Phase 1b Trial Evaluating Tolerability and Activity of Targeted Fibroblast Growth Factor Receptor Inhibition in Localized Upper Tract Urothelial Carcinoma.

PURPOSE: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations. MATERIALS AND METHODS: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel. RESULTS: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9). CONCLUSIONS: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

Antegrade administration of mitomycin gel for upper tract urothelial carcinoma via percutaneous nephrostomy tube: a multi-institutional retrospective cohort study.

OBJECTIVES: To assess the safety profile of antegrade mitomycin gel instillation through a percutaneous nephrostomy tube (PCNT) for upper tract urothelial carcinoma (UTUC) with the aim of decreasing morbidity associated with therapy. PATIENTS AND METHODS: Patients undergoing antegrade administration of mitomycin gel via PCNT were retrospectively included for analysis from four tertiary referral centres between 2020 and 2022. The primary outcome was safety profile, as graded by Common Terminology Criteria for Adverse Events (v5.0). Post-therapy disease burden was assessed by primary disease evaluation (PDE) via ureteroscopy. RESULTS: Thirty-two patients received at least one dose of mitomycin gel via PCNT for UTUC, 29 of whom completed induction and underwent PDE. Thirteen patients (41%) had residual tumour present prior to induction therapy. At a median of 15.0 months following first dose of induction therapy, ureteric stenosis occurred in three patients (9%), all of whom were treated without later recurrence or chronic stenosis. Other adverse events included fatigue (27%), flank pain (19%), urinary tract infection (12%), sepsis (8%) and haematuria (8%). No patients had impaired renal function during follow-up and there were no treatment-related deaths. Seventeen patients (59%) had no evidence of disease at PDE and have not experienced recurrence at a median follow-up of 13.0 months post induction. CONCLUSIONS: Administration of mitomycin gel via a PCNT offers a low rate of ureteric stenosis, demonstrates a favourable safety profile, and is administered without general anaesthesia.

Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.

Local Tumor Bed Recurrence Following Partial Nephrectomy in Patients with Small Renal Masses.

PURPOSE: We examined the incidence, characteristics and treatment of patients with tumor bed recurrence after partial nephrectomy. MATERIALS AND METHODS: We retrospectively reviewed the charts of 2,256 patients with sporadic small renal masses treated with partial nephrectomy between 2000 and 2014. Local tumor bed recurrence was strictly defined as detection of a new enhancing lesion 1) specifically in the surgical defect or 2) in the same region (eg lower pole) as the partial nephrectomy site. To determine differences in multiple characteristics 44 patients (1.9%) with local recurrence were compared to 163 randomly selected patients who underwent partial nephrectomy with no recurrence. RESULTS: Patients with local tumor bed recurrence were more likely to have a solitary kidney (27% vs 4%, p <0.01) and bilateral disease at presentation (23% vs 10.4%, p = 0.02) compared to the group with no recurrence. Positive margins were found in 15.9% of local tumor bed recurrences compared to 3% of the control group (p <0.01). Median time between partial nephrectomy and the detection of local tumor bed recurrence was 23 months (range 2 to 107). Male gender, a solitary kidney at partial nephrectomy, positive surgical margins, multiple tumors, and higher nephrometry score and pathological stage were associated with local tumor bed recurrence. CONCLUSIONS: Local tumor bed recurrence after partial nephrectomy is associated with several preoperative factors, including multiple tumors and a solitary kidney, as well as intraoperative and postoperative factors such as a positive surgical margin and higher pathological stage.

The Role of Metastasectomy in Patients with Renal Cell Carcinoma with Sarcomatoid Dedifferentiation: A Matched Controlled Analysis.

