Changes in the Perioperative Management and Outcomes of Patients With Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy at Memorial Sloan Kettering Cancer Center: Over 20 Years of Experience.

INTRODUCTION: We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period. METHODS: Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models. RESULTS: Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable. CONCLUSIONS: We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma.

PURPOSE: Vascular-targeted photodynamic therapy with the intravascular photosensitizing agent padeliporfin (WST-11/TOOKAD-Soluble) has demonstrated therapeutic efficacy as an ablative treatment for localized cancer with potential adaptation for endoscopic management of upper tract urothelial carcinoma. This Phase I trial (NCT03617003) evaluated the safety of vascular-targeted photodynamic therapy with WST-11 in upper tract urothelial carcinoma. MATERIALS AND METHODS: Nineteen patients underwent up to 2 endoscopic vascular-targeted photodynamic therapy treatments, with follow-up for up to 6 months. Patients who had residual or recurrent upper tract urothelial carcinoma (any grade/size) failing prior endoscopic treatment or unable or unwilling to undergo surgical resection were eligible for inclusion. The primary endpoint was to identify the maximally tolerated dose of laser light fluence. A dose escalation model was employed, with increasing light fluence (100-200 mW/cm) using a modified continual reassessment method. The secondary endpoint was treatment efficacy, defined by absence of visible tumor and negative urine cytology 30 days posttreatment. RESULTS: Fourteen (74%) patients received the maximally tolerated dose of 200 mW/cm, 2 (11%) of whom experienced a dose-limiting toxicity. The initial 30-day treatment response rate was 94% (50% complete, 44% partial). Eight patients underwent a second treatment, with a final observed 68% complete response rate. Leading toxicities were flank pain (79%) and hematuria (84%), which were transient. No ureteral strictures associated with treatment were identified during follow-up. CONCLUSIONS: Vascular-targeted photodynamic therapy with WST-11 has an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option for upper tract urothelial carcinoma. The recently initiated multicenter Phase 3 ENLIGHTED trial (NCT04620239) is expected to provide further evidence on this therapy.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Oncologic outcomes of patients with lymph node invasion at prostatectomy and post-prostatectomy biochemical persistence.

BACKGROUND: Pathologic nodal invasion at prostatectomy is frequently associated with persistently elevated prostate-specific antigen (PSA) and with increased risk of disease recurrence. Management strategies for these patients are poorly defined. We aimed to explore the long-term oncologic outcomes and patterns of disease progression. METHODS: We included men treated between 2000 and 2017 who had lymph node invasion at radical prostatectomy and persistently detectable prostate-specific antigen post-prostatectomy. Postoperative imaging and management strategies were collated. Patterns of recurrence and probability of metastasis-free survival, prostate cancer-specific survival, and overall survival (OS) were assessed. RESULTS: Among our cohort of 253 patients, 126 developed metastasis. Twenty-five had a positive scan within 6 months of surgery; of these, 15 (60%) had a nodal metastasis, 10 (40%) had a bone metastasis, and 4 (16%) had local recurrence. For metastasis-free survival, 5- and 10-year probabilities were 52% (95% CI 45%, 58%) and 37% (95% CI 28%, 46%), respectively. For prostate cancer-specific survival, 5- and 10-year probabilities were 89% (95% CI 84%, 93%) and 67% (95% CI 57%, 76%), respectively. A total of 221 patients proceeded to hormonal deprivation treatment alone. Ten patients received postoperative radiotherapy. CONCLUSIONS: Biochemical persistence in patients with lymph node invasion is associated with high risk of disease progression and reduced prostate cancer-specific survival. Management was hindered by the limitation of imaging modalities utilized during the study period in accurately detecting residual disease. Novel molecular imaging may improve staging and help design a therapeutic strategy adapted to patients' specific needs.

Survival Impact of Variant Histology Diagnosis in Upper Tract Urothelial Carcinoma.

