Impact of Smoking and Smoking Cessation on Oncologic Outcomes in Primary Non–muscle-invasive Bladder Cancer

Background

Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC) development, but the impact on oncologic outcomes remains poorly understood.

Objective

To analyse the effects of smoking status, cumulative exposure, and time from smoking cessation on the prognosis of patients with primary non–muscle-invasive bladder cancer (NMIBC).

Design, setting, and participants

We collected smoking data from 2043 patients with primary NMIBC. Smoking variables included smoking status, average number of cigarettes smoked per day (CPD), duration in years, and time since smoking cessation. Lifetime cumulative smoking exposure was categorised as light short term (≤19 CPD, ≤19.9 yr), light long term (≤19 CPD, ≥20 yr), heavy short term (≥20 CPD, ≤19.9 yr) and heavy long term (≥20 CPD, ≥20 yr). The median follow-up in this retrospective study was 49 mo.

Interventions

Transurethral resection of the bladder with or without intravesical instillation therapy.

Outcome measurements and statistical analysis

Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on outcomes.

Results and limitations

There was no difference in clinicopathologic factors among never (24%), former (47%), and current smokers (29%). Smoking status was associated with the cumulative incidence of disease progression in multivariable analysis (p = 0.003); current smokers had the highest cumulative incidences. Among current and former smokers, cumulative smoking exposure was associated with disease recurrence (p < 0.001), progression (p < 0.001), and overall survival (p < 0.001) in multivariable analyses that adjusted for the effects of standard clinicopathologic factors and smoking status; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation >10 yr reduced the risk of disease recurrence (hazard ratio [HR]: 0.66; 95% confidence interval [CI], 0.52–0.84; p < 0.001) and progression (HR: 0.42; 95% CI, 0.22–0.83; p = 0.036) in multivariable analyses. The study is limited by its retrospective nature.

Conclusions

Smoking status and a higher cumulative smoking exposure are associated with worse prognosis in patients with NMIBC. Smoking cessation >10 yr abrogates this detrimental effect. These findings underscore the need for integrated smoking cessation and prevention programmes in the management of NMIBC patients.     

Long-term Cancer-specific Outcomes of TaG1 Urothelial Carcinoma of the Bladder

Background

Few studies have investigated the natural history of TaG1 urothelial carcinoma of the bladder (UCB).

Objective

To assess the long-term outcomes of patients with TaG1 UCB and the impact of immediate postoperative instillation of chemotherapy (IPIC).

Design, setting, and participants

A retrospective analysis of 1447 patients with TaG1 UCB treated between 1996 and 2007 at eight centers. Median follow-up was 67.2 mo (interquartile range: 67.9). Patients were stratified into three European Association of Urology (EAU) guidelines risk categories; high-risk patients (n = 11) were excluded.

Intervention

Transurethral resection of the bladder with or without IPIC.

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression models addressed factors associated with disease recurrence, disease progression, death of disease, and any-cause death.

Results and limitations

Of the 1436 patients, 601 (41.9%) and 835 (58.1%) were assigned to low- and intermediate-risk categories, respectively. The actuarial estimate of 5-yr recurrence-free survival was 56% (standard error: ±1). Advancing age (p = 0.04), tumor >3 cm (p = 0.001), multiple tumors (p < 0.001), and recurrent tumors (p < 0.001) were independently associated with increased risk of disease recurrence, whereas IPIC was associated with decreased risk (p = 0.001). The actuarial estimate of 5-yr progression-free survival was 95% ± 1. Advancing age (p < 0.001) and multiple tumors (p = 0.01) were independent risk factors for disease progression. Five-year cancer-specific survival was 98% ± 1. Advancing age (p = 0.001) and previous recurrence (p = 0.04) were associated with increased risk, whereas female gender (p = 0.02) was associated with decreased risk of cancer-specific mortality. Compared with low-risk patients, intermediate-risk patients were at significantly higher risk of disease recurrence, disease progression, and cancer-specific mortality (all p < 0.01). Limitations include the retrospective design of the study and the lack of a central pathology review.

