Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Improved patient selection for conservative management, neoadjuvant chemotherapy, and/or extended lymphadenectomy is urgently needed. We developed a highly accurate preoperative model to predict muscle‐invasive and non‐organ‐confined upper tract urothelial carcinoma based on standard imaging and ureteroscopy features.

OBJECTIVE

? To create a preoperative multivariable model to identify patients at risk of muscle‐invasive (pT2+) upper tract urothelial carcinoma (UTUC) and/or non‐organ confined (pT3+ or N+) UTUC (NOC‐UTUC) who potentially could benefit from radical nephroureterectomy (RNU), neoadjuvant chemotherapy and/or an extended lymph node dissection.

PATIENTS AND METHODS

? We retrospectively analysed data from 324 consecutive patients treated with RNU between 1995 and 2008 at a tertiary cancer centre. ? Patients with muscle‐invasive bladder cancer were excluded, resulting in 274 patients for analysis. ? Logistic regression models were used to predict pT2+ and NOC‐UTUC. Pre‐specified predictors included local invasion (i.e. parenchymal, renal sinus fat, or periureteric) on imaging, hydronephrosis on imaging, high‐grade tumours on ureteroscopy, and tumour location on ureteroscopy. ? Predictive accuracy was measured by the area under the curve (AUC).

RESULTS

? The median follow‐up for patients without disease recurrence or death was 4.2 years. ? Overall, 49% of the patients had pT2+, and 30% had NOC‐UTUC at the time of RNU. ? In the multivariable analysis, only local invasion on imaging and ureteroscopy high grade were significantly associated with pathological stage. ? AUC to predict pT2+ and NOC‐UTUC were 0.71 and 0.70, respectively.

CONCLUSIONS

? We designed a preoperative prediction model for pT2+ and NOC‐UTUC, based on readily available imaging and ureteroscopic grade. ? Further research is needed to determine whether use of this prediction model to select patients for conservative management vs RNU, neoadjuvant chemotherapy, and/or extended lymphadenectomy will improve patient outcomes.     

International validation of the prognostic value of subclassification for AJCC stage pT3 upper tract urothelial carcinoma of the renal pelvis

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Tumour stage is a powerful predictor of clinical outcomes and the most important factor driving clinical decision‐making after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). It has been suggested that renal pelvic pT3 subclassification into microscopic infiltration of the renal parenchyma (pT3a) versus macroscopic infiltration or invasion of peripelvic adipose tissue (pT3b) has strong prognostic value. This is an external validation study of the prognostic value of pT3 subclassification of renal pelvic UTUC in a large international cohort of patients treated with RNU. pT3b UTUC is associated with features of aggressive tumour biology, disease recurrence and cancer‐specific mortality. However, pT3 subclassification is not an independent predictor of clinical outcomes.

OBJECTIVE

• ? To externally validate the prognostic value of subclassification of pT3 renal pelvic upper tract urothelial carcinoma (UTUC) in a large international cohort of patients treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The RNU specimens with pT3 UTUC of the renal pelvis from 284 patients at 11 centres located in Asia, North America and Europe were retrospectively evaluated. All specimens were reviewed by genitourinary pathologists at each institution. Tumours were categorized as pT3a (microscopic infiltration of the renal parenchyma) or pT3b (macroscopic infiltration of the renal parenchyma and/or infiltration of peripelvic adipose tissue).

RESULTS

• ? Overall, 148 (52%) tumours were classified as pT3a and 136 (48%) as pT3b. Patients with pT3b disease were more likely to have high‐grade tumours and sessile tumour architecture (all P≤ 0.02). Patients with pT3b tumours were at increased risk of disease recurrence (5‐year estimates: 55% versus 42%, P= 0.012) and cancer‐specific mortality (CSM) (5‐year estimates: 48% versus 40%, P= 0.04). Lymph node status, tumour architecture and tumour grade were independently associated with disease recurrence, whereas lymph node status, tumour architecture and lymphovascular invasion were independently associated with CSM. Subclassification of pT3 tumours was not associated with recurrence or CSM in multivariable analyses.