PURPOSE: Little is known regarding the prognostic implications of variant histology in upper tract urothelial carcinoma (UTUC). We sought to evaluate the impact of variant histology UTUC on patient survival outcomes at our institution. MATERIALS AND METHODS: We identified 705 patients who underwent nephroureterectomy for UTUC at our institution between January 1995 and December 2018. We tested the association between variant histology and cancer-specific survival (CSS) and overall survival (OS) using separate multivariable Cox models after adjusting for pathological stage. RESULTS: Forty-seven patients (6.7%) had variant histology, with prevalence increasing over time (p=0.003). Other demographic and surgical characteristics were similar between variant histology and pure urothelial carcinoma groups. While patients with variant histology were more likely to receive neoadjuvant chemotherapy (38% vs 15%, p <0.001), they were also more likely to have a higher pathological T stage (p <0.001). Variant histology was associated with significantly worse CSS (HR: 2.14; 95% CI 1.33, 3.44; p=0.002) and OS (HR: 1.74; 95% CI 1.15, 2.63; p=0.008). After adjusting for pathological T stage, variant histology was not significantly associated with CSS (HR: 1.17; 95% CI 0.72, 1.89; p=0.5) or OS (HR: 1.20; 95% CI 0.79, 1.84; p=0.4). CONCLUSIONS: Variant histology UTUC is associated with advanced stage and poor survival, and could serve as a useful biomarker for high-risk disease when pathological stage is unknown. However, the inferior CSS and OS with variant histology can be explained by the higher tumor stage on nephroureterectomy. Thus, finding variant histology on surgical pathology does not provide additional prognostic information beyond stage.

Focal therapy for primary and salvage prostate cancer treatment: a narrative review.

Despite innovations in surgical technology and advancements in radiation therapy, radical treatments for clinically localized prostate cancer are associated with significant patient morbidity, including both urinary and sexual dysfunction. This has created a vital need for therapies and management strategies that provide an acceptable degree of oncologic efficacy while mitigating these undesirable side effects. Successful developments in screening approaches and advances in prostate imaging have allowed clinicians to identify, localize, and more precisely target early cancers. This has afforded urologists with an important opportunity to develop and employ focal ablation techniques that selectively destroy tumors while preserving the remainder of the gland, thus avoiding detrimental treatment effects to surrounding sensitive structures. A lack of high-level evidence supporting such an approach had previously hindered widespread adoption of focal treatments, but there are now numerous published clinical trials which have sought to establish benchmarks for safety and efficacy. As the clinical evidence supporting a potential role in prostate cancer treatment begins to accumulate, there has been a growing acceptance of focal therapy in the urologic oncology community. In this narrative review article, we describe the techniques, advantages, and side effect profiles of the most commonly utilized focal ablative techniques and analyze published clinical trial data supporting their evolving role in the prostate cancer treatment paradigm.

Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model.

PURPOSE: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. EXPERIMENTAL DESIGN: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. RESULTS: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. CONCLUSIONS: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.

Functional and Oncological Outcomes of Renal Surgery for Hilar Tumors: Informing the Decisions in Risk-Adapted Management.

OBJECTIVE: To describe the safety and efficacy of partial nephrectomy (PN) in comparison to radical nephrectomy (RN) for surgically managed renal hilar tumors. MATERIALS AND METHODS: We retrospectively reviewed institutional records of patients with a small (<5 cm) solitary renal (hilar or non-hilar) mass who underwent PN or RN between 2008 and 2018. Hilar tumors were defined as those at medial position, abutting the renal vessels. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method. RESULTS: Of 1,951 eligible patients, 399 had hilar tumors (292 scheduled for PN, 107 RN) and 1,552 had non-hilar tumors (scheduled for PN). We found no significant differences in survival measures between hilar and non-hilar tumors in patients selected for PN. Patients scheduled for PN for hilar tumors had higher rates of ≥grade II postoperative surgical complications compared to patients scheduled to receive PN for non-hilar tumors (13% vs 8.6%; log-rank P = .018) and non-statistically significantly elevated rates of ≥grade II complications compared to patients scheduled for RN for hilar tumors (13% vs 6.5%; difference 6%, 95% CI 0.4%, 13%; log-rank P = .07). CONCLUSION: PN for hilar and non-hilar renal masses (<5cm) experience comparable oncologic outcomes though increased risk of complications for hilar masses. PN for hilar tumors was associated with better renal function and overall survival with non-statistically elevated risk of grade II or higher complications than RN. A renal tumor located at the hilum should not be a contra-indication for performing PN.

The potential risk of tumor progression after use of dehydrated human amnion/chorion membrane allograft in a positive margin resection model.