Conclusions

TaG1 UCB patients experience heterogeneous risks of disease recurrence. We validated the EAU guidelines risk stratification in TaG1 UCB patients. IPIC was associated with a reduced risk of disease recurrence in patients with low- and intermediate-risk TaG1 UCB.     

Pretreatment Neutrophil-to-Lymphocyte Ratio Is Associated with Advanced Pathologic Tumor Stage and Increased Cancer-specific Mortality Among Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

Background

Pretreatment neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been associated with adverse survival in a variety of malignancies. However, the relationship between NLR and oncologic outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) has not been well studied.

Objective

To evaluate the association of preoperative NLR with clinicopathologic outcomes following RC.

Design, setting, and participants

We identified 899 patients who underwent RC without neoadjuvant therapy at our institution between 1994 and 2005 and who had a pretreatment NLR.

Outcome measurements and statistical analysis

Preoperative NLR (within 90 d prior to RC) was recorded. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazard and logistic regression models were used to analyze the association of NLR with clinicopathologic outcomes.

Results and limitations

Median postoperative follow-up was 10.9 yr (interquartile range: 8.3–13.9 yr). Higher preoperative NLR was associated with significantly increased risks of pathologic, extravesical tumor extension (odds ratio [OR]: 1.07; p = 0.03) and lymph node involvement (OR: 1.09; p = 0.02). Univariately, 10-yr cancer-specific survival was significantly worse among patients with a preoperative NLR (≥2.7 [51%] vs <2.7 [64%]; p < 0.001). Moreover, on multivariate analysis, increased preoperative NLR was independently associated with greater risks of disease recurrence (hazard ratio [HR]: 1.04; p = 0.02), death from bladder cancer (HR: 1.04; p = 0.01), and all-cause mortality (HR: 1.03; p = 0.01).

Conclusions

Elevated preoperative NLR among patients undergoing RC is associated with significantly increased risk for locally advanced disease as well as subsequent disease recurrence, and cancer-specific and all-cause mortality. These data suggest that serum NLR may be a useful prognostic marker for preoperative patient risk stratification, including consideration for neoadjuvant therapy and clinical trial enrollment.     

Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients

Background

The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.

Objective

To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).

Design, setting, and participants

Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.

Outcome measurements and statistical analysis

Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).

Results and limitations

Female patients were older at the time of RC (p = 0.033) and had higher rates of pathologic stage T3/T4 disease (p < 0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p = 0.022 and p = 0.11, respectively). Female gender was an independent predictor for CSM (p = 0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).

Conclusions

We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.     

Validation of the AJCC TNM Substaging of pT2 Bladder Cancer: Deep Muscle Invasion Is Associated with Significantly Worse Outcome

Background

The current TNM bladder cancer staging system stratifies bladder muscle invasion into superficial (pT2a) and deep (pT2b). Controversy exists regarding the significance of the extent of muscle invasion on clinical outcome.

Objective

Our aim was to compare the cancer-specific outcomes of patients with pT2 urothelial carcinoma of the bladder (UCB) at radical cystectomy (RC) in a large international cohort of patients.

Design, setting, and participants

The records of patients treated with RC for UCB at six centers were reviewed. Of the 2605 reviewed patients, 565 (21.7%) had pT2 disease. None of the patients received preoperative systemic chemotherapy or radiotherapy.

Measurements

Patients’ characteristics and outcome were evaluated.

Results and limitations

The median patient age in the entire group was 66.2 yr. Of the 565 patients with pT2 UCB, 249 patients (44.1%) had substage pT2a; 316 patients (55.9%) had pT2b. One hundred and eleven patients (19.6%) had metastases to regional lymph nodes. Median follow-up was 50.5 mo. Recurrence-free survival (73.2% vs 58.7%) and cancer-specific survival (78.0% vs 65.1%) estimates were significantly better for pT2a patients compared with those with pT2b (p = 0.002 and p = 0.001, respectively). Pathologic T2 substaging was associated with worse recurrence-free and cancer-specific survival after adjusting for the effects of standard pathologic features (p = 0.011 and p = 0.006, respectively). The statistical significance of these associations was reconfirmed in subgroup analysis limited to those patients with pathologically negative lymph nodes.