PURPOSE: Management of metastatic renal cell carcinoma with sarcomatoid dedifferentiation remains a therapeutic challenge with no standard treatment strategies. We evaluated whether metastasectomy has any survival benefit in patients with metastatic sarcomatoid dedifferentiation treated with radical nephrectomy. MATERIALS AND METHODS: From an institutional database of 273 patients with sarcomatoid dedifferentiation treated with nephrectomy we matched 80 with synchronous and asynchronous metastases for age, ECOG (Eastern Cooperative Oncology Group) performance status, histology and lymph node status. Matched pairs were then retained only if patients who did not undergo metastasectomy were alive at metastasectomy comparable to matched surgical patients to decrease the bias of survival outcomes. Overall survival from nephrectomy was studied using univariable and multivariable proportional hazards regression. RESULTS: Median overall survival was 8.3 (95% CI 6.5-10.5) and 18.5 months (95% CI 11.5-42.9) in patients with synchronous and asynchronous metastases, respectively. Overall survival in patients who underwent metastasectomy for synchronous metastasis compared to nonsurgical patients was 8.4 and 8.0 months (p = 0.35), respectively. Similarly, overall survival in patients with asynchronous metastases treated with metastasectomy compared to the nonsurgical group was 36.2 and 13.7 months, respectively (p = 0.29). On multivariable analysis positive lymph nodes at nephrectomy were associated with an increased risk of death in the synchronous and asynchronous patient subgroups (HR 2.1, 95% CI 1.1-4.0, p = 0.03 and HR 3.3, 95% CI 1.2-9.2, p = 0.02, respectively). CONCLUSIONS: In the current study there was no clear evidence of benefit in patients with sarcomatoid dedifferentiation who underwent metastasectomy after nephrectomy. Particularly, the group of patients with pathological lymph node positive disease at nephrectomy had considerably worse survival.

Surgical Management of Local Retroperitoneal Recurrence of Renal Cell Carcinoma after Radical Nephrectomy.

PURPOSE: Isolated local retroperitoneal recurrence after radical nephrectomy for renal cell carcinoma poses a therapeutic challenge. We investigated outcomes in patients with localized retroperitoneal recurrence treated with surgical resection. MATERIALS AND METHODS: This was a retrospective, single institutional study of 102 patients with retroperitoneal recurrence treated with surgery from 1990 to 2014. Demographics, clinical and pathological features, location of retroperitoneal recurrence and perioperative complications are reported using descriptive statistics. We studied recurrence-free and cancer specific survival using univariate and multivariate analyses. RESULTS: Median age at retroperitoneal recurrence diagnosis was 55 years (IQR 49-64). Cancer was pT3-4 in 62 patients (60.8%) and pN1 in 20 (19.6%). No patients had distant metastatic disease at retroperitoneal recurrence surgery. Median time from nephrectomy to retroperitoneal recurrence diagnosis was 19 months (IQR 5-38.8). The median size of the resected retroperitoneal recurrence was 4.5 cm (IQR 2.7-7). Median followup after recurrence surgery was 32 months (IQR 16-57). Metastatic progression was observed in 60 patients (58.8%) postoperatively. Neoadjuvant and salvage systemic therapy was administered in 46 (45.1%) and 48 patients (47.1%), respectively. On multivariate analysis pathological nodal stage at original nephrectomy and maximum diameter of retroperitoneal recurrence were identified as independent risk factors for cancer specific death. CONCLUSIONS: Clinicopathological factors at nephrectomy as well as retroperitoneal recurrence surgery are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with retroperitoneal recurrence with acceptable complications and still has a dominant role in the management of isolated locally recurrent RCC.

Role of metastasectomy in metastatic renal cell carcinoma.

PURPOSE OF REVIEW: Management of patients with metastatic renal cell carcinoma is challenging and continues to be delivered in a multidisciplinary context. Even with the advent of systemic targeted therapy, complete remission with these new agents is rare using systemic therapy alone. Surgical resection of the primary tumor and metastatic deposits continues to play an important role in managing patients with metastatic renal cell carcinoma when aiming for complete remissions. To date, despite the lack of level 1 evidence, metastasectomy appears to prolong survival and achieve long-term cure in carefully selected patients. This review examines current evidence for the role of metastasectomy in renal cell carcinoma. RECENT FINDINGS: Studies continue to consistently support a benefit of complete metastasectomy for overall and cancer-specific survival at most sites for resection, with the exception of brain and bone, which tend to perform for symptomatic relief and palliation. Metastasectomy has not yet been examined in a randomized setting. The debate of survival benefit because of selection bias of patients or differences in tumor biology is relevant and has yet to be resolved in the literature. Clearly, careful patient selection remains paramount in optimizing survival benefit from metastasectomy. SUMMARY: Patients with isolated surgically resectable metastatic disease, with long disease-free intervals, and with good performance status are likely to benefit the most from metastasectomy.

