Pathologic stage as a surrogate for oncologic outcomes after receipt of neoadjuvant chemotherapy for high-grade upper tract urothelial carcinoma

ObjectiveWhether pathologic stage at radical nephroureterectomy (RNU) can serve as an appropriate surrogate for oncologic outcomes in patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) treated with neoadjuvant chemotherapy (NAC) is not defined. We sought to determine whether patients who achieve pathologically non-muscle-invasive (ypT0, ypTa, ypT1, ypTis) HG UTUC after receipt of NAC exhibit oncologic outcomes comparable to those who are inherently low stage without chemotherapy.MethodsWe identified 647 UTUC patients who underwent RNU among 3 institutions from 1993to2016. Patients with low or unknown grade, pathologic muscle invasion, or receipt of adjuvant chemotherapy were excluded. We compared clinicopathologic data and oncologic outcomes between pT0-1 and ypT0-1 patients. Kaplan-Meier analysis was used to assess overall (OS), cancer-specific (CSS), and systemic recurrence-free (RFS) survival. Predictors of these endpoints were identified using Cox regression.Results234 (43 ypT0-1, 191 pT0-1) patients with HG UTUC were included. Two patients exhibited pathologic complete response after NAC. OS (P = 0.055), CSS (P = 0.152), and RFS (P = 0.098) were similar between ypT0-1 and pT0-1 patients. Predictors of worse outcomes included African-American race (RFS, CSS, and OS), Charlson score (OS), and systemic recurrence (OS and CSS).ConclusionsPatients with HG UTUC who achieve ypT0-1 stage after NAC exhibit favorable oncologic outcomes comparable to those inherently non-muscle-invasive who do not receive chemotherapy. Improvements in clinical staging will play an important role in better defining candidacy for NAC in treating HG UTUC while minimizing overtreatment. Furthermore, pathologic stage may serve as an appropriate early surrogate for oncologic endpoints in designing clinical trials.     

Does neoadjuvant chemotherapy have therapeutic benefit for node-positive upper tract urothelial carcinoma? Results of a multi-center cohort study

ObjectiveThe indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC).Materials and methodsAmong 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes.ResultsOf the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016).ConclusionFor node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.     

A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma

Context

The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit.

Objective

To update the current evidence on the role of NC and AC for UTUC patients.

Evidence acquisition

We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed.

Evidence synthesis

No randomized trials investigated the role of AC for UTUC. There was one prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; p = 0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24–0.99; p = 0.048). Benefit was not seen for non-cisplatin–based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22–0.76; p = 0.005).

Conclusions

There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility.

Patient summary

After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.     

Neoadjuvant versus adjuvant chemotherapy for upper tract urothelial carcinoma

BackgroundPresently, no level I evidence is available to support the use of neoadjuvant chemotherapy (N)(AC) in patients diagnosed with high-grade upper tract urothelial carcinoma (UTUC). We aimed to compare outcomes of patients treated with radical nephroureterectomy (RNU) who received NAC vs. those who received AC.MethodsThe National Cancer Database was queried for UTUC patients with cT2-4N0M0 disease treated with RNU and NAC or AC. The role of NAC or AC on overall survival (OS) was evaluated by means of a multivariable Cox regression. Time to death was evaluated from diagnosis.ResultsOverall, 936 patients were identified, 128 (14%) received NAC whereas 808 (86%) received AC. No difference was observed between NAC vs. AC in terms of OS (P = 0.9). When sub-stratifying patients who received NAC in responders (cT>pT, given pN0; n = 46 [36%]) vs. nonresponders (n = 82 [64%]), we found that, relatively to AC, the subgroup of patients who did not respond to NAC had higher risk of dying from any cause (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.03,1.91; P = 0.03), whereas the sub-group who responded to NAC had better OS (HR: 0.45; 95% CI: 0.24,0.85; P = 0.01). The 5-year OS rates for responders to NAC vs. nonresponders vs. AC were: 71% vs. 26% vs. 43%, respectively. A landmark analysis fitted at 6 months after diagnosis, including 903 patients (NAC: 126 vs. AC: 777) confirmed our findings.Conclusionwhile we found no difference in outcomes between NAC vs. AC in high-grade UTUC, we found a hypothesis-generating association between survival and response to NAC. Further studies aimed at identifying potential responders to NAC are warranted.     