Conclusions

In this large international cohort, pathologic substaging helped to stratify patients with lymph node–negative pT2 UCB into statistically significantly different risk groups. These data support the value of the current American Joint Committee on Cancer TNM staging.     

Perioperative Blood Transfusion and Radical Cystectomy: Does Timing of Transfusion Affect Bladder Cancer Mortality?

Background

While perioperative blood transfusion (BT) has been associated with adverse outcomes in multiple malignancies, the importance of BT timing has not been established.

Objective

The objective of this study was to evaluate whether intraoperative BT is associated with worse cancer outcomes in bladder cancer patients treated with radical cystectomy (RC).

Design, setting, and participants

Outcomes from two independent cohorts of consecutive patients with bladder cancer treated with RC were analyzed.

Outcome measurements and statistical analysis

Recurrence-free survival, cancer-specific survival (CSS), and overall survival were estimated and multivariate analyses were performed to evaluate the association of BT timing with cancer outcomes.

Results and limitations

In the primary cohort of 360 patients, 241 (67%) received perioperative BT, including 162 intraoperatively and 79 postoperatively. Five-year CSS was 44% among patients who received an intraoperative BT versus 64% for patients who received postoperative BT (p = 0.0005). After multivariate analysis, intraoperative BT was associated with an increased risk of cancer mortality (hazard ratio [HR]: 1.93; p = 0.02), while receipt of postoperative BT was not (p = 0.60). In the validation cohort of 1770 patients, 1100 (62%) received perioperative BT with a median postoperative follow-up of 11 yr (interquartile range: 8.0–15.7). Five-year RFS (p < 0.001) and CSS (p < 0.001) were significantly worse among patients who received an intraoperative BT. Intraoperative BT was independently associated with recurrence (HR: 1.45; p = 0.001), cancer-specific mortality (HR: 1.55; p = 0.0001), and all-cause mortality (HR: 1.40; p < 0.0001). Postoperative BT was not associated with risk of disease recurrence or cancer death.

Conclusions

Intraoperative BT is associated with increased risk of bladder cancer recurrence and mortality.

Patient summary

In this study, the effects of blood transfusion on bladder cancer surgery outcomes were evaluated. Intraoperative blood transfusion, but not postoperative transfusion, was associated with higher rates of recurrence and cancer-specific mortality.     

The Impact of Perioperative Blood Transfusion on Cancer Recurrence and Survival Following Radical Cystectomy

Background

While the receipt of a perioperative blood transfusion (PBT) has been associated with an increased risk of mortality for a number of malignancies, the relationship between PBT and survival following radical cystectomy (RC) for bladder cancer (BCa) has not been well established.

Objective

To evaluate the association of PBT with disease recurrence and mortality following RC.

Design, setting, and participants

We identified 2060 patients who underwent RC at the Mayo Clinic between 1980 and 2005. PBT was defined as transfusion of allogenic red blood cells during RC or postoperative hospitalization.

Outcome measurements and statistical analysis

Survival was estimated using the Kaplan-Meier method and was compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of PBT with outcome, controlling for clinicopathologic variables.

Results and limitations

A total of 1279 patients (62%) received PBT. The median number of units transfused was 2 (interquartile range [IQR]: 2–4). Patients receiving PBT were significantly older (median: 69 yr vs 66 yr; p < 0.0001), had a worse Eastern Cooperative Oncology Group performance status (p < 0.0001), and were more likely to have muscle-invasive tumors (56% vs 49%; p = 0.004). Median postoperative follow-up was 10.9 yr (IQR: 7.9–15.7). Receipt of PBT was associated with significantly worse 5-yr recurrence-free survival (58% vs 64%; p = 0.01), cancer-specific survival (59% vs 72%; p < 0.001), and overall survival (45% vs 63%; p < 0.001). On multivariate analyses, PBT remained associated with significantly increased risks of postoperative tumor recurrence (hazard ratio [HR]: 1.20; p = 0.04), death from BCa (HR: 1.31; p = 0.003), and all-cause mortality (HR: 1.27; p = 0.0002). Among patients who received PBT, an increasing number of units transfused was independently associated with increased cancer-specific mortality (HR: 1.07; p < 0.0001) and all-cause mortality (HR: 1.05; p < 0.0001). Limitations include selection bias and lack of standardized transfusion criteria.