Risk stratification of pubertal children and postpubertal adolescents with clinical stage I testicular nonseminomatous germ cell tumors.

PURPOSE: The COG (Children's Oncology Group) currently recommends surveillance for all children and adolescents with clinical stage I testicular germ cell tumors. However, up to 30% of adults with clinical stage I testicular germ cell tumors harbor occult metastatic disease. In adults with clinical stage I nonseminoma some groups advocate a risk stratified approach. Occult metastases were noted in 50% of patients with features such as lymphovascular invasion or embryonal carcinoma predominance in the orchiectomy. However, to our knowledge there are no data on the impact of high risk features in such pubertal children and postpubertal adolescents. MATERIALS AND METHODS: We reviewed an institutional testis cancer database for pubertal children and postpubertal adolescents younger than 21 years. We tested the hypothesis that lymphovascular invasion, or 40% or greater embryonal carcinoma in the orchiectomy specimen, would increase the risk of occult metastases, ie relapse during surveillance or positive nodes on retroperitoneal lymph node dissection. RESULTS: We identified 23 patients with a median age of 18.6 years (range 7.1 to 20.9) at diagnosis. Of these patients 14 (60.9%) were on surveillance, 9 (39.1%) underwent primary retroperitoneal lymph node dissection and none received initial chemotherapy. Seven patients (30.4%) had occult metastatic disease. High risk pathological features were found in the orchiectomy specimen in 12 patients (52.2%), including all 12 (52.2%) with 40% or greater embryonal carcinoma and 3 (13.0%) with lymphovascular invasion. Seven patients (58.3%) with high risk features had occult metastatic disease vs none (0%) without high risk features (log rank p = 0.031). CONCLUSIONS: Approximately half of pubertal children and postpubertal adolescents with high risk clinical stage I testicular germ cell tumors harbor occult metastatic disease. These results may be useful when discussing prognosis and treatment with patients and families.

A comparison of pediatric, adolescent, and adult testicular germ cell malignancy.

BACKGROUND: Testicular germ cell tumors (T-GCTs) occur from infancy to adulthood, and are the most common solid tumor in adolescent and young adult males. Traditionally, pediatric T-GCTs were perceived as more indolent than adult T-GCTs. However, there are few studies comparing these groups and none that specifically evaluate adolescents. METHODS: An institutional database of T-GCT patients was reviewed and patients were categorized into Pediatric, aged 0-12 years, Adolescent, aged 13-19 years, and Adult, older than 20 years, cohorts. Demographics, tumor characteristics, disease stage, treatment, event-free survival (EFS), and overall survival (OS) were compared between groups. RESULTS: Overall, 413 patients (20 pediatric, 39 adolescent, 354 adult) met study criteria and were followed for a median of 2.0 years (0.1-23.6). Adolescents presented with more advanced stage than children (P = 0.018) or adults (P = 0.008). There was a higher rate of events in Adolescents (13, 33.3%) than in Adults (61, 17.2%) or Children (2, 10.0%). Three-year EFS was 87.2% in the Pediatric group, 59.9% in Adolescents and 80.0% in Adults (P = 0.011). In a multivariate analysis, controlling for stage, IGCCCG risk, and histology, the hazard ratio (HR) for an event was: 1 (Reference) for Adults, HR = 0.82 (95% CI 0.19-3.46; P = 0.33) for the Pediatric group, and HR = 2.22 (95% CI 1.21-4.07; P = 0.01) for Adolescents. Five-year OS was 100% in the Pediatric group, 84.8% in Adolescents, and 92.8% in Adults (P = 0.388). CONCLUSION: Lower EFS in adolescent T-GCT patients was observed than in either children or adults. Elucidating factors associated with inferior outcomes in adolescents is an important focus of future research.