CONCLUSION

• ? Patients with pT3b UTUC were more likely to have tumours with aggressive pathological features and were at higher risk of disease recurrence and CSM after RNU compared with patients with pT3a disease. However, the pT3 subclassification did not remain an independent predictor of disease recurrence or CSM after controlling for tumour grade, lymph node status, tumour architecture and lymphovascular invasion.

     

Risk of Cancer-specific Mortality following Recurrence After Radical Nephroureterectomy

Purpose

To describe the natural history and identify predictors of cancer-specific survival in patients who experience disease recurrence after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

Of 2,494 UTUC patients treated with RNU without neoadjuvant chemotherapy, 597 patients experienced disease recurrence. A total of 148 patients (25?%) received adjuvant chemotherapy before disease recurrence. Multivariable Cox regression model addressed time to cancer-specific mortality after disease recurrence.

Results

The median time from RNU to disease recurrence was 12?months (interquartile range 5?C22). A total of 491 (82?%) of 597 patients died from UTUC, and 8 patients (1.3?%) died from other causes. The median time from disease recurrence to death of UTUC was 10?months. Actuarial cancer-specific survival estimate at 12?months after disease recurrence was 35?%. On multivariable analysis that adjusted for the effects of standard clinicopathologic characteristics, higher tumor stages [hazard ratio (HR) pT3 vs. pT0?CT1: 1.66, p?=?0.001; HR pT4 vs. pT0?CT1: 1.90, p?=?0.002], absence of lymph node dissection (HR 1.28, p?=?0.041), ureteral tumor location (HR 1.44, p?<?0.0005) and a shorter interval from surgery to disease recurrence (p?<?0.0005) were significantly associated with cancer-specific mortality. The adjusted 6-, 12- and 24-month postrecurrence cancer-specific mortality was 73, 60 and 57?%, respectively.

Conclusions

Approximately 80?% of patients who experience disease recurrence after RNU die within 2?years after recurrence. Patients with non-organ-confined stage, absence of lymph node dissection, ureteral tumor location and/or shorter time to disease recurrence died of their tumor more quickly than their counterparts. These factors should be considered in patient counseling and risk stratification for salvage treatment decision making.     

A delay in radical nephroureterectomy can lead to upstaging

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVE

To examine the association between the delay from diagnosis of upper‐tract urothelial carcinoma (UTUC) to radical nephroureterectomy (RNU), and the pathological features and outcomes, as the decision to proceed to RNU for an individual patient is complex.

PATIENTS AND METHODS

The records of 187 patients who had RNU were reviewed; the interval from diagnosis to RNU was analysed as both a continuous (months) and categorical variable (<3 vs ≥3 months). Logistic regression and survival analyses were used to evaluate the association between time from diagnosis to RNU with pathological characteristics and clinical outcomes.

RESULTS

The median time from diagnosis to RNU was 45 days (interquartile range 68). A delay from diagnosis to RNU analysed as a continuous variable was associated with advanced stage, higher grade, previous endoscopic procedure, tumour necrosis, infiltrative tumour architecture, and lymphovascular invasion (P = 0.034), but not disease recurrence or cancer‐specific mortality. In the subgroup of patients (90, 48.1%) who had muscle‐invasive disease (≥pT2) a longer delay from diagnosis to RNU as a continuous variable was associated with advanced stage (P = 0.030), higher grade (P = 0.014), infiltrative tumour architecture (P = 0.044), lymphovascular invasion (P = 0.034), disease recurrence (P = 0.02), and cancer‐specific mortality (P = 0.03).

CONCLUSIONS

Our data suggest that a delay in the interval from diagnosis to RNU is associated with more advanced disease stage. These findings might have important implications for trial design in the ongoing evaluation of neoadjuvant regimens. Timely consideration of definitive treatment for patients with high‐risk UTUC is of high importance. Further studies are necessary to validate these hypothesis‐generating findings.     

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.     

