Brian A. Costello

Independent Validation of the 2010 American Joint Committee on Cancer TNM Classification for Renal Cell Carcinoma: Results From a Large, Single Institution Cohort

PURPOSE In 2010 the American Joint Committee on Cancer updated the renal cell carcinoma TNM classification. Without independent validation of the new classification its predictive ability for cancer specific survival and generalizability remains unknown. In this setting we determined the predictive ability of the 2010 TNM classification compared to that of the 2002 classification. MATERIALS AND METHODS Using the nephrectomy registry at our institution we retrospectively reviewed the records of 3,996 patients with unilateral or bilateral synchronous renal cell carcinoma treated with radical nephrectomy or nephron sparing surgery between 1970 and 2006. Cancer specific survival was estimated using the Kaplan-Meier method and predictive ability was evaluated using the concordance index. RESULTS There were 1,165 deaths (29.1%) from renal cell carcinoma a median of 1.9 years after surgery compared to a median followup of 7.4 years for survivors. The estimated 10-year cancer specific survival rate was 96%, 80%, 66%, 55%, 36%, 26%, 25% and 12% for patients with 2010 primary tumor classifications of pT1a, pT1b, pT2a, pT2b, pT3a, pT3b, pT3c and pT4, respectively (p <0.001). The multivariate concordance index for the 2002 and 2010 TNM classifications was 0.848 and 0.850, respectively. CONCLUSIONS The new 2010 classification remains a robust predictor of cancer specific survival compared to the 2002 classification by dividing pT2 lesions into pT2a and pT2b, reclassifying ipsilateral adrenal involvement as pT4, reclassifying renal vein involvement as pT3a and simplifying nodal involvement as pN0 vs pN1. However, the 2010 TNM classification showed only modest improvement in predictive ability compared to the 2002 classification.

Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: A systematic review and meta-analysis

PURPOSE The relative effectiveness of partial vs radical nephrectomy remains unclear in light of the recent phase 3 European Organization for the Research and Treatment of Cancer trial. We performed a systematic review and meta-analysis of partial vs radical nephrectomy for localized renal tumors, considering all cause and cancer specific mortality, and severe chronic kidney disease. MATERIALS AND METHODS Cochrane Central Register of Controlled Trials, MEDLINE®, EMBASE®, Scopus and Web of Science® were searched for sporadic renal tumors that were surgically treated with partial or radical nephrectomy. Generic inverse variance with fixed effects models were used to determine the pooled HR for each outcome. RESULTS Data from 21, 21 and 9 studies were pooled for all cause and cancer specific mortality, and severe chronic kidney disease, respectively. Overall 31,729 (77%) and 9,281 patients (23%) underwent radical and partial nephrectomy, respectively. According to pooled estimates partial nephrectomy correlated with a 19% risk reduction in all cause mortality (HR 0.81, p < 0.0001), a 29% risk reduction in cancer specific mortality (HR 0.71, p = 0.0002) and a 61% risk reduction in severe chronic kidney disease (HR 0.39, p < 0.0001). However, the pooled estimate of cancer specific mortality for partial nephrectomy was limited by the lack of robustness in consistent findings on sensitivity and subgroup analyses. CONCLUSIONS Our findings suggest that partial nephrectomy confers a survival advantage and a lower risk of severe chronic kidney disease after surgery for localized renal tumors. However, the results should be evaluated in the context of the low quality of the existing evidence and the significant heterogeneity across studies. Future research should use higher quality evidence to clearly demonstrate that partial nephrectomy confers superior survival and renal function.

Survival after complete surgical resection of multiple metastases from renal cell carcinoma

Although a role for resection of solitary metastases from renal cell carcinoma (RCC) has been described, the utility of surgery in patients with multiple sites of disease has been less well defined. The authors report the survival of patients who underwent complete metastasectomy for multiple RCC metastases.

Exosomal miR-1290 and miR-375 as Prognostic Markers in Castration-resistant Prostate Cancer

BACKGROUND Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. OBJECTIVE To identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC). DESIGN, SETTING, AND PARTICIPANTS RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors. RESULTS AND LIMITATIONS RNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥ 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate < 0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10(-6)). CONCLUSIONS Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further evaluation of these candidate miRNAs. PATIENT SUMMARY In this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer.

