Thomas F. Chromecki

Validation of the pre-treatment neutrophil–lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients

Background:The neutrophil–lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Several studies suggest a negative impact of increased NLR for patient’s survival in different types of cancer. However, previous findings from small-scale studies revealed conflicting results about its prognostic significance with regard to different clinical end points in non-metastatic renal cell carcinoma (RCC) patients. Therefore, the aim of our study was the validation of the prognostic significance of NLR in a large cohort of RCC patients.Methods:Data from 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 at a single centre, were evaluated retrospectively. Cancer-specific, metastasis-free, as well as overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of NLR, multivariate Cox regression models were applied for all three different end points. Influence of the NLR on the predictive accuracy of the Leibovich prognosis score was determined by Harrells concordance index.Results:Multivariate analysis identified increased NLR as an independent prognostic factor for overall (hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.10–2.31, P=0.014), but not for cancer-specific (HR=1.59, 95% CI=0.84–2.99, P=0.148), nor for metastasis-free survival (HR=1.39, 95% CI=0.85–2.28, P=0.184). The estimated concordance index was 0.79 using the Leibovich risk score and 0.81 when NLR was added.Conclusion:Regarding patients’ OS, an increased NLR represented an independent risk factor, which might reflect a higher risk for severe cardiovascular and other comorbidities. Adding the NLR to well-established prognostic models such as the Leibovich prognosis score might improve their predictive ability.

Impact of gender on bladder cancer incidence, staging, and prognosis

IntroductionWhile patient gender is an important factor in the clinical decision-making for the management of bladder cancer, there are minimal evidence-based recommendations to guide health care professionals. Recent epidemiologic and translational research has shed some light on the complex relationship between gender and bladder cancer. Our aim was to review the literature on the effect of gender on bladder cancer incidence, biology, mortality, and treatment.MethodsUsing MEDLINE, we performed a search of the literature between January 1975 and April 2011.ResultsAlthough men are nearly 3–4 times more likely to develop bladder cancer than women, women present with more advanced disease and have worse survival. Recently, a number of population-based and multicenter collaborative studies have shown that female gender is associated with a significantly higher rate of cancer-specific recurrence and mortality after radical cystectomy. The disparity between genders is proposed to be the result of a differences exposure to carcinogens (i.e., tobacco and chemicals) as well as reflective of genetic, anatomic, hormonal, societal, and environmental factors. Explanations for the differential behavior of bladder cancer between genders include sex steroids and their receptors as well as inferior quality of care for women (inpatient length of stay, referral patterns, and surgical outcomes).ConclusionsIt is imperative that health care practitioners and researchers from disparate disciplines collectively focus efforts to appropriately develop gender-specific evidence-based guidelines for bladder cancer patients. We must strive to develop multidisciplinary collaborative efforts to provide tailored gender-specific care for bladder cancer patients.

Predicting Clinical Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

BACKGROUND Novel prognostic factors for patients after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) have recently been described. OBJECTIVE We tested the prognostic value of pathologic characteristics and developed models to predict the individual probabilities of recurrence-free survival (RFS) and cancer-specific survival (CSS) after RNU. DESIGN, SETTING, AND PARTICIPANTS Our study included 2244 patients treated with RNU without neoadjuvant or adjuvant therapy at 23 international institutions. Tumor characteristics included T classification, grade, lymph node status, lymphovascular invasion, tumor architecture, location, and concomitant carcinoma in situ (CIS). The cohort was randomly split for development (12 centers, n=1273) and external validation (11 centers, n=971). INTERVENTIONS All patients underwent RNU. MEASUREMENTS Univariable and multivariable models addressed RFS, CSS, and comparison of discrimination and calibration with American Joint Committee on Cancer (AJCC) stage grouping. RESULTS AND LIMITATIONS At a median follow-up of 45 mo, 501 patients (22.3%) experienced disease recurrence and 418 patients (18.6%) died of UTUC. On multivariable analysis, T classification (p for trend <0.001), lymph node metastasis (hazard ratio [HR]: 1.98; p=0.002), lymphovascular invasion (HR: 1.66; p<0.001), sessile tumor architecture (HR: 1.76; p<0.001), and concomitant CIS (HR: 1.33; p=0.035) were associated with disease recurrence. Similarly, T classification (p for trend<0.001), lymph node metastasis (HR: 2.23; p=0.001), lymphovascular invasion (HR: 1.81; p<0.001), and sessile tumor architecture (HR: 1.72; p=0.001) were independently associated with cancer-specific mortality. Our models achieved 76.8% and 81.5% accuracy for predicting RFS and CSS, respectively. In contrast to these well-calibrated models, stratification based upon AJCC stage grouping resulted in a large degree of heterogeneity and did not improve discrimination. CONCLUSIONS Using standard pathologic features, we developed highly accurate prognostic models for the prediction of RFS and CSS after RNU for UTUC. These models offer improvements in calibration over AJCC stage grouping and can be used for individualized patient counseling, follow-up scheduling, risk stratification for adjuvant therapies, and inclusion criteria for clinical trials.

