C-reactive protein: A biomarker of survival in patients with localized upper tract urothelial carcinoma treated with radical nephroureterectomy

Background and objectiveSerum C-reactive protein (CRP) is one particular marker of systemic inflammation, and an elevated CRP level is associated with poor outcome in various malignancies. While the clinical value of CRP levels in upper tract urothelial carcinoma (UTUC) has not yet been fully evaluated, we investigated the impact of CRP elevation as a biomarker of patient prognosis in UTUC.Materials and methodsA total of 183 patients who underwent radical nephroureterectomy (RNU) for localized UTUC (pTa-4N0M0) were identified between 1993 and 2009. The associations between the levels of serum CRP and patient outcome were analyzed.ResultsThirty-three patients experienced disease recurrence, and 28 died of the disease during the median follow-up period of 39 months. Using the defined cutoff level of CRP >0.5 mg/dl as elevated, preoperative CRP (pre-CRP) levels were elevated in 42 patients (23.0%). Kaplan-Meier curves revealed that subsequent tumor recurrences and worse cancer-specific survival could be significantly predicted in the elevated pre-CRP group. The 5-year recurrence-free survival rate was 63.6% in the elevated pre-CRP group and 83.4% in their counterparts (P < 0.001), and the 5-year cancer-specific survival rate was 64.7% in the elevated pre-CRP group and 84.3% in their counterparts (P = 0.001). Multivariate analysis revealed that elevated pre-CRP, in addition to pathologic T stage, was an independent risk factor for subsequent disease recurrence (P = 0.003, hazard ration (HR) = 2.83), and the decrease in cancer-specific survival (P = 0.012, HR = 2.65). In subgroup analysis using patients with pT3 tumors or greater, multivariate analysis also showed that elevated pre-CRP was an independent risk factor for a decrease in both recurrence-free and cancer-specific survival.ConclusionsPre-CRP level was an independent predictor of patient survival in localized advanced UTUC. Patients with pre-CRP >0.5 mg/dl were strongly predicted to have worse prognostic outcomes following RNU. Due to its low cost and easy accessibility, CRP may be a useful biomarker for localized UTUC.     

Trends of lymphadenectomy in upper tract urothelial carcinoma (UTUC) patients treated with radical nephroureterectomy

Introduction

To evaluate temporal trends in the delivery and extent of lymphadenectomy (LND) in radical nephroureterectomy (RNU) performed in upper tract urothelial carcinoma (UTUC) patients.

Methods

We evaluated a multi institutional collaborative database composed by 1512 consecutive patients diagnosed with UTUC treated with RNU between 1990 and 2016. Year of surgery were grouped in five periods: 1990–1996, 1997–2002, 2003–2007, 2008–2012 and 2013–2016. Data about LND were available for all patients and numbers of nodes removed and positive were reported by dedicate uropathologists. The Mann–Whitney and Chi square tests were used to compare the statistical significance of differences in medians and proportions, respectively.

Results

Five hundred forty-five patients (36.0%) received a concomitant LND while 967 (64.0%) did not; 41.9% of open RNU patients received a concomitant LND compared to 24.4% of laparoscopic RNU patients. The rate of concomitant LND increased with time in the overall, laparoscopic and open RNU patients (all p?<?0.03). Patients treated with open RNU also had an increasing likelihood to receive an adequate concomitant LND (p?<?0.001) while those undergoing a laparoscopic approach did not (p?=?0.1). Patients treated with concomitant LND had a median longer operative time of 20 min (p?=?0.01). There were no differences in perioperative outcomes and complications between patients who received a concomitant LND and those who did not (p?>?0.1).

Conclusion

Although an increased trend was observed, most patients treated with RNU did not receive LND. Surgeons using a laparoscopic RNU were less likely to perform a concomitant LND, and when done, they remove less nodes.

     

Laparoscopic radical nephroureterectomy is associated with worse survival outcomes than open radical nephroureterectomy in patients with locally advanced upper tract urothelial carcinoma

Purpose

To compare survival outcomes between laparoscopic radical nephroureterectomy (LRNU) and open radical nephroureterectomy (ORNU) in upper urinary tract urothelial carcinoma (UTUC) patients.

Methods

We retrospectively analyzed the data of 371 UTUC patients who underwent ORNU (n = 271) or LRNU (n = 100) between 1992 and 2012. The survival outcomes included intravesical recurrence (IVR)-free survival, overall survival (OS), and cancer-specific survival (CSS). The Kaplan–Meier method and log-rank test were used to estimate and compare survival curves between groups. Factors associated with survival outcomes were evaluated using univariable and multivariable Cox proportional hazard models.