Predictive model for systemic recurrence following cisplatin-based neoadjuvant chemotherapy and radical nephroureterectomy for high risk upper tract urothelial carcinoma

IntroductionNeoadjuvant chemotherapy (NAC) is increasingly used prior to radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Systemic recurrence (SR) carries a dismal prognosis. We sought to determine risk factors associated with SR in this setting.MethodsWe evaluated a multi-center database of patients with UTUC who received cisplatin-based NAC before RNU. Final pathology at RNU was dichotomized into ypT<2 vs ypT≥2. Univariable and multivariable analyses were performed to identify risk factors associated with SR. Three groups were defined based on the number of significant risk factors (groups 1, 2, 3 for 0-1, 2, 3 risk factors, respectively) and evaluated for recurrence-free survival (RFS) using the Kaplan-Meier method.Results106 patients were identified between 2004 and 2018. Median age was 67.0 years [IQR = 61-73.3]; 57 (54%) and 49 (46 %) patients received MVAC and GC, respectively. Final pathological stage was ypT<2 in 57 (54%); 23% (24/106) had SR. On univariable analysis, pathological variables on final specimen including ypT≥2, lymphovascular invasion (ypLVI), and nodal involvement were associated with SR. On multivariable analysis, ypLVI OR = 4.1 (95% CI 1.2-13.6; P = 0.024) and pathological nodal involvement OR = 4.5 (95% CI 1.3-15.7; P = 0.017) were predictive of recurrence. Stratifying by the number of risk factors, the 2-year RFS was 95%, 55%, and 18% for groups 1, 2, and 3 respectively (log-rank <0.001).ConclusionThis model evaluates the risk of SR following NAC and RNU to guide counseling and decision-making after surgery. Adverse pathological variable including ypLVI and nodal involvement, in combination with ypT-stage, are strongly associated with SR.     

National trends in clinical and pathologic staging for upper tract urothelial carcinoma: Implications for neoadjuvant chemotherapy

IntroductionWith growing support of perioperative chemotherapy for upper tract urothelial carcinoma (UTUC), current biopsy methods are challenging, and little is known as to the degree to which patients would appropriately receive neoadjuvant chemotherapy (NAC) from biopsy alone. Herein, we sought to assess the rates of appropriate clinical use of NAC and identify clinicopathologic factors associated with aggressive UTUC amongst patients undergoing radical nephroureterectomy (RNU) for clinically localized disease.MethodsFrom 2004 to 2013, we identified all treatment naïve patients diagnosed with clinically localized, high grade UTUC (cTa-4Nx) who underwent RNU from the National Cancer Database (NCDB). Pathologic criteria for NAC (pT2-4N0,x; pTanyN1) from RNU represented the primary outcome. Bivariate and multivariable analyses were utilized to identify covariates associated with primary outcome to determine appropriate use of NAC.ResultsDuring the study interval, 5,362 patients were diagnosed with clinically localized UTUC and underwent RNU. Overall, 49.1% of patients presented with an unknown primary tumor stage (Tx) and 24.5% had invasive UTUC from biopsy. On multivariable analysis, upper tract tumor size was associated with invasive UTUC eligible for NAC (all P < 0.05). Amongst patients with cTx UTUC from biopsy, half of patients had pathologic noninvasive UTUC (pTa,is,1) from RNU and would be overtreated with NAC.ConclusionSignificant uncertainty persists in assigning primary upper tract tumor depth and represents a key barrier to widespread implementation of NAC for patients with high grade UTUC. Further research is needed to more accurately determine clinical criteria to identify patients for NAC.     