Conclusions

We found that PBT is associated with significantly increased risks of cancer recurrence and mortality following RC. While external validation is required, continued efforts to reduce the use of blood products in these patients are warranted.     

Insulin-like Growth Factor Messenger RNA-binding Protein 3 Expression Helps Prognostication in Patients with Upper Tract Urothelial Carcinoma

Background

Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC.

Objective

To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU).

Design, setting, and participants

We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008.

Intervention

All patients were diagnosed with UTUC and underwent RNU.

Outcome measurement and statistical analysis

Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality.

Results and limitations

IMP3 was expressed in 12.2% of patients with UTUC (n = 76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12–53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p < 0.01), cancer-specific survival (34.5% vs 78.9%; p < 0.01), and overall survival (15.6% vs 64.8%; p < 0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p < 0.01), cancer-specific mortality (HR: 2.15; p < 0.01), and all-cause mortality (HR: 2.07; p < 0.01). Major limitations include the retrospective design and relatively short follow-up time.

Conclusions

IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU.     

Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer

Background

Cigarette smoking is the most well-established risk factor for developing bladder cancer.

Objective

To investigate the role of smoking status on the clinical outcome of patients with non-muscle-invasive bladder cancer.

Design, setting, and participants

Data obtained during a prospective phase 3 study with three schedules of epirubicin were used for statistical analysis. Smoking status (obtained when entering the study), other prognostic variables, and clinical outcome measures of 718 patients were analyzed. Mean follow-up was 2.5 yr.

Measurements

The primary outcome measure was recurrence-free survival (RFS).

Results and limitations

Demographics were similar for nonsmokers versus ex-smokers and current smokers, except for gender (p < 0.001) and grade (p = 0.022). In univariate analyses, RFS was significantly shorter in male patients (p = 0.020), in patients with a history of recurrences (p < 0.003), in patients with multiple tumors (p < 0.004), in patients with a history of intravesical therapy (p = 0.037), and in ex-smokers and current smokers (p = 0.005). In multivariate analyses, a history of recurrences, multiplicity, and smoking status remained significant factors for predicting RFS. Gender and initial therapy were no longer a significant influence on RFS.Because progression was uncommon (n = 25) and follow-up was short and focused only on recurrences, no conclusion can be drawn on progression-free survival. A limitation of the study were the questionnaires. They were only used when entering the study, and there were no questions about passive smoking and other causal factors.

Conclusions

In this prospective study, the significance of known factors (history of recurrences and number of tumors) in predicting RFS was confirmed. Another significant factor that appears to predict RFS is smoking status: ex-smokers and current smokers had a significantly shorter RFS compared with nonsmokers.     

Prognostic Value of Perinodal Lymphovascular Invasion Following Radical Cystectomy for Lymph Node–positive Urothelial Carcinoma

Background

Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined.

Objective

To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival.

Design, setting, and participants

A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%).

Intervention

Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases.

Outcome measurements and statistical analysis

Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11–38).

Results and limitations

Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p < 0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p = 0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p = 0.856), and the incremental accuracy of prediction is of uncertain clinical value.

Conclusions

We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.     

CEACAM1: A Novel Urinary Marker for Bladder Cancer Detection

Background

Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein; CEACAM1) is expressed in normal bladder urothelium and in angiogenically activated endothelial cells, where it exhibits proangiogenic properties.

Objective

The aim of this study was to evaluate the value of urinary CEACAM1 for detection of urothelial carcinoma of the bladder (UCB).

Design, setting, and participants

This prospective study included 175 patients.

