body composition on survival. Multivariable Cox proportional hazard models were performed adjusting for age, Charlson comorbidity index, race and clinical stage. ANOVA was used to compare obese and nonobese men with and without sarcopenia or myosteatosis. RESULTS: Of 182 men accrued, 37.4% were obese, 53.3% sarcopenic and 59.3% myosteatotic. Over a median followup of 33.9 months, body mass index was associated with reduced mortality (HR 0.93, p=0.02), as was visceral adiposity (HR 0.99, p=0.003). Men with high body mass index without sarcopenia/myosteatosis lived significantly longer than men with high body mass index with sarcopenia/myosteatosis or normal body mass index men (F[3,91]=4.03, p=0.01). CONCLUSIONS: Both high body mass index and visceral adiposity in metastatic or castrate-resistant prostate cancer are associated with reduced mortality, independent of sarcopenia and myosteatosis. Therefore, routine clinical workup should include calculation of body mass index and measurement of waist circumference. Morphometric analysis of computerized tomography imaging can identify patients at risk for poor prognosis.

Radiotherapy after radical prostatectomy: Effect of timing of postprostatectomy radiation on functional outcomes.

INTRODUCTION AND OBJECTIVE: The timing of radiotherapy (RT) after prostatectomy is controversial, and its effect on sexual, urinary, and bowel function is unknown. This study seeks to compare patient-reported functional outcomes after radical prostatectomy (RP) and postprostatectomy radiation as well as elucidate the timing of radiation to allow optimal recovery of function. METHODS: The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study is a prospective, population-based, observational study of men with localized prostate cancer. Patient-reported sexual, urinary, and bowel functional outcomes were measured using the 26-item Expanded Prostate Index Composite at baseline and at 6, 12, 36, and 60 months after enrollment. Functional outcomes were compared among men undergoing RP alone, post-RP adjuvant radiation (RP + aRT), and post-RP salvage radiation (RP + sRT) using multivariable models controlling for baseline clinical, demographic, and functional characteristics. RESULTS: Among 1,482 CEASAR participants initially treated with RP for clinically localized prostate cancer, 11.5% (N = 170) received adjuvant (aRT, N = 57) or salvage (sRT, N = 113) radiation. Men who received post-RP RT had worse scores in all domains (sexual function [-9.0, 95% confidence interval {-14.5, -3.6}, P < 0.001], incontinence [-8.8, {-14.0, -3.6}, P < 0.001], irritative voiding [-5.9, {-9.0, -2.8}, P < 0.001], bowel irritative [-3.5, {-5.8, -1.2}, P = 0.002], and hormonal function [-4.5, {-7.2, -1.7}, P = 0.001]) compared to RP alone at 5 years of follow-up. Compared to men treated with RP alone in an adjusted linear model, sRT was associated with significantly worse scores in all functional domains. aRT was associated with significantly worse incontinence, urinary irritation, and hormonal function domain scores compared to RP alone at 5 years of follow-up. On multivariable modeling, RT administered approximately 24 months after RP was associated with the smallest decline in sexual domain score, with an adjusted mean decrease of 8.85 points (95% confidence interval [-19.8, 2.1]) from post-RP, pre-RT baseline. CONCLUSIONS: In men with localized prostate cancer, post-RP RT was associated with significantly worse sexual, urinary, and bowel function domain scores at 5 years compared to RP alone. Radiation delayed for approximately 24 months after RP may be optimal for preserving erectile function compared to radiation administered closer to the time of RP.

Metastatic Hormone-sensitive Prostate Cancer: Current Perspective on the Evolving Therapeutic Landscape.

INTRODUCTION: The treatment landscape for patients with metastatic hormone-sensitive prostate cancer (mHSPC) has changed dramatically in the past five years, despite little change in the preceding 20 years. Such rapid change can make it difficult for clinicians to remain abreast of the current literature and synthesize the relevant data to inform evidence-based treatment decisions. METHODOLOGY: We performed a narrative, comprehensive review of treatment options for patients with mHSPC as of December 31, 2019. Specifically, we focused on phase II and III randomized controlled trials assessing the role of chemotherapy, novel androgen axis targeting agents, local-(prostate) directed therapy, and metastasis-directed therapy. RESULTS: The data support a survival benefit with the addition of four different agents to androgen deprivation among men with newly diagnosed prostate cancer-docetaxel, abiraterone acetate, enzalutamide, and apalutamide. While not directly compared, the efficacy of these agents appears similar. That said, there are differences in their toxicity profiles and notable differences in cost between agents. Although analyses encompassing men with low- and high-volume metastases failed to demonstrate a significant survival benefit for radiotherapy treatment to the prostate, new data demonstrates a benefit for men with low-volume metastatic disease. Ongoing trials will assess whether this applies to local surgical treatment. Similarly, metastasis-directed therapy appears beneficial among carefully selected patients. CONCLUSION: Treatment options for patients with mHSPC are rapidly changing following years of stagnation. A number of systemic therapies offer benefit without significant clinical differences between them. The role for local treatment of the prostate as well as metastatic sites continues to evolve.