High rates of advanced disease,complications, and decline of renal function after radical nephroureterectomy

ObjectivesRecurrences remain common following radical nephroureterectomy (RNU) for locally advanced upper-tract urothelial carcinoma (UTUC). We review a cohort of RNU patients to identify the incidence of locally advanced disease, decline in renal function, complications, and utilization of adjuvant chemotherapy (AC).MethodsInstitutional databases from 7 academic medical centers identified 414 RNU patients treated between 2003 and 2012 who had not received neoadjuvant chemotherapy. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation. Complications were classified according to the modified Clavien system. Cox proportional hazard modeling and Kaplan-Meier analysis determined factors associated with cancer-specific survival.ResultsOf 414 patients, 177 (43%) had locally advanced disease, including 118 pT3N0/Nx, 13 pT4N0/Nx, and 46 pTanyN+. Estimated 3- and 5-year cancer-specific survival was 47% and 34%, respectively. Only 31% of patients with locally advanced UTUC received AC. Mean estimated glomerular filtration rate declined from 59 to 51 ml/min/1.73 m² following RNU, including a new-onset decline below 60 and 45 ml/min/1.73 m² in 25% and 15% of patients, respectively (P<0.001 for both). Complications occurred in 46 of 177 (26%) patients, of which one-quarter were grade III or IV. Increasing age (Hazard Ratio (HR) 1.4, P = 0.03), positive surgical margins (HR 2.1, P = 0.01), and positive lymph nodes (HR 4.3, P<0.001) were associated with an increased risk of death from UTUC, whereas receipt of AC (HR 0.85, P = 0.05) was associated with a decrease in UTUC mortality.ConclusionsUnder one-third of RNU patients with locally advanced UTUC cancers received AC. Perioperative complications and decline in renal function may have contributed to this low rate. Such data further underscore the need for continued discussion regarding the use of chemotherapy in a neoadjuvant setting for appropriately selected patients with UTUC.     

Variant histology as a significant predictor of survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma

Objectives

To investigate the effect of variant histology (VH) on survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma (UTUC) and the effect of adjuvant chemotherapy on the survival of patients with UTUC with VH.

Effect of concomitant variant histology on the prognosis of patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy

ObjectiveTo evaluate the prognostic effect of concomitant variant histology (CVH) on survival outcomes in patients with upper urinary tract urothelial carcinoma (UTUC) after radical nephroureterectomy.Materials and methodsData on 417 patients with UTUC treated with radical nephroureterectomy without preoperative adjuvant therapy were retrospectively reviewed with a focus on CVH. Clinicopathological features and prognostic factors were compared between patients with pure UTUC and patients with UTUC with CVH. The primary end points were cancer-specific survival (CSS), disease recurrence-free survival (DFS), and overall survival (OS).ResultsUTUC with CVH was present in 90 (21.6%) of 417 patients. At a median follow-up of 26 months, 153 (36.7%) had died of UTUC, 161 (38.6%) had experienced a relapse, and 176 (42.2%) had died of other causes. UTUC with CVH was significantly associated with advanced tumor stage, high tumor grade, tumor diameter, lymphovascular invasion, lymph node metastasis, positive surgical margins, and tumor architecture compared with pure UTUC (all P<0.01). The estimated 5-year CSS, DFS, and OS rates were 64.9%, 61.1%, and 62.1%, respectively, in the pure UTUC group, compared with 36.3%, 34.3%, and 26.5%, respectively, in the UTUC with CVH group (P<0.001). Multivariate analysis demonstrated that CVH was an independent predictor of CSS (hazard ratio [HR] = 1.594; 95% CI: 1.125–2.259; P = 0.009), DFS (HR = 1.549; 95% CI: 1.077–2.152; P = 0.017), and OS (HR = 1.685; 95% CI: 1.212–2.343; P = 0.002).ConclusionsApproximately one-fifth of the specimens of patients with UTUC were observed to exhibit CVH. CVH was an independent prognostic factor for CSS, DFS, and OS in patients with UTUC on both univariate and multivariate analyses. Genitourinary pathologists should look for potential CVH components in UTUC specimens and report this in routine pathological practice. The presence of CVH should identify patients as candidates for consultation regarding early adjuvant therapy and intensive surveillance protocols.     