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 indicators for upper tract urothelial carcinoma after radical nephroureterectomy: the impact of lymphovascular invasion

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? In an array of urological and non‐urological malignancies, lymphovascular invasion (LVI) is a pathological feature known to be associated with adverse outcomes for recurrence and survival. For some cancers, LVI has therefore been incorporated into American Joint Committee on Cancer TNM staging algorithms. This study presents an analysis of the impact of LVI in upper urinary tract urothelial carcinoma (UTUC) treated at our institution over a 20‐year period. In addition to known associations with features of aggressive disease and overall survival, we were able to show that LVI‐positive status upsets the TNM staging for UTUC. Namely, patients with superficial stage and LVI‐positive disease have overall survival outcomes similar to those of patients with muscle‐invasive LVI‐negative carcinoma. Such evidence may support the addition of LVI to future TNM staging algorithms for UTUC.

OBJECTIVE

• ? To assess the impact of lymphovascular invasion (LVI) on the prognosis of patients with upper urinary tract urothelial cell carcinoma (UTUC) treated with radical nephroureterectomy (RNU).

PATIENTS AND METHODS

• ? The Columbia University Medical Center Urologic Oncology database was queried and 211 patients undergoing RNU for UTUC between 1990 and 2010 were identified.
• ? These cases were retrospectively reviewed, and the prognostic significance of relevant clinical and pathological variables was analysed using log‐rank tests and Cox proportional hazards regression models.
• ? Actuarial survival curves were calculated using the Kaplan–Meier method.

RESULTS

• ? LVI was observed in 68 patients (32.2%).
• ? The proportion of LVI increased with advancing stage, high grade, positive margin status, concomitant carcinoma in situ, and lymph node metastases. The 5‐ and 10‐year overall survival rates were 74.7% and 53.1% in the absence of LVI, and 35.7% and 28.6% in the presence of LVI, respectively.
• ? In multivariate analysis, age, race and LVI were independent predictors of overall survival.

CONCLUSIONS

• ? The presence of LVI on pathological review of RNU specimens was associated with worse overall survival in patients with UTUC.
• ? LVI status should be included in the pathological report for RNU specimens to help guide postoperative therapeutic options.
• ? With confirmation from large international studies, inclusion of LVI in the tumour‐node‐metastasis staging system for UTUC should be considered.

     

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.     

Lymphadenectomy at the time of nephroureterectomy for upper tract urothelial cancer

Context

The role of lymph node dissection (LND) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial cancer (UTUC) is still controversial.

Objective

To analyze the impact of lymph node invasion on the outcome of patients, the staging, and the possible therapeutic role of LND in UTUC.

Evidence acquisition

A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in UTUC. Keywords included upper tract urothelial neoplasms, lymphadenectomy, lymph node excision, lymphatic metastases, nephroureterectomy, imaging, and survival.

Evidence synthesis

Regional nodes are frequently involved in UTUC and represent the most common metastatic site. Regional nodal status is a significant predictor of patient outcomes, especially in invasive disease. Therefore, select patients treated with RNU at high risk for regional nodal metastases should undergo LND to improve disease staging, which would identify those who could benefit from adjuvant systemic therapy. Several retrospective studies suggested the potential therapeutic role of LND in UTUC. An accurate LND could remove some nodal micrometastases not identified on routine pathologic examination, thus improving local control and cancer-specific survival. Radical surgery and LND might be curative in a subpopulation with limited nodal disease, as described in bladder cancer. A clear knowledge of the limits of LND and a template of LND for UTUC are still needed.

Conclusions

An extended LND can provide better disease staging and may be curative in patients with limited nodal disease. However, current evidence is based on retrospective studies, which limits the ability to standardize either the indication or the extent of LND. Prospective trials are required to determine the impact of LND on survival in patients with UTUC and identify patients for a risk-adapted approach such as close follow-up or adjuvant chemotherapy.     

Chronological age is not an independent predictor of clinical outcomes after radical nephroureterectomy

Purpose

Higher chronological age has been suggested to confer worse prognosis in patients with upper tract urothelial carcinoma (UTUC). The aim of the current study was to test this hypothesis in a large multicenter external validation cohort of patients treated with radical nephroureterectomy (RNU) while controlling for patient performance status.