OBJECTIVE: The objective of this study was to examine the impact of dehydrated human amnion/chorion membrane (dHACM) allografts on prostate and bladder cancer growth in the setting of residual disease and positive surgical margins. MATERIALS AND METHODS: A commercially available version of dHACM was used. Cytokines were identified and quantified, followed by comparative analysis of cell growth in two different human cell lines: prostate cancer (LNCaP) and bladder cancer (UM-UC-3), in vitro and in vivo. Tumor growth between the two groups, membrane versus no membrane implant, was compared and immunohistochemistry studies were conducted to quantify CD-31, Ki-67, and vimentin. A Student's unpaired t-test was used to determine statistical significance. RESULTS: The UM-UC-3 and LNCaP cells grew quicker in medium plus 10% serum and dHACM extract than in the other media (p = 0.03). A total of 28 distinct cytokines were found in the extract, 11 of which had relatively high concentrations and are associated with prostate and bladder cancer tumor progression. In vivo LNCaP model, after 10 weeks, the median tumor volume in the membrane group was almost threefold larger than the partial resection alone (p = 0.01). Two weeks after resection, in the UM-UC-3 model, the membrane group reached fourfold larger than the partial resection without membrane group (p < 0.01). In both groups, the expression of CD-31 and Ki-67 markers were similar and showed no statistical significance (p > 0.05). It was only in the LNCaP tumors that vimentin expression was significantly higher in the group without membrane compared with the membrane group (p = 0.008). CONCLUSION: The use of dHACM after partial tumor resection is related to faster tumor relapse and growth in prostate and urothelial cancer in vivo models, showing a potential risk of rapid local recurrence in patients at high risk of positive margins.

Phase III Trial of Intravenous Mannitol Versus Placebo During Nephron-sparing Surgery: Post Hoc Analysis of 3-yr Outcomes.

Our recently reported phase III trial demonstrated that patients undergoing nephron-sparing surgery (NSS) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m2 who received mannitol had no improvement in renal function at 6 mo compared with those who received placebo. Some authors have suggested that benefit is restricted to subgroups, such as those with comorbidities. We assessed whether preoperative eGFR, or other patient and surgical factors modified the effect of mannitol on postoperative outcomes at 6 mo and with extended follow-up. We also assessed whether mannitol was associated with differences in long-term GFR years after surgery. No significant difference between the mannitol or placebo groups (mean eGFR difference: 1.4; 95% confidence interval: -2.6, 5.3; p = 0.5) was found in the 134 patients with known eGFR at 3 yr after NSS. At both 6 mo and 3 yr, the effect of mannitol was not significantly modified by patient or surgical factors including preoperative eGFR. In summary, we validated our original trial conclusions by finding that intraoperative use of mannitol does not improve either short- or long-term renal function in patients undergoing NSS. Specifically, there is no evidence that comorbidities, including lower preoperative eGFR, modify the effect of mannitol. PATIENT SUMMARY: Use of mannitol at the time of partial nephrectomy does not improve either short- or long-term renal function even in patients with comorbidities, including lower preoperative renal function. The routine use of intraoperative mannitol should be discontinued.

Performance Prediction for Surgical Outcomes in Partial Nephrectomy Using Nephrometry Scores: A Comparison of Arterial Based Complexity (ABC), RENAL, and PADUA Systems.

BACKGROUND: Several standardized scoring systems are used to quantify renal tumor complexity on the basis of anatomic features to predict perioperative and postoperative outcomes of partial nephrectomy (PN). OBJECTIVE: To compare the predictive accuracy and utility of the Arterial Based Complexity (ABC), RENAL, and PADUA scores. DESIGN, SETTING, AND PARTICIPANTS: Between January 2013 and March 2016, 304 patients at our institution underwent PN plus complete triphasic contrast computed tomography (CT) scans. Two urologists independently scored CT images to retrospectively evaluate each patient using the ABC, RENAL, and PADUA nephrometry scoring systems. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Interobserver variability was reported for each of the three nephrometry scores; κ=1 represented perfect agreement between the two urologists and κ=0 represented as much agreement as expected by chance. Univariate and multivariable linear regression models were used to investigate associations of the nephrometry scores with estimated blood loss (EBL), ischemia time, and estimated glomerular filtration rate (eGFR) at 18 mo. Coefficients of determination (R2) were compared to determine which nephrometry score accounted for the most variation in outcome. RESULTS AND LIMITATIONS: The κ value was 0.52 for ABC, 0.53 for RENAL, and 0.63 for PADUA (all p≤0.001). On univariate analysis, there were no significant associations between nephrometry scores and postoperative eGFR; all three scores were highly associated with ischemia time (p<0.0001) and EBL (p≤0.001). R2 was not significantly different among the three scoring systems. On multivariable analysis, all three nephrometry scores were significantly associated with ischemia time (p<0.0001) and EBL (p≤0.01); only the RENAL score was associated with postoperative eGFR (p=0.044), so its performance on this metric could not be compared to that of ABC or PADUA. CONCLUSIONS: The ABC, RENAL, and PADUA systems have similar performance for predicting EBL and ischemia time outcomes in PN, and are thus equally useful for assessing PN complexity. Further education and training are needed to reduce interobserver variability. PATIENT SUMMARY: A new score system called Arterial Based Complexity (ABC) can be used to evaluate the complexity of a renal tumor and predict how difficult the tumor resection (partial nephrectomy) may be. This system performs well compared to other established systems and seems easy to learn and use.