Histological variants and lymphovascular invasion in upper tract urothelial carcinoma can stratify prognosis after radical nephroureterectomy

ObjectivesPatients with histological variants (HV) of bladder cancer have more advanced disease and poorer survival rates than those with pure urothelial carcinoma (UC). Moreover, lymphovascular invasion (LVI) is an important biomarker after RNU in systematic reviews and meta-analyses. Thus, here we investigated the clinical and prognostic impact of HV and LVI in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU).MethodsData from 223 UTUC patients treated with RNU without neoadjuvant chemotherapy were retrospectively evaluated. We analyzed differences in clinicopathological features and survival rates between patients with pure UC and those with HV. Conditional survival (CS) analysis was performed to obtain prognostic information over time.ResultsA total of 32 patients (14.3%) had HV, with the most common variant being squamous differentiation, followed by glandular differentiation. UTUC with HV was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and LVI, compared to pure UC (all P < 0.01). Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were all significantly worse in the HV group compared to the pure UC group (all, P < 0.001). In multivariable analysis, HV and LVI were independent predictors of CSS and OS. We classified the patients into three groups using these two predictors: low-risk (neither HV nor LVI), intermediate-risk (either HV or LVI), and high-risk (both HV and LVI). Significant differences in PFS, CSS, and OS rates were found among the 3 groups. In CS analysis, the conditional PFS, CSS, and OS rates at 1, 2, 3, 4, and 5 years improved with increased duration of event-free survival. CS analysis revealed that most progression events occurred within 2 years after RNU, and patients with risk factors had worse PFS at all time points.ConclusionsA risk model using HV and LVI can stratify PFS, CSS, and OS of patients treated with RNU. In addition, CS analysis revealed that HV and LVI were poor prognostic factors over time after RNU.     

Association between lymphovascular invasion and oncological outcome in node-negative upper tract urothelial carcinoma with different stage

ObjectivesTo evaluate the prognostic impact of lymphovascular invasion (LVI) on node-negative upper tract urothelial carcinoma (UTUC) in patients treated with radical nephroureterectomy (RNU).Materials and methodsA retrospective study was performed in single tertiary referral center of middle Taiwan between 2001 and 2015. Seven hundred and twenty-eight patients were diagnosed of UTUC and underwent RNU with ipsilateral bladder cuff excision including 303 and 195 patients with N0 and Nx status respectively. LVI status was assessed as a prognostic factor for cancer-specific (CSS) and overall survival (OS) using univariate and multivariate Cox regression analysis.ResultsLVI was observed in 82 patients (16.5%). LVI presentation associated with smoking status, advanced tumor stage, high tumor grade, positive surgical margin, and consequence lung/liver/bone metastasis. In the multivariate analysis, LVI was failed to predict CSS, OS, and disease-free survival (DFS) (hazard ratio [HR] [95% confidence interval [CI]: 1.07 [0.55–2.09], 1.05 [0.62–1.79], 1.15 [0.69–1.92], in CSS, OS, DFS, respectively). In the subgroup analysis of pT1-2 disease, the CSS, OS, and DFS were associated with LVI status (HR [95% CI]: 2.29 [0.44–11.84], 3.17 [1.16–8.67], 2.66 [1.04–6.79], in CSS, OS, DFS, respectively). In contrast, there was no difference in pT3 disease.ConclusionIn conclusion, LVI status was not associated with survival outcomes of node-negative UTUC in our study. The subgroup analysis showed different prognostic impacts of LVI status in node-negative UTUC with T1-2 and T3 stage. Further evidence to clarify the prognostic effect is needed to make LVI became a practical factor in clinical decision-making.     