Materials and methods

We retrospectively reviewed the data from 1,169 patients treated with RNU for UTUC. Age at RNU was analyzed both as a continuous and categorical variable (<50?years, n?=?66; 50?C59.9?years, n?=?185; 60?C69.9?years, n?=?367; 70?C79.9?years, n?=?419; ??80?years, n?=?132). Median follow-up was 37?months.

Results

Actuarial recurrence-free, cancer-specific, and all-cause survival estimates at 5?years after RNU were 69, 73, and 61%, respectively. Advanced age was associated with female gender, higher ECOG status, higher ASA score, and a lower probability of receiving adjuvant chemotherapy (all P values????0.02). In multivariable analyses, advanced age was associated with decreased recurrence-free (P?=?0.021), cancer-specific (P?=?0.002), and all-cause survival (P?P?>?0.001).

Conclusions

We confirmed that advanced patient age at the time of RNU is associated with worse clinical outcomes after surgery. However, ECOG performance status abrogated the association. Furthermore, a large proportion of elderly patients were cured with RNU. This suggests that chronological age alone is an inadequate indicator criterion to predict response of older UTUC patients to RNU.     

Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study

Study Type – Therapy (multi‐centre retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UUT‐UCs) are rare tumours. Because of the aggressive pattern of UC, radical nephroureterectomy (RNU) with bladder cuff removal remains the ‘gold‐standard’ treatment. However, conservative strategies, such as segmental ureterectomy (SU) or endourological management, have also been developed in patients with imperative indications. Some teams are now advocating the use of conservative management more commonly in cases of elective indications of UUT‐UCs. Due to the paucity of cases of UUT‐UC, only limited data are available on the oncological outcomes afforded by conservative management. We retrospectively investigated the oncological outcomes after SU and RNU in a large multi‐institutional database. Overall, 52 patients were treated with SU and 416 with RNU. There was no statistical difference between the RNU and SU groups for the 5‐year probability of cancer‐specific survival, recurrence‐free survival and metastasis‐free survival. The type of surgery was not a significant prognostic factor in univariate analysis. The results were the same in a subgroup analysis of only unifocal tumours of the distal ureter with a diameter of <2 cm and of low stage (≤T2). Our results suggest that oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases.

OBJECTIVE

• ? To compare recurrence‐free survival (RFS), metastasis‐free survival (MFS) and cancer‐specific survival (CSS) after segmental ureterectomy (SU) vs radical nephroureterectomy (RNU) for urothelial carcinoma (UC) of the upper urinary tract (UUT‐UC) located in the ureter.

PATIENTS AND METHODS

• ? We performed a multi‐institutional retrospective review of patients with UUT‐UC who had undergone RNU or SU between 1995 and 2010.
• ? Type of surgery, Tumour‐Node‐Metastasis status, tumour grade, lymphovascular invasion and positive surgical margin were tested as prognostic factors for survival.

RESULTS

• ? In all, 52 patients were treated with SU and 416 with RNU. The median (range) follow‐up was 26 (10–48) months.
• ? The 5‐year probability of CSS, RFS and MFS for SU and RNU were 87.9% and 86.3%, respectively (P= 0.99); 37% and 47.9%, respectively (P= 0.48); 81.9% and 85.4%, respectively (P= 0.51).
• ? In univariable analysis, type of surgery (SU vs RNU) failed to affect CSS, RFS and MFS (P= 0.94, 0.42 and 0.53, respectively).
• ? In multivariable analyses, pT stage and pN stage achieved independent predictor status for CSS (P= 0.005 and 0.007, respectively); the positive surgical margin and pT stage were independent prognostic factors of RFS and MFS (P= 0.001, 0.04, 0.009 and 0.001, respectively).
• ? The main limitation of the study is its retrospective design, which is due to the rarity of the disease.

CONCLUSIONS

• ? Short‐term oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases and should be considered an option.
• ? In every other case, RNU still represents the ‘gold standard’ for the treatment of UUT‐UC.

     

Independent Predictors for Bladder Outcomes after Treatment of Intravesical Recurrence following Radical Nephroureterectomy in Patients with Primary Upper Tract Urothelial Carcinoma

Background

Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU.