Results

The three-year IVR-free survival rates were similar between the ORNU and LRNU groups (59.9 and 61.7 %, p = 0.267). However, the LRNU group showed worse five-year OS (59.1 vs. 75.2 %, p = 0.027) and CSS (66.1 vs. 80.2 %, p = 0.015) rates than the ORNU group. In particular, on stratifying the study cohort by pathological stages, significant differences in OS (p = 0.007) and CSS (p = 0.005) between the surgical approaches were observed only in locally advanced disease (pT3/T4). In multivariable analysis, LRNU was an independent predictor of worse OS (p = 0.001) and CSS (p = 0.006) than ORNU. Likewise, in multivariable analysis in patients with pT3/T4 stage, LRNU was significantly associated with worse OS (hazard ratio [HR] 2.59, p = 0.001) and CSS (HR 2.50, p = 0.005).

Conclusions

Our data suggest that in UTUC patients, LRNU, compared to ORNU, is generally associated with unfavorable OS and CSS results. In particular, LRNU should be performed in locally advanced UTUC patients after careful consideration of its impact on patient survival.

     

Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma

Purpose

Women have been associated with adverse outcomes after radical cystectomy for lower tract urothelial carcinoma. We evaluated the prognostic value of gender in an international cohort of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

We retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at nine centers located in Asia, Canada, and Europe. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. Median follow-up was 40?months (interquartile range: 18?C75).

Results

The majority of patients was of men (516, 68.4%). Women were older than men at the time of RNU (median: 69.2 vs. 66.5?years; P?=?0.0003). Women were less likely to have high-grade disease, undergo lymph node dissection, and to receive adjuvant chemotherapy. Gender was not associated with pathologic stage, lymph node metastasis, lymphovascular invasion, concomitant CIS, tumor architecture, or tumor necrosis. On univariable Cox regression analyses, there was no association between gender and cancer recurrence (P?=?0.76) or cancer-specific mortality (P?=?0.30). On multivariable Cox regression analyses that adjusted for the effects of clinicopathologic features, gender was not associated with disease recurrence (P?=?0.47) or cancer-specific survival (P?=?0.15).

Conclusions

We found no difference in histopathologic features and outcomes between men and women treated with RNU for UTUC. Nevertheless, epidemiologic and mechanistic molecular studies should be encouraged to design, analyze, and report gender-specific associations to aid in our understanding of gender impact on UTUC incidence, progression, and metastasis.     

Influence of late-stage chronic kidney disease on overall survival in patients with upper tract urothelial carcinoma following radical nephroureterectomy

ObjectivesThe prevalence of both chronic kidney disease (CKD) and upper tract urothelial carcinoma (UTUC) in Taiwan is unusually high, and we aimed to investigate the impact of preoperative renal function on UTUC after radical nephroureterectomy.Materials and methodsBetween 2000 and 2013, 248 UTUC patients were enrolled in this retrospective study after excluding patients who had concomitant muscle-invasive bladder cancer, whose tumor metastasized at initial presentation, and who received perioperative chemotherapy or radiotherapy. The significance of CKD on overall survival (OS), cancer-specific survival (CSS), and bladder recurrence-free survival (BRFS) was evaluated by Cox proportional hazard model.ResultsThe median follow-up time was 45.41 months. Overall 5-year OS, CSS, and BRFS rates were 78.27%, 87.81%, and 70.42%, respectively. Aging, late-stage CKD, and nonorgan-confined primary tumor stage were independent predictors for OS after adjustment. Nonorgan-confined primary tumor stage and lymph node involvement were two independent predictors for CSS after adjustment. Concomitant bladder tumor was the only significant predictor for BRFS after adjustment.ConclusionPatients with late-stage CKD had a higher risk of having poor OS. Patients with concomitant bladder tumor had a greater risk of having bladder cancer recurrence despite primary tumor stage. Concomitant bladder tumor, however, had no effect on OS and CSS in this study.     

Preoperative prognostic factors after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma

Purpose

To evaluate the clinical significance of preoperative biomarkers such as laboratory data, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and clinicopathological factors in patients undergoing radical nephroureterectomy for upper urinary tract urothelial carcinoma.