Is neutrophil-to-lymphocytes ratio a clinical relevant preoperative biomarker in upper tract urothelial carcinoma? A meta-analysis of 4385 patients

Background

Preoperative blood-based inflammatory biomarkers have been suggested to improve staging and prognostication in patients with upper-tract urothelial carcinoma (UTUC). Neutrophil-to-lymphocyte ratio (NLR) is the most studied blood-based biomarker. NLR is an indicator of systemic inflammation and has been shown to be associated with a poor prognosis in various malignancies. The aim of this study was to analyze the current evidence regarding the prognostic significance of preoperative NLR in patients undergoing radical nephroureterectomy (RNU) for UTUC to assess its prognostic potential.

Materials and methods

A systematic search of Web of Science, Medline/PubMed and Cochrane library was performed on the 1st of October, 2017. Studies were deemed eligible if they compared patients with high NLR before surgical treatment for UTUC to patients with low NLR to determine its predictive value for survival using multivariable logistic regression analysis. We performed a formal meta-analysis for cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS).

Results

Nine studies including a total of 4385 patients assessing the importance of NLR were included in this meta-analysis. The cut-off NLR varied in the eligible studies ranging from 2 to 3. Increased pretreatment NLR predicted OS (pooled HR 1.64 95% CI; 1.23–2.17), RFS (pooled HR 1.60 95% CI; 1.16–2.20) and CSS (pooled HR 1.73 95% CI; 1.23–2.44) in multivariable analyses.

Conclusion

In this meta-analysis, preoperative blood-based NLR is associated with worse prognosis in patients who underwent RNU for UTUC. NLR could be used to improve clinical decision making regarding RNU vs. kidney-sparing surgery, extent of lymphadenectomy, perioperative systemic therapy and follow-up schedule.

     

Adjuvant chemotherapy improves survival of patients with high-risk upper urinary tract urothelial carcinoma: a propensity score-matched analysis

Background

The purposes of this study were to determine whether adjuvant chemotherapy (AC) improved the prognosis of patients with high-risk upper urinary tract urothelial carcinoma (UTUC)and to identify the patients who benefited from AC.

Methods

Among a multi-center database of 1014 patients who underwent RNU for UTUC, 344 patients with ≥ pT3 or the presence of lymphovascular invasion (LVI) were included. Cancer-specific survival (CSS) estimates were calculated by the Kaplan-Meier method, and groups were compared by the log-rank test. Each patient’s probability of receiving AC depending on the covariates in each group was estimated by logistic regression models. Propensity score matching was used to adjust the confounding factors for selecting patients for AC, and log-rank tests were applied to these propensity score-matched cohorts. Cox proportional hazards regression modeling was used to identify the variables with significant interaction with AC. Variables included age, pT category, LVI, tumor grade, ECOG performance status and low sodium or hemoglobin score, which we reported to be a prognostic factor of UTUC.

Results

Of the 344 patients, 241 (70%) had received RNU only and 103 (30%) had received RNU+AC. The median follow-up period was 32 (range 1–184) months. Overall, AC did not improve CSS (P = 0.12). After propensity score matching, the 5-year CSS was 69.0% in patients with RNU+AC versus 58.9% in patients with RNU alone (P = 0.030). Subgroup analyses of survival were performed to identify the patients who benefitted from AC. Subgroups of patients with low preoperative serum sodium (≤ 140 mEq/ml) or hemoglobin levels below the normal limit benefitted from AC (HR 0.34, 95% CI 0.15–0.61, P = 0.001). In the subgroup of patients with normal sodium and normal hemoglobin levels, 5-year CSS was 77.7% in patients with RNU+AC versus 80.2% in patients with RNU alone (P = 0.84). In contrast, in the subgroup of patients with low sodium or low hemoglobin levels, 5-year CSS was 71.0% in patients with RNU+AC versus 38.5% in patients with RNU alone (P < 0.001).