Methods

A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis.

Results

Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors.

Conclusions

This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.     

Advanced patient age is associated with inferior cancer‐specific survival after radical nephroureterectomy

Study Type – Prognosis (case series)
Level of Evidence 4

OBJECTIVE

To assess the impact of patient age on outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

PATIENTS AND METHODS

Data were collected on 1453 patients treated with RNU at 13 centres. Pathological slides were reviewed by dedicated genitourinary pathologists according to standardized criteria. Age at RNU was analysed both as a continuous and categorical variable (<50, n = 85; 50–59.9, n = 229; 60–69.9, n = 416; 70–79.9, n = 523; ≥80 years, n = 200).

RESULTS

Patients aged <50 years were less likely to have undergone previous ureteroscopy and to have a history of bladder cancer (P ≤ 0.026). Advanced age was associated with infiltrative architecture and female gender (P ≤ 0.003). Patients aged >70 years were less likely to undergo lymphadenectomy and to receive adjuvant chemotherapy (P ≤ 0.026). In multivariable analyses, being older was associated with decreased all‐cause (AC) survival (>60 years) and cancer‐specific survival (CSS; >80 years) after controlling for the effects of standard pathological features (P ≤ 0.006). However, addition of age did not improve the predictive accuracy of a base model that included standard pathological features for prediction of either disease recurrence, AC survival or CSS.

CONCLUSIONS

Being older at the time of RNU was associated with decreased survival. This finding could be due to a change in the biological potential of the tumour cell, a decrease in the host’s defence mechanisms, or differences in care patterns. Further work is needed to improve our understanding of UTUC outcomes in this growing segment of the population and to develop strategies to improve cancer control in the elderly.     

Peripelvic/periureteral fat invasion is independently associated with worse prognosis in pT3 upper tract urothelial carcinoma

Purpose

To elucidate the reasons for conflicting results regarding the prognostic significance of tumor location in upper tract urothelial carcinoma (UTUC), we analyzed the stage-specific impact of tumor location on oncological outcomes following radical nephroureterectomy (RNU).

Methods

Data from 392 patients who underwent RNU with curative intent between 1991 and 2010 were reviewed. Prognostic impact of tumor location and various clinicopathological factors for recurrence-free survival (RFS) and cancer-specific survival (CSS) was evaluated using Kaplan–Meier and Cox regression analyses at each pathological stage. Tumor location was classified as renal pelvis or ureter, and pT3 tumors were further stratified as invading the renal parenchyma or peripelvic or periureteral fat.

Results

In stage-specific analysis, tumor location did not have prognostic significance in patients with ≤pT2 tumors, whereas RFS and CSS rates were significantly lower in patients with pT3 ureteral tumors than renal pelvic tumors. Subgroup analysis showed that RFS and CSS rates were significantly higher for pT3 tumors invading the renal parenchyma than the peripelvic or periureteral fat. On multivariate analysis in pT3 tumors adjusting other clinicopathological parameters, tumor location remained significant predictors for both RFS and CSS. Compared with tumors invading renal parenchyma, tumors invading peripelvic fat or periureteral fat were associated with about 3.5 times higher risk for cancer-specific mortality (p < 0.05).

Conclusions

Location-dependent survival difference exists only in patients with pT3 UTUC. Conflicting institutional results regarding tumor location in UTUC may be due to difference in the proportions of parenchymal versus peripelvic fat invasion in pT3 pelvic tumors.     

Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients

Purpose

The purpose of this study is to assess the association of concomitant carcinoma in situ (CIS) with disease recurrence and cancer-related death in a multi-institutional series of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

We collected retrospectively the data of 772 patients treated with RNU and ipsilateral bladder cuff excision at 9 international institutions in Asia, Europe, and Northern America from 1987 to 2008. Surgical specimens were processed according to standard pathologic procedures at each institution. Univariable and multivariable Cox regression models addressed time to recurrence and cancer-specific mortality.