Robotic or open superficial inguinal lymph node dissection as staging procedures for clinically node negative high risk penile cancer.

OBJECTIVE: To evaluate perioperative and oncologic outcomes of a cohort of clinically node negative high-risk penile cancer patients undergoing robotic assisted inguinal lymph node dissection (RAIL) compared to patients undergoing open superficial inguinal lymph node dissection (OSILND). PATIENTS AND METHODS: We retrospectively reviewed the clinical characteristics and outcomes of clinically node negative high-risk penile cancer patients undergoing RAIL at MDACC from 2013-2019. We sought to compare this to a contemporary open cohort of clinically node negative patients treated from 1999 to 2019 at MDACC and Moffit Cancer Center (MCC) with an OSILND. Descriptive statistics were used to characterize the study cohorts. Comparison analysis between operative variables was performed using Fisher's exact test and Wilcoxon's rank-sum test. The Kaplan-Meier method was used to estimate survival endpoints. RESULTS: There were 24 patients in the RAIL cohort, and 35 in the OSILND cohort. Among the surgical variables, operative time (348.5 minutes vs. 239.0 minutes, P < 0.01) and the duration of operative drain (37 vs. 22 days P = 0.017) were both significantly longer in the RAIL cohort. Complication incidences were similar for both cohorts (34.3% for OSILND vs. 33.3% for RAIL), with wound complications making up 33% of all complications for RAIL and 31% of complications for OSILND. No inguinal recurrences were noted in either cohort. The median follow-up was 40 months for RAIL and 33 months for OSILND. CONCLUSIONS: We observed similar complication rates and surgical variable outcomes in our analysis apart from operative time and operative drain duration. Oncological outcomes were similar between the two cohorts. RAIL was a reliable staging and potentially therapeutic procedure among clinically node negative patients with penile squamous cell carcinoma with comparable outcomes to an OSILND cohort.

The association of body mass index with tumor aggression among men undergoing radical prostatectomy.

OBJECTIVES: To evaluate the association of preoperative body mass index (BMI) on adverse pathology in peripheral (PZ) and transition zone (TZ) tumors at time of prostatectomy for localized prostate cancer. METHODS: Clinical and pathologic characteristics were obtained from up to 100 consecutive prostatectomy patients from 10 prostate surgeons. BMI groups included normal (18.5-24.9), overweight (25-29.9) and obese (> 29.9). "Aggressive" pathology was defined as the presence of Grade Group (GG) 3 or higher and/or pT3a or higher. Pathologic characteristics were evaluated for association with BMI using univariate analyses. Our primary outcome was the association of BMI with adverse pathology, which was assessed using logistic regression accounting for patient age. We hypothesized that obese BMI would be associated with aggressive TZ tumor. RESULTS: Among 923 patients, 140 (15%) were classified as "normal" BMI, 413 (45%) were "overweight", and 370 (40%) were "obese." 474 patients (51%) had aggressive PZ tumors while 102 (11%) had aggressive TZ tumors. "Obese" BMI was not associated with aggressive TZ tumor compared to normal weight. Increasing BMI group was associated with overall increased risk of aggressive PZ tumor (HR 1.56 [95CI 1.04-2.34]; P = 0.03). Among patients with GG1 or GG2, increasing BMI was associated with presence of pT3a or higher TZ tumor (P = 0.03). CONCLUSIONS: Increased BMI is associated with adverse pathology in PZ tumors. TZ adverse pathology risk may be increased among obese men with GG1 or GG2 disease, which has implications for future studies assessing behavioral change among men whose tumors are actively monitored.

Favorable patient reported outcomes after penile plication for wide array of peyronie disease abnormalities.