Conclusions

High-risk UTUC patients, especially subgroups of patients with lower sodium and hemoglobin levels, could benefit from AC after RNU.

     

Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract: An International Validation Study

Background

Lymphovascular invasion (LVI) identified following pathologic slide review has been shown to be an independent predictor of recurrence-free survival (RFS) and cancer-specific survival (CSS) in a multicenter series of patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). However, the validity of LVI in everyday practice, where pathologic re-review of all slides is uncommon, has not been assessed.

Objective

Our aim was to evaluate the prognostic role of LVI in an international cohort of patients treated with RNU for UTUC without pathologic slide review.

Design, setting, and participants

Data from 762 patients treated with RNU for UTUC without neoadjuvant chemotherapy were collected at nine centers located in Europe, Asia, and Canada.

Measurements

We evaluated patients’ characteristics, RFS, and CSS.

Results and limitations

LVI was present in 148 patients (19.4%). At a median follow-up of 34 mo, 23.5% of the patients developed disease recurrence and 19.8% died of UTUC. The 5-yr RFS and CSS rates were 79.3% and 82.1%, respectively, in the absence of LVI compared with 45.1% and 45.8%, respectively, in the presence of LVI (p values <0.0001). On multivariable Cox regression analyses, LVI was an independent predictor of RFS (hazard ratio [HR]: 3.3; p = 0.005) and CSS (HR: 5.9; p < 0.0001). Similarly, among patients with pN0/Nx disease, LVI was an independent predictor of RFS (HR: 2.1; p = 0.001) and CSS (HR: 2.3; p < 0.0001).

Conclusions

In a large multicenter series of patients treated with RNU for UTUC and for which no pathologic slide review was performed, LVI was present in approximately 20% and was an independent predictor of both RFS and CSS. LVI status should always be included in the pathologic report of RNU specimens, and patients with LVI should be considered for adjuvant therapy studies.     

The comparison of oncologic outcomes between metastatic upper tract urothelial carcinoma and urothelial carcinoma of the bladder after cisplatin-based chemotherapy

ObjectiveTo compare the oncologic outcomes and prognostic factors between metastatic upper tract urothelial carcinoma (UTUC) and UC of the bladder (UCB) after cisplatin-based chemotherapy.Materials and methodsWe retrospectively reviewed patients with metastatic UTUC and UCB after methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) or gemcitabine/cisplatin chemotherapy between 1997 and 2014 at Kaohsiung Chang Gung Memorial Hospital. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Univariate and multivariate analyses with Cox proportional hazard models were also performed to assess the effect of prognostic factors.ResultsTotally, 203 patients were enrolled into our study, including 120 patients with UTUC and 83 patients with UCB. For patients with UTUC, the median PFS was 7.3 months vs. 4.0 months (P<0.001), and the median OS was 17.0 months vs. 10.5 months (P<0.001) for MVAC and gemcitabine/cisplatin, respectively. For patients with UCB, the median PFS (P = 0.35) and OS (P = 0.06) of the 2 groups were insignificant. In multivariate analyses, number of metastatic sites was the identical prognostic factor for OS between UTUC (hazard ratio [HR] = 2.74; 95% CI: 1.63–4.62; P<0.001) and UCB (HR = 3.12; 95% CI: 1.52–6.39; P = 0.002). Presence of liver metastasis (HR = 1.84; 95% CI: 1.05–2.23; P = 0.03) and MVAC chemotherapy (HR = 0.54; 95% CI: 0.35–0.83; P<0.001) were significantly correlated to survival only for UTUC, not for UCB.ConclusionOur study suggests discordant oncologic outcomes and prognostic factors between metastatic UTUC and UCB after cisplatin-based chemotherapy. A prospective study is warranted to validate our results.     