Results

Concomitant CIS was present in 88 patients (11.4%); it was associated with more advanced pathologic stage, higher tumor grade, and presence of lymphovascular invasion (all P-values?P-values?P?=?0.007) and CSS (HR: 1.7, P?=?0.048). Similar findings were reconfirmed in subgroups analyses limited to T2, organ confined, and N0/Nx UTUC, or patients who did not receive adjuvant chemotherapy.

Conclusions

Presence of concomitant CIS is an independent predictor of both RFS and CSS in patients treated with RNU for UTUC. This information may be useful in risk stratification of UTUC patients for follow-up and additional therapy.     

Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973–2005

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Upper‐tract urothelial carcinoma (UTUC) is a relatively uncommon urological malignancy with survival and outcomes data largely determined from single‐centre series which can be limited by relatively small case numbers. Through review of a large population based cohort, this study provides valuable information regarding epidemiological and survival patterns for over 13,000 patients with UTUC diagnosed over the past three decades.

OBJECTIVE

? To evaluate epidemiological and survival patterns of upper‐tract urothelial carcinoma (UTUC) over the past 30 years through a review of a large, population‐based database.

PATIENTS AND METHODS

? Data from the Surveillance, Epidemiology and End Results (SEER) database from 1973 to 2005 were reviewed in 10‐year increments to evaluate disease trends. ? Univariate and multivariate survival analyses identified prognostic variables for outcomes.

RESULTS

? In total, 13 800 SEER‐registered cases of UTUC were included. The overall incidence of UTUC increased from 1.88 to 2.06 cases per 100 000 person‐years during the period studied, with an associated increase in ureteral disease (0.69 to 0.91) and a decrease in renal pelvic cancers (1.19 to 1.15). ? The proportion of in situ tumours increased from 7.2% to 31.0% (P < 0.001), whereas local tumours declined from 50.4% to 23.6% (P < 0.001). ? There was no change in the proportion of patients presenting with distant disease. ? In multivariate analysis, increasing patient age (P < 0.001), male gender (P < 0.001), black non‐Hispanic race (P < 0.001), bilateral UTUC (P= 0.001) and regional/distant disease (P < 0.001) were all associated with poorer survival outcomes.

CONCLUSIONS

? The incidence of UTUC has slowly risen over the past 30 years. ? Increased use of bladder cancer surveillance regimens and improved abdominal cross‐sectional imaging may contribute to the observed stage migration towards more in situ lesions. ? Although pathological disease characteristics impact cancer outcomes, certain sociodemographic factors also appear to portend worse prognosis.     

Impact of Tumor Location on Prognosis for Patients with Upper Tract Urothelial Carcinoma Managed by Radical Nephroureterectomy

Background

There is a lack of consensus regarding the prognostic significance of ureteral versus renal pelvic upper tract urothelial carcinoma (UTUC).

Objective

To investigate the association of tumor location on outcomes for UTUC in an international cohort of patients managed by radical nephroureterectomy (RNU).

Design, setting, and participants

A retrospective review of institutional databases from 10 institutions worldwide identified patients with UTUC.

Intervention

The 1249 patients in the study underwent RNU with ipsilateral bladder cuff resection between 1987 and 2007.

Measurements

Data accrued included age, gender, race, surgical approach (open vs laparoscopic), tumor pathology (stage, grade, lymph node status), tumor location, use of perioperative chemotherapy, prior endoscopic therapy, urothelial carcinoma recurrence, and mortality from urothelial carcinoma. Tumor location was divided into two groups (renal pelvis and ureter) based on the location of the dominant tumor.

Results and limitations

The 5-yr recurrence-free and cancer-specific survival estimates for this cohort were 75% and 78%, respectively. On multivariate analysis, only pathologic tumor (pT) classification (p < 0.001), grade (p < 0.02), and lymph node status (p < 0.001) were associated with disease recurrence and cancer-specific survival. When adjusting for these variables, there was no difference in the probability of disease recurrence (hazard ratio [HR]: 1.22; p = 0.133) or cancer death (HR: 1.23; p = 0.25) between ureteral and renal pelvic tumors. Adding tumor location to a base prognostic model for disease recurrence and cancer death that included pT stage, tumor grade, and lymph node status only improved the predictive accuracy of this model by 0.1%. This study is limited by biases associated with its retrospective design.