Methods

Between 1995 and 2011, a total of 99 patients treated at our institution for upper urinary tract urothelial carcinoma were enrolled in this study. The prognostic significance of various preoperative data and clinicopathological factors were analyzed. Univariate and multivariate analyses were performed using the Kaplan–Meier method with the log-rank test and a Cox proportional hazards regression model.

Results

Median patient age was 73 years (range 44–86 years), and the median follow-up period after radical nephroureterectomy was 37.9 months (range 6.6–171.4 months). The 5-year intravesical recurrence-free survival and cancer-specific survival estimates were 47.1 and 70.0 %, respectively. On multivariate analysis, concomitant bladder carcinoma was an independent predictor of intravesical recurrence (hazard ratio 3.689; P = 0.002), and infiltration (hazard ratio 14.842; P = 0.002), preoperative serum creatinine level (hazard ratio 9.992; P = 0.005), preoperative serum hemoglobin level (hazard ratio 6.370; P = 0.018) and ECOG PS (hazard ratio 4.326; P = 0.037) were associated with worse cancer-specific survival. This study is limited by biases associated with its retrospective design.

Conclusions

This study indicates that not only clinicopathological factors, but also preoperative biomarkers, such as serum creatinine and hemoglobin levels and ECOG PS, predict a poor survival in patients with upper urinary tract urothelial carcinoma.     

Impact of micropapillary histological variant on survival after radical nephroureterectomy for upper tract urothelial carcinoma

Purpose

To assess the impact of micropapillary histological variant on oncological outcome after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinomas (UTUCs).

Methods

A French multicenter retrospective study was performed on patients who underwent RNU between 1995 and 2010. Pathological reports were reviewed to identify patients with pure urothelial carcinomas (PUC) and those with micropapillary histological variant (MPC). Uni- and multivariate Cox regression analyses were performed to identify factors predictive of survival.

Results

Overall, 519 patients were included and divided into two groups: 480 PUC and 39 MPC. Median follow-up were 28 and 19 months, respectively (p = 0.63). There was no difference between the two groups for gender, age and tumor location (pelvicalyceal or ureteral). MPC was associated with high-stage and high-grade UTUC (p < 0.001 and 0.04). No difference was observed between the two groups for 5-year cancer-specific survival (76.1 vs. 88.2 %; p = 0.54). The 5-year metastasis-free survival was significantly lower in the MPC group (48.9 vs. 73.8 %; p = 0.037). In multivariate analysis, pT stage, lymphovascular invasion, margin status and adjuvant chemotherapy administration were independent predictors of specific survival (p = 0.002; 0.001; 0.02; 0.01), contrary to histological variant (p = 0.94).

Conclusions

Micropapillary histological variant was associated with advanced UTUC and reduced metastasis-free survival after RNU. It should be considered as an aggressive tumor and thus be stated in any pathological report after radical surgery.     

Outcome prediction following radical nephroureterectomy for upper tract urothelial carcinoma

ObjectiveTo predict overall survival, cancer, and metastasis specific survival in upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU).Materials and MethodsAll nonmetastatic UTUC patients who underwent RNU with a curative intent at 1 institution between December 1998 and January 2017 were included.  Detailed data were collected. End points for this study included OS, CCS, and MFS. Univariate and multivariate analysis were conducted. Log Rank tests and Kaplan-Meier curves were generated. Backward elimination and boot strapping was used to identify the most parsimonious model with the smallest number of variables in order to predict the outcomes of interest. A separate second institution data base was used for external validation.ResultsThere were 218 patients in the development cohort. Mean follow-up was 42 months (±39.6). There was 99 (45.4%) deaths, 28 (12.8%) cancer related deaths, 72 (33%) recurrences, and 54 (24.8%) metastases. The c-index for our model was 0.71 for OS, 0.72 for MFS and 0.74 for CSS. The nomograms did not show significant deviation from actual observations using our calibration plots. We divided the patient into 3 different groups (low, intermediate and high risk) based on their final total score for each outcome and compared them. On external validation our accuracy was 78.4%, 71.4%, and 75.3% for OS, CSS, and MFS survival respectively.ConclusionWe designed a predictive model for survival outcomes following RNU in UTUC. This model uses simple, readily available data for patients without the need for expensive or additional testing.     

Impact of body mass index on the oncological outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma

Purpose

To evaluate the association between body mass index (BMI) and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

We retrospectively reviewed 237 consecutive patients treated with RNU for UTUC at our institution between 1990 and 2012. Univariable and multivariable cox regression models investigated the association of BMI with disease recurrence, cancer-specific mortality, and overall mortality.