Disease-free survival as a surrogate for overall survival in upper tract urothelial carcinoma

Objectives

The primary endpoint in trials of perioperative systemic therapy for urothelial carcinoma is 5-year overall survival (OS). A shorter-term endpoint could significantly speed the translation of advances into practice. We hypothesized that disease-free survival (DFS) could be a surrogate endpoint for OS in upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy (RNU).

Patients and methods

The study included 2,492 patients treated with RNU with curative intent for UTUC.

Results

2/3-year DFS estimates were 78/73 %, and the 5-year OS estimate was 64 %. The overall agreements between 2- and 3-year DFS with 5-year OS were 85 and 87 %, respectively. Agreements were similar when analyzed in subgroups stratified by pathological stages, lymph node status, and adjuvant chemotherapy. The kappa statistic was 0.59 (95 % CI 0.55–0.63) for 2-year DFS/5-year OS and 0.64 (95 % CI 0.61–0.68) for 3-year DFS/5-year OS, indicating moderate reliability. The hazard ratio for DFS as a time-dependent variable for predicting OS was 11.5 (95 % CI 9.1–14.4), indicating a strong relationship between DFS and OS.

Conclusions

In patients treated with RNU for UTUC, DFS and OS are highly correlated, regardless of tumor stage and adjuvant chemotherapy. While significant differences in DFS, assessed at 2 and 3 years, are highly likely to persist in OS at 5 years, marginal DFS advantages may not translate into OS benefit. External validation is necessary before accepting DFS as an appropriate surrogate endpoint for clinical trials investigating advanced UTUC patients.     

Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma

ObjectiveMacroscopic sessile tumor architecture was associated with adverse outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Before inclusion in daily clinical decision-making, the prognostic value of tumor architecture needs to be validated in an independent, external dataset. We tested whether macroscopic tumor architecture improves outcome prediction in an international cohort of patients.Material and methodsWe retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at 9 centers located in Asia, Canada, and Europe. Tumor architecture was macroscopically categorized as either papillary or sessile. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates.ResultsMacroscopic sessile architecture was present in 20% of the patients. Its prevalence increased with advancing pathologic stage and it was significantly associated with established features of biologically aggressive UTUC, such as tumor grade, lymph node metastasis, lymphovascular invasion, and concomitant CIS (all P values < 0.02). The median follow-up for patients who were alive at last follow-up was 40 months (IQR: 18–75 months, range: 1–271 months). Two-year RFS and CSS for tumors with papillary architecture were 85% and 90%, compared with 58% and 66% for those with macroscopic sessile architecture, respectively (P values < 0.0001). On multivariable Cox regression analyses, macroscopic sessile architecture was an independent predictor of both RFS (hazard ratio {HR}: 1.5; P = 0.036) and CSS (HR: 1.5; P = 0.03).ConclusionWe confirmed the independent prognostic value of macroscopic tumor architecture in a large, independent, multicenter UTUC cohort. It should be reported in every pathology report and included in post-RNU predictive models in order to refine current clinical decision making regarding follow-up protocol and adjuvant therapy.     

Effectiveness of adjuvant radiotherapy for high recurrence risk patients with upper tract urothelial carcinoma

PurposeA recent study has shown that upper tract urothelial carcinoma (UTUC) patients with high-risk factors have a high local recurrence rate. The purpose of this work was to investigate the benefit of adjuvant radiotherapy (ART) for patients with high recurrence factors.MethodsFour hundred twenty-four UTUC patients who received radical nephroureterectomy (RNU) in our hospital between 2010 and 2018 were reviewed. The significance of factors on cancer-specific survival (CSS) and recurrence-free survival (RFS) were assessed using Cox multivariate analysis. In patients with high recurrence factors, propensity score matching was used to adjust the confounding factors for ART.ResultsThe median follow-up time was 40 (range 3–77) months. Multivariate analysis showed that multifocal tumor, G3, pT3/4 stage and positive lymph node (N+) were independent predictors for worse RFS. Multifocal tumor and pT3/4 stage were independent predictors of worse CSS in UTUC after surgery. A total of 286 patients with these high recurrence factors were identified: 192 (67.1%) patients received RNU only, and 94 (32.9%) patients received ART. Overall, ART did not improve CSS (ART 86.1% vs. RNU 78.5%.; P = 0.11). After propensity score matching, ART significantly improved the CSS of patients with high recurrence factors. The 3-year CSS was 73.1% in patients treated with RNU alone vs. 86.1% in patients treated with ART (P = 0.016).ConclusionsResults of our study demonstrated benefit of adjuvant radiotherapy in cancer specific survival in UTUC patients with high recurrence factors(multifocal tumor ,pT3/4,G3 and positive lymph node).     

Gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes

PurposeTo evaluate gemcitabine-cisplatin (GC) neoadjuvant cisplatin-based chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer and identify clinical parameters associated with pR.Materials and methodsWe studied 150 consecutive cases of muscle-invasive bladder cancer that received GC NAC followed by open RC (2000–2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance.ResultsNo significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non–muscle-invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (P = 0.99). NAC pR (≤pT1) demonstrated improved 5-year CSS rates (90.6% vs. 27.1%, P<0.01) and decreased nodal positivity rates (0% vs. 41.3%, P<0.01) when compared with nonresponders (≥pT2). Clinicopathologic outcomes were inferior in NAC pathologic nonresponders when compared with the entire RC-only–treated cohort. A lower pathologic nonresponder rate was seen in patients tolerating sufficient dosing of NAC as stratified by the Johns Hopkins Hospital Dose Index (P = 0.049), congruent with the National Comprehensive Cancer Network guidelines. A multivariate classification tree model demonstrated 60 years of age or younger and clinical stage cT2 as significant of NAC response (P< 0.05).ConclusionsPathologic nonresponders fare worse than patients proceeding directly to RC alone do. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients who are most likely to benefit from GC NAC.     

The expression of urokinase-type plasminogen activator system in upper tract urothelial carcinoma and its prognostic value after radical nephroureterectomy

BackgroundTo evaluate the expression pattern and prognostic role of the urokinase-type plasminogen activator (uPA) system in patients who underwent radical nephroureterectomy (RNU) for nonmetastatic upper tract urothelial carcinoma (UTUC).MethodsA total of 732 patients who were treated with RNU for clinically nonmetastatic UTUC comprised our analytical cohort. Immunohistochemical staining of uPA, uPA receptor (uPAR) and uPA inhibitor (PAI-1) was performed using Murine IgG1 monoclonal antibodies. Outcomes of interest were recurrence-free survival, cancer-specific survival, and overall survival.ResultsThe median age of the patients was 69.8 years and 56.6% of them were males. Overall, overexpression of uPA, uPAR, and PAI-1 was observed in 292 (39.9%), 346 (47.3%), and 345 (47.1%) patients, respectively. The uPA system components showed a statistically significant association with adverse clinicopathologic features such as lymphovascular invasion, multifocality, sessile tumors, and advanced pathologic stage (P < 0.01). On multivariable models, higher pathologic tumor stage, multifocality, and lymph node involvement were associated with RFS, OS, and CSS, but not the overexpression of uPA, uPAR, or PAR-1. In patients with organ-confined disease (≤pT2N0), however, uPA was significantly associated with RFS (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.21–3.43), OS (HR: 1.59, 95% CI:1.08–2.24) and CSS (HR: 2.55, 95% CI:1.44–4.52). uPA improved the predictive accuracy of a standard post-RNU model for all 3 endpoints, in organ-confined disease, by a prognostically significant margin.ConclusionsOverexpression of uPA system components was associated with adverse clinicopathologic characteristics and survival outcomes on the univariable, but not multivariable analyses. uPA expression was an independent predictor of survival outcomes in patients with organ-confined disease. While the clinical value of the uPA system remains limited in this cohort, further studies are needed to identify a marker or constellation of markers of high predictive value to help in counseling and treatment planning of UTUC patients.