Measurements

Immunohistochemistry for CEACAM1 was performed on UCB sections of 10 patients. Enzyme-linked immunosorbent assay (ELISA) for CEACAM1 was performed on urine specimens of healthy volunteers (n = 30), patients with benign prostatic hyperplasia (BPH; n = 5), severe cystitis (n = 5), non–muscle-invasive UCB (n = 72), muscle-invasive UCB (n = 21), or past history of UCB without evidence of disease (n = 42). Western blot analysis was performed on a subgroup of these subjects (n = 53).

Results and limitations

CEACAM1 immunostaining in normal urothelium disappears in noninvasive UCB but appears in endothelial cells of adjacent vessels. Western blotting revealed presence of CEACAM1 in the urine of no healthy volunteers, of 76% of noninvasive UCB patients, and of 100% of invasive UCB patients. ELISA analysis confirmed that urinary CEACAM1 levels were significantly higher in UCB patients compared with control subjects (median: 207 ng/ml vs 0 ng/ml; p < 0.001). The area under the curve for UCB detection was 0.870 (95% confidence interval [CI]: 0.810–0.931). In multivariable logistic regression analyses that adjusted for the effects of age and gender, higher CEACAM1 levels were associated with cancer presence (hazard ratio [HR]: 2.89; 95% CI: 2.01–4.15; p < 0.001) and muscle-invasive cancer (HR: 5.53; 95% CI: 1.68–18.24; p = 0.005). The cut-off level of 110 ng/ml yielded sensitivity of 74% and specificity of 95% for detecting UCB. Sensitivity was 88% for detecting high-grade UCB and 100% for detecting invasive-stage UCB. Larger studies are necessary to establish the diagnostic and prognostic roles of this highly promising novel marker in UCB.

Conclusions

Urinary CEACAM1 levels discriminate UCB patients from non-UCB subjects. Moreover, urinary levels of CEACAM1 increased with advancing stage and grade.     

Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy: A Multi-Institutional Analysis of 1249 Cases

Background

Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce.

Objective

We compared recurrence and cause-specific mortality rates of ONU and LNU.

Design, setting, and participants

Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC).

Measurements

Univariable and multivariable survival models tested the effect of procedure type (ONU [n = 979] vs LNU [n = 270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment.

Results and limitations

Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p < 0.001) and less lymphovascular invasion (14.8% vs 21.3%, p = 0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p = 0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p < 0.001] and 2.0 [p = 0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p = 0.1 for both).

Conclusions

Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.     

Illness Uncertainty and Quality of Life of Patients with Small Renal Tumors Undergoing Watchful Waiting: A 2-year Prospective Study

Background

Few studies have examined factors associated with the quality of life (QOL) of patients with renal tumors. Illness uncertainty may influence QOL.

Objective

To prospectively examine the influence of uncertainty on general and cancer-specific QOL and distress in patients undergoing watchful waiting (WW) for a renal mass.

Design, setting, and participants

In 2006–2010, 264 patients were enrolled in a prospective WW registry. The decision for WW was based on patient, tumor, and renal function characteristics at the discretion of the urologist and medical oncologist in the context of the physician–patient interaction. Participants had suspected clinical stage T1–T2 disease, were aged ≥18 yr, and spoke and read English. The first 100 patients enrolled in the registry participated in this study.

Outcome measurements and statistical analysis

Patients completed questionnaires on demographics, illness uncertainty (Mishel Uncertainty in Illness Scale), general QOL (Medical Outcomes Study 36-item short-form survey), cancer-specific QOL (Cancer Rehabilitation Evaluation System–Short Form), and distress (Impact of Events Scale) at enrollment and at 6, 12, and 24 mo. Age, gender, ethnicity, tumor size, estimated glomerular filtration rate, comorbidities, and assessment time point were controlled for in the models.

Results and limitations

Among the sample, 27 patients had biopsies, and 17 patients had proven renal cell carcinoma. Growth rate was an average of 0.17 cm/yr (standard deviation: 0.35). Mean age was 72.5 yr, 55% of the patients were male, and 84% of the patients were Caucasian. Greater illness uncertainty was associated with poorer general QOL scores in the physical domain (p = 0.008); worse cancer-related QOL in physical (p = 0.001), psychosocial (p < 0.001), and medical (p = 0.034) domains; and higher distress (p < 0.001).