Conclusions

There is no difference in outcomes between patients with renal pelvic tumors and with ureteral tumors following nephroureterectomy. These data support the current TNM staging system, whereby renal pelvic and ureteral carcinomas are classified as one integral group of tumors.     

Risk stratification of patients with nodal involvement in upper tract urothelial carcinoma: value of lymph-node density

OBJECTIVE

To determine the risk factors associated with clinical outcome in patients with lymph node (LN)‐positive urothelial carcinoma of the upper urinary tract (UTUC) treated with radical nephroureterectomy (RNU) and lymphadenectomy, focusing on the concept of LN density (LND).

PATIENTS AND METHODS

Patients undergoing RNU with regional lymphadenectomy were identified through multi‐institutional databases. All pathology slides were re‐evaluated by genitourinary pathologists unaware of the clinical data. The exposure variable used was LND (continuously coded and that of all possible thresholds) with recurrence‐free and disease‐specific survival (DSS) serving as the outcome measures.

RESULTS

Of 432 patients undergoing RNU with lymphadenectomy, 135 (31%) had LN metastases. Within a median follow‐up of 4.1 years, 90 of the 135 patients with LN metastases (68%) had disease recurrence and 76 (58%) died from UTUC. The mean (sem ) 5‐year recurrence‐free and DSS probabilities were 27 (4)% and 33 (5)%, respectively. The median (range) LND was 50 (3–100)%. The most informative threshold for LND in relation to outcome was 30%. In multivariable analyses that adjusted for the effects of tumour stage and grade, patients with a LND of ≥30% were at greater risk of both cancer recurrence, with 5‐year rates of 25 (5)% vs 38 (8)% (hazard ratio 1.8, P = 0.021) and mortality, with 5‐year rates of 30 (6)% vs 48 (9)% (1.7, P = 0.032) compared to those with a LND of <30%. Our results are primarily limited by a lack of standardization in the lymphadenectomy template.

CONCLUSION

We evaluated the concept of LND for the first time in UTUC. LND provides additional prognostic information in patients with node‐positive disease after RNU. The use of LND in clinical trials might provide an additional insight into the value of LN dissection in patients undergoing RNU.     

Impact of surgical waiting time on survival in patients with upper tract urothelial carcinoma: A national cancer database study

Purpose

To evaluate the impact of surgical waiting time (SWT) on the survival outcome in patients with upper tract urothelial carcinoma (UTUC).

No overt influence of lymphadenectomy on cancer-specific survival in organ-confined versus locally advanced upper urinary tract urothelial carcinoma undergoing radical nephroureterectomy: a retrospective international, multi-institutional study

Purpose

Lymph node dissection (LND) is not routinely performed during radical nephroureterectomy (RNU) in upper tract urothelial carcinomas (UTUC), and its clinical relevance is unclear. The purpose of the present study was to evaluate the impact of LND on clinical outcomes in a large multicenter series of RNU for UTUC.

Methods

Detailed data on 785 patients subject to RNU were provided by nine international academic centers. The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were evaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models evaluated the association of nodal status with recurrence-free (RFS) and cancer-specific (CSS) survival.

Results

One hundred and ninety patients had LND. Pathological N stage was pN0 in 17%, pNx in 76%, and pN+ in 7%. The median follow-up period of the entire cohort was 34?months (interquartile range [IQR]: 15?C65?months). Overall, five-year RFS and CSS estimates were 72.2 and 76%, respectively. In multivariable Cox regression analyses, pN0/pNx substaging was not an independent predictor of either RFS (hazard ratio [HR]: 1.1; P?=?0.631) or CSS (HR: 1.3; P?=?0.223). Similar results were obtained in a subgroup analysis limited to patients with organ-confined disease (HR: 0.9; P?=?0.907 for RFS; HR: 0.4; P?=?0.419 for CSS). Conversely, in patients with locally advanced disease, patients with pN0 disease have significantly better cancer-related outcomes (HR: 0.3; P?P?Conclusion The present series suggests pNx is more significantly associated with a worse prognosis than pN0, but only in patients with locally advanced UTUC.