Contemporary Trends in Nephrectomy for Renal Cell Carcinoma in the United States: Results From a Population Based Cohort

PURPOSE Despite benefits in functional renal outcome and the similar oncological efficacy of partial nephrectomy for renal cell carcinoma, previous studies show marked underuse of partial nephrectomy. We describe national trends in partial and radical nephrectomy using a contemporary, population based cohort. MATERIALS AND METHODS Using the 2003 to 2008 Nationwide Inpatient Sample we identified 188,702 patients treated with partial or radical nephrectomy for renal cell carcinoma at a total of 1,755 hospitals. Multivariate logistic regression was used to assess the independent associations of patient and hospital characteristics with partial nephrectomy. Post-estimations from multivariate logistic regression were done to ascertain the annual predicted probability of partial nephrectomy by hospital feature. RESULTS Overall 149,636 (79.3%) and 39,066 patients (20.7%) underwent radical and partial nephrectomy for renal cell carcinoma, respectively. Partial nephrectomy use increased each year from 16.8% in 2003 to 25.1% in 2008 (p for trend <0.001). On multivariate analysis patients were more likely to undergo partial nephrectomy at teaching (OR 1.31, p <0.001) and urban (OR 1.13, p = 0.05) hospitals compared to nonteaching and rural hospitals, respectively. Each quartile of higher nephrectomy annual volume was associated with higher odds of partial nephrectomy compared to the lowest quartile (OR 1.21, p <0.001). Although annual predicted partial nephrectomy use increased across all hospitals, differences in annual partial nephrectomy use by teaching status, site (urban vs rural) and case volume persisted with time. CONCLUSIONS Although the use of partial nephrectomy for renal cell carcinoma is increasing nationally across all hospitals, academic and urban hospitals as well as those with higher nephrectomy volume continue to show higher partial nephrectomy use for renal cell carcinoma.

Overall Survival and Development of Stage IV Chronic Kidney Disease in Patients Undergoing Partial and Radical Nephrectomy for Benign Renal Tumors

BACKGROUND Although partial nephrectomy (PN) has been associated with improved renal function compared with radical nephrectomy (RN) for renal cell carcinoma, the impact on overall survival (OS) remains controversial. OBJECTIVE To evaluate comparative OS and renal function in patients following PN and RN for a renal mass where malignancy was not a confounding factor. DESIGN, SETTING, AND PARTICIPANTS Using the Mayo Clinic Nephrectomy Registry, we retrospectively identified 442 patients with unilateral sporadic benign renal masses treated surgically with PN or RN between 1980 and 2008. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome measures were OS and the incidence of new-onset stage IV chronic kidney disease (CKD), determined using the Kaplan-Meier method. Cox models were used to test the association of nephrectomy type with these outcomes. RESULTS AND LIMITATIONS Overall, 206 and 236 patients with benign renal masses were surgically treated with RN and PN, respectively. Patients who underwent RN were older (median age: 67 vs 64 yr; p=0.02) and had larger tumors (median size: 5.0 vs 2.7 cm; p<0.001). Median follow-up for patients still alive at last follow-up was 8.3 yr (range: 0.1-27.9 yr). Estimated OS (95% confidence interval [CI]) rates at 10 and 15 yr were 69% (62-76%) and 53% (45-62%) for RN compared with 80% (73-87%) and 74% (65-83%) following PN (p=0.032). After adjusting for covariates of interest, patients treated with RN were significantly more likely to die from any cause (hazard ratio [HR]: 1.75; 95% CI, 1.08-2.83; p=0.023) or develop stage IV CKD (HR: 4.23; 95% CI, 1.80-9.93; p<0.001) compared with patients who underwent PN. Limitations include the retrospective design, selection bias for surgical approach, and referral bias to a tertiary care facility. CONCLUSIONS Our data suggest that PN may confer a clinical benefit for improved renal function and better OS compared with RN after excluding the confounding effect of malignancy.

Outcomes and clinicopathologic variables associated with late recurrence after nephrectomy for localized renal cell carcinoma