Conclusions

This study is among the first to prospectively examine the QOL of patients with renal tumors undergoing WW and the psychosocial factors that influence QOL. Illness uncertainty predicted general QOL, cancer-specific QOL, and distress. These factors could be targeted in psychosocial interventions to improve the QOL of patients on WW.     

Combination of CK20 and Ki-67 Immunostaining Analysis Predicts Recurrence,Progression, and Cancer-Specific Survival in pT1 Urothelial Bladder Cancer

Background

The prognostic value of CK20, Ki-67, and p53 has been investigated for non–muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers.

Objective

To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers.

Design, setting, and participants

Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected.

Intervention

Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4–8 wk. A total of 76 patients underwent cystectomy.

Outcome measurements and statistical analysis

We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS).

Results and limitations

At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44–24.15; p = 0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45–5.43, p = 0.002). Ki-67 (HR: 3.83; 95% CI, 1.59–9.26; p = 0.003), and CK20 (HR: 8.44; 95% CI,1.16–61.34; p = 0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p = 0.026), PFS (p = 0.003), and CSS (p < 0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study.

Conclusions

Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.     

Features Associated with Recurrence Beyond 5 Years After Nephrectomy and Nephron-Sparing Surgery for Renal Cell Carcinoma: Development and Internal Validation of a Risk Model (PRELANE score) to Predict Late Recurrence Based on a Large Multicenter Database (CORONA/SATURN Project)

Background

Approximately 10–20% of recurrences in patients treated with nephrectomy for renal cell carcinoma (RCC) develop beyond 5 yr after surgery (late recurrence).

Objective

To determine features associated with late recurrence.

Design, setting, and participants

A total of 5009 patients from a multicenter database comprising 13 107 RCC patients treated surgically had a minimum recurrence-free survival of 60 mo (median follow-up [FU]: 105 mo [range: 78–135]); at last FU, 4699 were disease free (median FU: 103 mo [range: 78–134]), and 310 patients (6.2%) experienced disease recurrence (median FU: 120 mo [range: 93–149]).

Interventions

Patients underwent radical nephrectomy or nephron-sparing surgery.

Outcome measurements and statistical analysis

Multivariable regression analyses identified features associated with late recurrence. Cox regression analyses evaluated the association of features with cancer-specific mortality (CSM).

Results and limitations

Lymphovascular invasion (LVI) (odds ratio [OR]: 3.07; p < 0.001), Fuhrman grade 3–4 (OR: 1.60; p = 0.001), and pT stage >pT1 (OR: 2.28; p < 0.001) were significantly associated with late recurrence. Based on accordant regression coefficients, these parameters were weighted with point values (LVI: 2 points; Fuhrman grade 3–4: 1 point, pT stage >1: 2 points), and a risk score was developed for the prediction of late recurrences. The calculated values (0 points: late recurrence risk 3.1%; 1–3 points: 8.4%; 4–5 points: 22.1%) resulted in a good-, intermediate- and poor-prognosis group (area under the curve value for the model: 70%; 95% confidence interval, 67–73). Multivariable Cox regression analysis showed LVI (HR: 2.75; p < 0.001), pT stage (HR: 1.24; p < 0.001), Fuhrman grade (HR: 2.40; p < 0.001), age (HR: 1.01; p < 0.001), and gender (HR: 0.71; p = 0.027) to influence CSM significantly. Limitations are based on the multicenter and retrospective study design.

Conclusions

LVI, Fuhrman grade 3/4, and a tumor stage >pT1 are independent predictors of late recurrence after at least 5 yr from surgery in patients with RCC. We developed a risk score that allows for prognostic stratification and individualized aftercare of patients with regard to counseling, follow-up scheduling, and clinical trial design.     