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.

Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location

To better define the predictors of bladder tumour development in patients operated for upper urinary tract urothelial cancer (UT‐UC).

External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology.

BACKGROUND The stage, size, grade, and necrosis (SSIGN) score has been created as an outcome prediction tool for clear-cell renal cell carcinoma (ccRCC) using review pathology. OBJECTIVE We evaluated the prognostic accuracy of the SSIGN score model using routine pathology records. DESIGN, SETTING, AND PARTICIPANTS We retrospectively evaluated pathology records of 1862 consecutive ccRCC patients with complete data including follow-up who had been operated between 1984 and 2006. INTERVENTION Surgical treatment of patients with ccRCC. MEASUREMENTS TNM stage, largest tumour diameter, tumour grade, and presence of histologic tumour necrosis were recorded. ccRCC were categorised according to the SSIGN-score algorithm as 0-15. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method for individual SSIGN-score categories (scores 0-1 and > or =10, respectively, were combined). For evaluation of the prognostic impact of stage, size, grade, and necrosis regarding CSS, a multivariate analysis using a Cox regression model was performed, and for assessment of prognostic accuracy, Harrells concordance index was performed. RESULTS AND LIMITATIONS Median tumour diameter was 5.0 cm (range: 0.6-22 cm). Tumour necrosis was noted in 607 tumours (32.6%). Median follow-up was 72.5 mo (range: 0-281 mo); 359 of 1862 patients (19.3%) died of RCC. Ten-year CSS rates for respective SSIGN scores in our study ranged from 96.5% (scores 0-1) to 19.2% (scores > or =10). pT categories, lymph-node status, distant metastases, high tumour grade (size > or =5 cm), and necrosis were each independent predictors of CSS. The Harrells concordance index was 0.823. Limitations included smaller sample sizes in higher risk categories and limited numbers of patients at risk after 10 yr. CONCLUSIONS Outcome prediction with the SSIGN score using routine pathology records was comparable to the original data based on review pathology. Combining scores into five categories improved discrimination. Our data support the routine use of the SSIGN score in clinical practice with regard to follow-up decisions and patient selection for adjuvant trials.

pT classification, grade, and vascular invasion as prognostic indicators in urothelial carcinoma of the upper urinary tract