OBJECTIVE To characterize the incidence and clinicopathologic factors associated with late recurrence after surgical resection for renal cell carcinoma (RCC) because the recurrence patterns >5 years after nephrectomy have been poorly described. METHODS We identified 1454 patients treated with nephrectomy for localized RCC from 1970 to 2000 who had remained free of disease for 5 years. Subsequent tumor recurrence was classified as renal recurrence and distant metastasis. The incidence of recurrence >5 years from surgery was estimated using the Kaplan-Meier method. The associations of clinicopathologic variables with late recurrence were analyzed using Cox proportional hazard regression models. RESULTS With a median postoperative follow-up of 13.9 years (range 5.1-38.9), 63 patients (4.3%) experienced late renal recurrence at a median of 9.3 years (range 5.1-25.3), and 172 patients (11.8%) developed late distant metastases at a median of 9.6 years (range 5.1-26.6) after surgery. The estimated recurrence-free survival rate at 10 and 15 years was 97.3% and 95.2% for renal recurrence, and 93.1% and 85.9% for distant metastases, respectively. On multivariate analysis, increased tumor size (hazard ratio [HR] 1.12; P < .001) was associated with late renal tumor recurrence, and increased tumor size (HR 1.07; P = .018), clear cell or collecting duct histologic features (HR 3.76; P < .001), and tumor Stage pT1b (HR 2.8; P < .001), pT2a (HR 4.5; P < .001), pT2b (HR 3.4; P = .007), and pT3-pT4 (HR 5.1; P < .001) were associated with distant metastasis. CONCLUSION After an initial 5-year postoperative disease-free interval, approximately 5% and 15% of patients will develop renal recurrence and distant metastases, respectively, during the next decade. Therefore, long-term surveillance remains necessary after nephrectomy.

Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.

Detection of Asymptomatic Recurrence During Routine Oncological Followup After Radical Cystectomy is Associated With Improved Patient Survival

PURPOSE Whether routine surveillance to detect tumor recurrence after radical cystectomy improves patient survival remains in debate. We determined the impact on all cause mortality of symptoms at recurrence after cystectomy. MATERIALS AND METHODS We identified 1,599 patients who underwent radical cystectomy for urothelial carcinoma at our institution between 1980 and 2000. Median postoperative followup was 9.8 years (range 0 to 30.3). Overall survival in patients with recurrence stratified by the mode of diagnosis (asymptomatic vs symptomatic) was estimated using the Kaplan-Meier method and compared with the log rank test. Cox proportional hazard regression models were used to evaluate the impact of the mode of diagnosing recurrence on survival. RESULTS A total of 606 patients (38%) experienced recurrence after surgery, of whom 137 (23%) were asymptomatic and 469 (77%) were symptomatic. Recurrence sites included abdomen/pelvis in 450 patients, bone in 185, thorax in 176, urothelium in 154 and brain in 39. The most common symptoms at recurrence were pain in 75.3% of patients, constitutional symptoms in 57.4% and hematuria in 12.4%. Five and 10-year overall survival in patients with symptomatic vs asymptomatic recurrence was 22% and 10% vs 46% and 26%, respectively (p <0.0001). On multivariate analysis patients who were symptomatic at recurrence were at almost 60% increased risk for death than those who were asymptomatic (HR 1.59, p = 0.0001). CONCLUSIONS Detecting asymptomatic recurrence after cystectomy was associated with significantly improved patient survival. Continued investigation to establish the optimal followup regimen remains necessary, balancing the benefit of early detection with the increased cost of routine surveillance.

Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome

Micropapillary urothelial carcinoma exhibits amplification of the human epidermal growth factor receptor, ERBB2(HER2), and overexpression of the ERBB2 protein product. The clinical significance of this has yet to be established. The objective of this study was to examine ERBB2 amplification and protein expression in micropapillary urothelial carcinoma and stage-matched typical urothelial carcinoma treated by radical cystectomy to assess the frequency of amplification and protein expression, and to determine the association with cancer-specific survival. Pathologic material and data from patients undergoing cystectomy at Mayo Clinic between 1980 and 2008 were reviewed. ERBB2 amplification by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry were assessed. Univariate and multivariate Cox proportional hazards regression models were used to evaluate for associations of ERBB2 amplification and protein expression with survival. ERBB2 amplification was identified in 9 (15%) of 61 micropapillary carcinomas compared with 9 (9%) of 100 urothelial carcinomas. In patients with micropapillary carcinoma, ERBB2 amplification was associated with a nearly threefold increased risk of cancer death. ERBB2 amplification (hazard ratio 4.3; P=0.0008) remained associated with an increased risk of death from bladder cancer among patients with micropapillary urothelial carcinoma on multivariate analysis. The association of cancer-specific survival and ERBB2 amplification was not seen in patients with urothelial carcinoma. ERBB2 immunohistochemistry correlated with ERBB2 amplification but there was no association of ERBB2 protein expression and survival. ERBB2 amplification is more frequent in micropapillary urothelial carcinoma than typical urothelial carcinoma, and patients with micropapillary carcinoma who have ERBB2 amplification have worse cancer-specific survival than those who do not. Identification of ERBB2 amplification in micropapillary carcinoma could provide important prognostic information and possibly provide a role for ERBB2 targeted therapy.