Management of Localized Kidney Cancer: Calculating Cancer-specific Mortality and Competing Risks of Death for Surgery and Nonsurgical Management

Background

For elderly individuals with localized renal cell carcinoma (RCC), surgical intervention remains the primary treatment option but may not benefit patients with limited life expectancy.

Objective

To calculate the trade-offs between surgical excision and nonsurgical management (NSM) with respect to competing causes of mortality.

Design, setting, and participants

Relying on a cohort of Medicare beneficiaries, all patients with nonmetastatic node-negative T1 RCC between 1988 and 2005 were abstracted.

Intervention

All patients were treated with partial nephrectomy (PN), radical nephrectomy (RN), or NSM.

Outcome measurements and statistical analysis

Cancer-specific mortality (CSM) and other-cause mortality (OCM) rates were modeled through competing-risks regression methodologies. Instrumental variable analysis was used to account for the potential biases associated with measured and unmeasured confounders.

Results and limitations

A total of 10 595 patients were identified. In instrumental variable analysis, patients treated with PN (hazard ratio [HR]: 0.45; 95% confidence interval [CI], 0.24–0.83; p = 0.01) or RN (HR: 0.58; 95% CI, 0.35–0.96; p = 0.03) had a significantly lower risk of CSM than those treated with NSM. In subanalyses restricted to patients ≥75 yr, the instrumental variable analysis failed to detect any statistically significant difference between PN (HR: 0.48; p = 0.1) or RN (HR: 0.57; p = 0.1) relative to NSM with respect to CSM. Similar trends were observed in T1a RCC only.

Conclusions

PN or RN is associated with a reduction of CSM among older patients diagnosed with localized RCC, compared with NSM. The same benefit failed to reach statistical significance among patients ≥75 yr. The harms of surgery need to be weighed against the marginal survival benefit for some patients.     

Extranodal Extension Is a Powerful Prognostic Factor in Bladder Cancer Patients with Lymph Node Metastasis

Background

Lymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable.

Objective

To assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters.

Design, setting, and participants

A retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo).

Intervention

All subjects underwent RC and bilateral pelvic lymphadenectomy.

Outcome measurements and statistical analysis

Each LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC.

Results and limitations

A total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p < 0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55–2.31; p < 0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52–2.37; p < 0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p < 0.001) and from 71.8% to 77.8% (p = 0.007), respectively. The main limitation of the study is its retrospective nature.

Conclusions

ENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC.     

The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy

Background

The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood.

Objective

To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU).

Design, setting, and participants

The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter.

Intervention

All patients were treated with either open or laparoscopic RNU.

Measurements

Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality.

Results and limitations

Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0-101). Tumor multifocality was significantly associated with a history of previous BCa (p = 0.032), lymph node involvement (p = 0.036), tumor location in the ureter (p = 0.003), higher tumor stage (p < 0.001), higher tumor grade (p < 0.001), sessile tumor architecture (p = 0.003), and LVI (p = 0.001). In organ-confined patients, tumor multifocality was an independent predictor of both disease progression (hazard ratio [HR]: 1.43; p = 0.019) and cancer-specific mortality (HR: 1.46; p = 0.027). When assessed in all patients, tumor multifocality was associated with both disease progression and cancer-specific mortality in univariable (p = 0.005 and p = 0.006, respectively) but not in multivariable analyses (p = 0.468 and p = 0.798, respectively). The main limitation is the retrospective design of the study.

Conclusions

Tumor multifocality is an independent prognosticator of disease progression and cancer-specific mortality in patients with organ-confined UTUC treated with RNU. Multifocal organ-confined patients with UTUC may need closer follow-up. Integration of tumor multifocality with other factors may help identify those patients who would benefit from multimodal therapy.     

Long-term Continence Outcomes in Men Undergoing Radical Prostatectomy for Clinically Localized Prostate Cancer

Background

Urinary incontinence is a common short-term complication of radical prostatectomy (RP). Little is known about the long-term impact of RP on continence.

Objective

To elucidate the long-term progression of continence after RP.