Clinicopathologic features predictive of patient outcome in upper urinary tract urothelial carcinoma are not well defined. The aim of this study was to assess the role of pT classification, tumor grade, and vascular invasion in predicting metastasis-free survival. A total of 190 consecutive invasive upper urinary tract urothelial cancers operated between 01/1984 and 12/2004 were re-evaluated with respect to pT classification, tumor grade (according to the three-tiered WHO 1973 and the recent two-tiered grading system following the WHO/ISUP consensus classification), as well as presence of lymph and/or blood vessel invasion. Prognostic impact was analyzed using the Kaplan–Meier method and the Log-Rank test. For multivariate testing, a Coxs proportional hazards regression model was used. pT1 was present in 81 (43%), pT2 in 29 (15%), pT3 in 73 (38%), and pT4 in seven (4%) cases. There were 12 (6%) G1, 96 (51%) G2, and 82 (43%) G3 tumors or 84 (44%) low-grade and 106 (56%) high-grade tumors according to the two-tiered system. The presence of vascular invasion in 72/190 (38%) tumors was associated with high pT classification (P<0.001) and high tumor grade (P<0.001). Disease progression occurred in 39% of patients, with 5- and 10-year metastasis-free survival rates of 56 and 45%, respectively. On univariate analysis, all investigated parameters showed prognostic significance. The negative influence of vascular invasion on patient outcome was strikingly strong in high pT classification and high-grade cancers. On multivariate analysis, pT classification (P<0.001) and vascular invasion (P<0.001) proved to be independent prognostic factors, whereas tumor grade according to the two-tiered system missed statistical significance (P=0.06). In conclusion, pT classification and vascular invasion are independent prognostic factors with respect to metastasis-free survival and should be used to guide adjuvant therapy strategies in affected patients. Presence (or absence) of vascular invasion should be commented upon separately in the pathology report.

Prognostic factors for upper urinary tract urothelial carcinoma

Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, which means there are little evidence-based data available to guide clinical decision-making. Although diagnosis and treatment of UTUC have improved significantly over the last 5 years, accurate risk stratification remains a challenge owing to the difficulty of clinical staging. A number of potential prognostic factors have been identified, encompassing clinical characteristics, pathological factors and molecular markers. Tumor stage and lymph node status are the most important predictors of survival in patients with UTUC. Preoperative evaluation for hydronephrosis can identify patients at risk of non-organ-confined disease. In the subgroup of patients with stage ≥pT2 disease, a longer interval between diagnosis and radical nephroureterectomy is associated with a higher risk of disease recurrence and cancer-specific mortality. Extensive tumor necrosis, sessile tumor architecture and lymphovascular invasion are independent predictors of clinical outcomes for patients with UTUC treated with radical nephroureterectomy. The incorporation of such prognosticators into clinical prediction models might help to guide decision-making with regard to timing of surveillance, type of treatment, performance of lymphadenectomy, and consideration of neoadjuvant or adjuvant systemic therapies.

Clinical nodal staging scores for bladder cancer: A proposal for preoperative risk assessment

BACKGROUND Radical cystectomy (RC) with pelvic lymph node dissection (LND) is the standard of care for refractory non-muscle-invasive and muscle-invasive bladder cancer. Although consensus exists on the need for LND, its extent is still debated. OBJECTIVE To develop a model that allows preoperative determination of the minimum number of lymph nodes (LNs) needed to be removed at RC to ensure true nodal status. DESIGN, SETTING, AND PARTICIPANTS We analyzed data from 4335 patients treated with RC and pelvic LND without neoadjuvant chemotherapy at 12 academic centers located in the United States, Canada, and Europe. MEASUREMENTS We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed clinical (preoperative) nodal staging scores (cNSS), which represent the probability that a patient has LN metastasis as a function of the number of examined nodes. RESULTS AND LIMITATIONS The probability of missing a positive LN decreased with an increasing number of nodes examined (52% if 3 nodes were examined, 40% if 5 were examined, and 26% if 10 were examined). A cNSS of 90% was achieved by examining 6 nodes for clinical Ta-Tis tumors, 9 nodes for cT1 tumors, and 25 nodes for cT2 tumors. In contrast, examination of 25 nodes provided only 77% cNSS for cT3-T4 tumors. The study is limited due to its retrospective design, its multicenter nature, and a lack of preoperative staging parameters. CONCLUSIONS Every patient treated with RC for bladder cancer needs an LND to ensure accurate nodal staging. The minimum number of examined LNs for adequate staging depends preoperatively on the clinical T stage. Predictive tools can give a preoperative estimation of the likelihood of nodal metastasis and thereby allow tailored decision-making regarding the extent of LND at RC.

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.