Results

From the 237 patients, 104 (44%) had a BMI < 25 kg/m², 88 (37%) had a BMI between 25 and 29.9 kg/m², and 45 (19%) had a BMI ≥ 30 kg/m² at the time of surgery. Within a median follow-up of 44 months (IQR: 24–79), 53 patients (22.4%) experienced a disease recurrence, 85 patients (35.9%) had bladder recurrence, and 44 patients (18.6%) died from the disease. The 5 year recurrence-free and cancer-specific survival rates were, respectively, 32 and 56% for BMI ≥ 30 kg/m², 45 and 74% for patients with BMI 25–29.9 kg/m², and 69 and 81% for patients with BMI < 25 kg/m². In multivariable analyses that adjusted for the effects of the standard clinico-pathological features, BMI ≥ 30 kg/m² was associated with a higher risk of disease recurrence (HR 3.23; 95% CI 2.3–6.6, p < 0.001) and cancer-specific mortality (HR 3.84; 95% CI 2.8–6.5; p < 0.001).

Conclusions

Obesity was independently associated with higher risks of disease recurrence and cancer-specific mortality in patients treated with RNU for 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.

Kidney disease progression in patients of upper tract urothelial carcinoma following unilateral radical nephroureterectomy

Objectives: To compare the renal outcomes in patients of unilateral renal cell carcinoma (RCC) with upper tract urothelial carcinoma (UTUC) following surgical resection of the tumor-bearing kidney, and to investigate the potential predictors in renal function decline. Patients and methods: In this retrospective cohort study, 319 RCC patients undergoing radical nephrectomy (RN) and 297 UTUC patients undergoing radical nephroureterectomy were recruited from a tertiary medical center between 2001 and 2010. Demographic data, co-morbidity, smoking habit, baseline estimated glomerular filtration rate (eGFR) calculated by chronic kidney disease-epidemiology equation, as well as tumor staging of RCC and UTUC, were recorded. The primary endpoint was serum creatinine doubling and/or end-stage renal disease (ESRD) necessitating long-term dialysis. Cox proportional hazard model and Fine and Gray's competing risk regression accounting for death were used to model renal outcome. Results: UTUC patients had a higher incidence rate of renal function deterioration than RCC patients did (15.01 vs. 2.68 per 100 person-years, p<0.001). In Cox proportional hazard model and Fine and Gray's competing risk regression, UTUC was significantly associated with increased risk of creatinine doubling and/or ESRD necessitating dialysis (hazard ratio, 3.13; 95% confidence interval, 2.01–4.87) as compared to RCC following unilateral RN. Nevertheless, our study is observational in nature and cannot prove causality. Conclusions: UTUC per se is strongly associated with kidney disease progression as compared to RCC following unilateral nephrectomy. Further studies are needed to elucidate this association.     

A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk,upper tract urothelial carcinoma: PURE-02

IntroductionAdvances in neoadjuvant therapy for patients with localized, nonmetastatic, upper tract urothelial carcinoma (UTUC) is needed.Patients and methodsPURE-02 was a feasibility study enrolling individuals with UTUC, at clinical stage N0M0, with high-risk features according to the modified European Association of Urology definition, based on the presence of either: high-grade disease, multifocality, tumor size ≥2 cm, and/or hydronephrosis. The treatment consisted of 3 courses of 200 mg pembrolizumab, intravenously, every 3 weeks, followed by radical nephroureterectomy (RNU). The endpoints were to assess the safety, pathological responses, and biomarkers.ResultsTen patients were enrolled between August 2018 and November 2020, 9 (90%) completed the neoadjuvant course. One treatment-related death occurred as a complication of severe myocarditis, myasthenia gravis, hepatitis and myositis. One (14.3%) patient achieved a clinical complete response and refused to undergo RNU. Two (20%) had disease progression and received subsequent chemotherapy, prior to RNU. Overall, 7 patients underwent RNU: one (14.3%) achieved an ypT1N0 response, although this patient was reported to have a cT1 tumor at baseline imaging. The remaining patients were nonresponders. Circulating tumor DNA assay did not identify patients likely to achieve a complete pathologic response.ConclusionSingle-agent neoadjuvant pembrolizumab did not appear to be a promising treatment strategy for patients with biomarker-unselected, high-risk localized UTUC.