Design, setting, and participants

From October 2000 through September 2012, 1788 men undergoing open RP for clinically localized prostate cancer by a single surgeon at an urban tertiary care center prospectively signed consent to be followed before RP and at 3, 6, 12, 24, 96, and 120 mo after RP. A consecutive sampling method was used and all men were included in this study.

Intervention

Men underwent open RP.

Outcome measurements and statistical analysis

Regression models controlled for preoperative University of California, Los Angeles–Prostate Cancer Index urinary function score (UCLA-PCI-UFS), age, prostate-specific antigen level, Gleason score, stage, nerve-sparing status, race, and marital status were used to evaluate the association of time since RP with two dependent variables: UCLA-PCI-UFS and continence status.

Results and limitation

The mean UCLA-PCI-UFS declined between 2 yr and 8 yr (83.8 vs 81.8; p = 0.007) and marginally between 8 yr and 10 yr (81.8 vs 79.6; p = 0.036) after RP, whereas continence rate did not significantly change during these intervals. Men ≥60 yr old experienced a decline in mean UCLA-PCI-UFS between 2 yr and 8 yr (p = 0.002) and a marginal decline in continence rate between 2 yr and 10 yr (p = 0.047), whereas these variables did not change significantly in men <60 yr old. These outcomes are for an experienced surgeon, so caution should be exercised in generalizing these results.

Conclusions

Between 2 yr and 10 yr after RP, there were slight decreases in mean UCLA-PCI-UFS and continence rates in this study. Men aged <60 yr had better long-term outcomes. These results provide realistic long-term continence expectations for men undergoing RP.     

Obesity Is Associated with Increased Prostate Growth and Attenuated Prostate Volume Reduction by Dutasteride

Background

Although obesity has been associated with larger prostate volumes (PV), few studies have actually investigated whether obesity enhances PV growth, especially among men using 5α-reductase inhibitors.

Objective

To examine whether obesity is associated with enhanced PV growth measured by serial transrectal ultrasound (TRUS) measurements.

Design, setting, and participants

We conducted a secondary analysis of the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, which was originally aimed at cancer risk reduction among high-risk men with a single negative prestudy biopsy.

Intervention

Per-protocol randomization to placebo or dutasteride and mandatory TRUS-guided biopsies at 2 yr and 4 yr.

Outcome measurements and statistical analysis

Percentage change in PV at 2 yr and 4 yr from baseline. We tested its association with baseline body mass index (BMI) groups of <25, 25–29.9, and ≥30 kg/m² using multivariable linear regression. Secondarily, we tested whether BMI was associated with the likelihood of having no PV reduction among men randomized to dutasteride using multivariable logistic regression.

Results and limitations

Of 8122 participants, we analyzed 71.8% and 54.5% with complete 2-yr and 4-yr PV data, respectively. In multivariable analysis, men on placebo with BMI ≥30 versus <25 kg/m² had enhanced PV growth from baseline (at 2 yr: 17.0% vs 10.7%, p < 0.001; at 4 yr: 29.4% vs 20.1%; p = 0.001). Men on dutasteride with BMI ≥30 versus <25 kg/m² had attenuated PV reduction from baseline (at 2 yr: −14.3% vs −18.5%; p = 0.002; at 4 yr: −13.2% vs −19.3%; p = 0.001) and higher likelihood of having no PV reduction (at 2 yr: odds ratio [OR]: 1.44; 95% confidence interval [CI], 1.08–1.93; p = 0.014; at 4 yr: OR: 1.62; 95% CI, 1.18–2.22; p = 0.003). We found no significant interactions between BMI and dutasteride on PV change at 2 yr and 4 yr (p interaction ≥0.36). No clinical outcomes or effects of weight change were assessed.

Conclusions

Obesity enhanced PV growth and attenuated PV reduction by dutasteride. The null interaction between obesity and dutasteride for PV change implies that the effect of obesity on dutasteride-treated men is likely a combination of dutasteride-driven PV reduction with obesity-driven PV growth rather than decreased dutasteride efficacy.

ClinicalTrials.gov identifier

NCT00056407.