PURPOSE: We present patient reported outcomes from our 5-year experience using penile plication to correct a wide variety of Peyronie disease malformations. MATERIALS AND METHODS: We reviewed the records of all men who underwent penile plication for Peyronie disease, as performed by one of us (AFM). All patients were treated with tunical plication without penile degloving via a 2 cm longitudinal penile incision regardless of curvature severity or erectile function. A concomitant inflatable penile prosthesis was placed in men with refractory erectile dysfunction. A questionnaire was administered to assess the patient perception of postoperative penile curvature, length, rigidity and adequacy for intercourse. RESULTS: Of 154 treated patients 78 (51%) and 65 (42%) had simple (less than 60 degrees) and complex (biplanar curvature, or curvature 60 degrees or greater) malformation, respectively, while 11 (7%) underwent plication plus inflatable penile prosthesis placement. A total of 132 patients responded to the questionnaire a mean 14 months after surgery. Overall, 96% of patients reported curvature improvement after penile plication, 93% reported erection adequate for sexual intercourse and 95% considered that the overall condition improved after surgery. Despite a significant difference in the number of plication sutures (mean 10 vs 7) and curvature angle correction (mean 57 vs 30 degrees, each p <0.005), self-reported outcomes of complex cases were equivalent to those of simple cases. While 84% of patients had no measureable decrease in stretched penile length, 103 of 154 (78%) reported a perceived penile length reduction after surgery. CONCLUSIONS: Penile plication without degloving is effective for correcting a wide variety of Peyronie disease malformations. It can be safely combined with inflatable penile prosthesis placement.

Reduction in hospital admission rates due to post-prostate biopsy infections after augmenting standard antibiotic prophylaxis.

PURPOSE: We evaluated the incidence of infectious complications requiring hospitalization after transrectal ultrasound guided prostate biopsy, comparing an augmented regimen of antibiotic prophylaxis to the standard regimen, and established cost-effectiveness at our center. MATERIALS AND METHODS: Our standard antibiotic prophylaxis regimen consisted of 3 days of ciprofloxacin or Bactrim™ DS in the perioperative period. An increase in hospital admissions related to infection after transrectal ultrasound guided biopsy from January 2010 through December 2010 led us to initiate an augmented regimen of 3 days of ciprofloxacin or Bactrim DS in addition to 1 dose of intramuscular gentamicin before biopsy from January 2011 to December 2011. Urine and blood cultures along with bacterial susceptibilities were obtained at admission and compared between the 2 groups. Cost analysis was done to determine the cost-effectiveness of standard and augmented regimens. RESULTS: The rate of hospitalization due to post-biopsy infections was 3.8% (11 patients among 290 biopsies) in 2010, which decreased to 0.6% (2 patients among 310 biopsies) in 2011 (p <0.001). Of the admitted patients who received standard prophylaxis, 73% had fluoroquinolone resistant Escherichia coli urinary infection and/or bacteremia and only 9% had strains resistant to gentamicin. Multivariate analysis showed that the standard regimen was significantly associated with hospital admission due to post-biopsy infection (HR 2.078 ± 0.84, p = 0.013). The augmented regimen resulted in a cost savings of $15,700 per 100 patients compared to the standard regimen. CONCLUSIONS: The addition of gentamicin to current prophylactic regimens significantly reduced the rate of hospitalization for post-biopsy infectious complications and was shown to be cost-effective.

Cost-effectiveness of standard vs intensive antibiotic regimens for transrectal ultrasonography (TRUS)-guided prostate biopsy prophylaxis.

UNLABELLED: Multiple studies have shown an increase in the hospital admission rates due to infectious complications after transrectal ultrasonography (TRUS)-guided prostate biopsy (TRUSBx), mostly related to a rise in the prevalence of fluoroquinolone-resistant organisms. As a result, multiple series have advocated the use of more intensive prophylactic antibiotic regimens to augment the effect of the widely used fluoroquinolone prophylaxis for TRUSBx. The present study compares the cost-effectiveness fluoroquinolone prophylaxis to more intensive prophylactic antibiotic regimens, which is an important consideration for any antibiotic regimen used on a wide-scale for TRUSBx prophylaxis. OBJECTIVE: To compare the cost-effectiveness of fluoroquinolones vs intensive antibiotic regimens for transrectal ultrasonography (TRUS)-guided prostate biopsy (TRUSBx) prophylaxis. PATIENTS AND METHODS: Risk of hospital admission for infectious complications after TRUSBx was determined from published data. The average cost of hospital admission due to post-biopsy infection was determined from patients admitted to our University hospital ≤1 week of TRUSBx. A decision tree analysis was created to compare cost-effectiveness of standard vs intensive antibiotic prophylactic regimens based on varying risk of infection, cost, and effectiveness of the intensive antibiotic regimen. RESULTS: Baseline assumption included cost of TRUSBx ($559), admission rate (1%), average cost of admission ($5900) and cost of standard and intensive antibiotic regimens of $1 and $33, respectively. Assuming a 50% risk reduction in admission rates with intensive antibiotics, the standard regimen was slightly less costly with average cost of $619 vs $622, but was associated with twice as many infections. Sensitivity analyses found that a 1.1% risk of admission for quinolone-resistant infections or a 54% risk reduction attributed to the more intensive antibiotic regimen will result in cost-equivalence for the two regimens. Three-way sensitivity analyses showed that small increases in probability of admission using the standard antibiotics or greater risk reduction using the intensive regimen result in the intensive prophylactic regimen becoming substantially more cost-effectiveness even at higher costs. CONCLUSION: As the risk of admission for infectious complications due to TRUSBx increases, use of an intensive prophylactic antibiotic regimen becomes significantly more cost-effective than current standard antibiotic prophylaxis.

Oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: comparison over the three decades.

OBJECTIVE: To evaluate temporal trends in clinicopathological features and oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. METHODS: Utilizing a multi-institutional database of patients treated with radical nephroureterectomy between 1983 and 2007, we compared clinicopathological features and survival outcomes over the past three decades using the following cohorts: group 1 comprised of patients treated before the 1990s (n = 106), group 2 from 1990 to1999 (n = 655), and group 3 from 2000 to 2007 (n = 701). Survival rates were compared using Kaplan-Meier survival analysis. RESULTS: The study included 1462 patients, 992 men and 470 women, with 36 months median follow up (range 1-250 months) after radical nephroureterectomy. Tumors were organ confined (≤T2/N0) in 88% and high-grade in 64%. Neoadjuvant and adjuvant systemic chemotherapy was administered in 47 (3.2%) and 171 (11.7%) patients, respectively. There was a significant increase in the use of laparoscopic radical nephroureterectomy, endoscopic management of urothelial carcinoma and utilization of perioperative chemotherapy between decades 1 to 3. There were no significant differences in pathological stage distribution. The overall 5-year disease-free survival rates were 66 ± 5%, 68.5 ± 2% and 71 ± 2%, and the 5-year cancer-specific survival rates were 75 ± 5%, 72 ± 2%, and 75 ± 2% for groups 1, 2 and 3, respectively, with no significant statistical differences between the three decades (P > 0.05). CONCLUSION: Outcomes after radical nephroureterectomy have not changed significantly over the past three decades, despite staging and surgical refinements. Utilization of perioperative systemic chemotherapy in urothelial carcinoma management remains low. Further improvements in outcomes of urothelial carcinoma patients necessitate rigorous investigation of multimodal treatment approaches.

Five and Ten-Year Outcomes of Neoadjuvant Chemotherapy and Surgery for High-Risk Upper Tract Urothelial Carcinoma.

BACKGROUND: Emerging data suggests improved outcomes in patients receiving neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. In one of the largest single-center experiences to date, we provide an updated analysis of outcomes of patients receiving NAC followed by RNU. PATIENTS AND METHODS: A retrospective review of patients with high-risk UTUC who received NAC followed by surgery between 2004 to 2017 was conducted. 126 patients were evaluated as part of the analysis. Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox modeling was used to evaluate for association with outcomes, and the cumulative incidence factor was used for competing risk analysis. RESULTS: Median OS time was 106 months. 14.3% of patients had a pathologic complete response and 60% were down-staged to ypT0-1 ypN0. The estimated 5 and 10-year DSS rates were 89.8% and 80.6%, respectively. The estimated 5 and 10-year metastasis-free survival rates were 81% and 75.4%, respectively. The estimated 5 and 10-year OS rates were 73.7% and 35.9 %, respectively. Recurrences mainly occurred in lymph nodes and lung at a median time of 15.5 months (IQR 8.9-27). The estimated 5 and 10-year cumulative incidence factor for death from UTUC was 9.5% and 16.1%, respectively. Limitations include retrospective nature and challenge of accurate pre-surgical staging. CONCLUSIONS: NAC prior to RNU in high-risk UTUC shows durable 5 and 10-year OS and DSS rates in a large single-institution series, confirming prior findings in prospective trials and retrospective studies.

Longitudinal GFR trends after neoadjuvant chemotherapy prior to nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: Renal function dictates sequencing and eligibility for definitive therapy in upper tract urothelial carcinoma. We investigated longitudinal glomerular filtration rate (GFR) changes after neoadjuvant chemotherapy (NAC) and nephroureterectomy (RNU). MATERIALS AND METHODS: Patients treated with ≥3 cycles of chemotherapy prior to RNU for UTUC from 2000 to 2019 were included. GFR was calculated by CKD-Epi before chemotherapy, before RNU, 1 to 3 months, and 12 months post-RNU. Pathologic stage and overall survival were compared in those with stable GFR (+/-10% of baseline) to the rest of the cohort. RESULTS: One hundred and fifty-two patients received ≥3 cycles of NAC, with 121 (79%) receiving at least 1 cycle of cisplatin. Renal function dropped by mean of 22.3 ml/min/1.73 m2 from the beginning of chemotherapy to 1-year post-surgery. In patients receiving cisplatin, a mean decline of 26.2 ml/min/1.73 m2 was observed vs. 8.8 ml/min/1.73 m2 without cisplatin-based NAC (P < 0.01). GFR after RNU was unchanged between 3 and 12 months postoperatively. At 1 to 3 months after RNU, 19% of patients had GFR<30 ml/min/1.73m2. Improvement in GFR during NAC was associated with invasive final pathologic stage (P = 0.018) and worse overall survival (P = 0.049). CONCLUSIONS: In patients managed with NAC prior to RNU, renal function stabilizes at 1 to 3 months post-operatively and remains clinically similar for cisplatin or non-cisplatin-based therapy. Improvement in GFR during NAC was associated with higher pathologic stage and poorer survival, especially in those receiving non-cisplatin-based therapy, an observation that requires further investigation.

Multimodal kidney-preserving approach in localised and locally advanced high-risk upper tract urothelial carcinoma.

Objectives: Multimodal kidney-preserving (MKP) strategies may be an option for patients with localised or locally advanced high-risk upper tract urothelial carcinoma (UTUC) who have a relative contraindication for nephroureterectomy (NU). Materials and methods: We studied patients with UTUC who were managed with MKP strategies, consisting of systemic anticancer therapy, with or without local/topical strategies after endoscopic control of intraluminal tumours. Primary end points were overall survival (OS) and progression-free survival (PFS). Results: Fourteen patients received MKP treatment between August 2013 and April 2020. Median baseline estimated glomerular filtration rate was 43 mL/min/1.73m2. MKP was mainly pursued to avoid dialysis (10/14, 71%), followed by low performance status and/or comorbidities (2/14, 14%). All patients had received systemic therapy: chemotherapy (64%) and immunotherapy (36%). Endoscopic control and/or laser ablation was feasible in 7 (50%) patients. Calculated overall risk of non-organ confined disease was 35%. Predicted 2-year and 5-year relapse-free probability (RFP) was 74% (24-92%) and 62% (10-85%), respectively. Median follow-up was 31 months (95% CI: 22.6, NE), median OS was 48.1 months (95% CI: 48.1, NE) and 2-year OS probability was 0.89 (95% CI: 0.71, 1). Median metastases-free survival was 48.1 months (95% CI: 26.8, NE), median PFS was 22.4 months (95% CI: 15.6, NE) and 2-year PFS probability was 0.48 (0.26, 0.89). Conclusion: Management of high-risk localised or locally advanced UTUC with MKP strategies was associated with good tolerance, preservation of renal function, and comparable PFS and OS to predicted in vulnerable patients. Prospective studies with more patients are needed to evaluate these possible benefits relative to current standards.