Nicole Benfante

Histological subtype of renal cell carcinoma significantly affects survival in the era of partial nephrectomy

OBJECTIVES To analyze whether the histological subtype of renal cell carcinoma (RCC) affects survival after surgical resection in contemporary patients, and if so, whether prognostic significance differs according to the type of surgical resection or tumor stage. MATERIALS AND METHODS From 2006 to 2014, 2,237 patients underwent surgical resection (25% radical nephrectomy and 75% partial nephrectomy [PN]) for nonmetastatic RCC at a tertiary referral center. Estimated survival function curves and Cox regression models evaluated the effect of histological subtype on recurrence-free survival (RFS) and overall survival (OS). Interaction analyses tested whether the effect of histological subtype depends on the type of surgical resection or tumor stage. RESULTS Patients with RCC stage T2 or lower and those with low-grade conventional clear cell, papillary or chromophobe RCC of any stage had 5-year RFS probabilities>90%. Patients with clear cell papillary RCC stage T3 or greater had predicted 5-year RFS of 81%. However, 5-year OS probabilities were>94% for clear cell papillary RCC of any stage. High-grade conventional clear cell and papillary RCC stage T2 or lower, low-grade conventional clear cell and chromophobe RCC of any stage conferred 5-year OS probabilities of >93%. Unclassified RCC demonstrated the lowest OS probabilities at any stage. In multivariable analyses, histological subtype affected RFS (P<0.0001) and OS (P = 0.026) following surgical resection, with no differences in this association for radical nephrectomy vs. PN (RFS, P = 0.2; OS, P = 0.4), and across pathologic stages (RFS, P = 0.1; OS, P = 0.3). Compared with low-grade conventional clear cell RCC, chromophobe (hazard ratio [HR] = 0.72, 95% CI: 0.30-1.75) and papillary RCC (HR = 0.30, 95% CI: 0.09-0.97) conferred lower risk of recurrence. Chromophobe (HR = 0.67, 95% CI: 0.30-1.52) and clear cell papillary RCC (HR = 0.91, 95% CI: 0.12-6.78) conferred the lowest risk of all-cause mortality. CONCLUSIONS In the era of PN for RCC, histological subtype remained a significant predictor of survival, regardless of type of surgical resection or tumor stage.

Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma

BACKGROUND Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. OBJECTIVE To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. DESIGN, SETTING, AND PARTICIPANTS DNA sequencing data were pooled from three collaborative genomic cohorts (n=754) and our institutional database (n=295). All patients had clinical data and identification of somatic mutations from their primary tumors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing (q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTS AND LIMITATIONS Association with tumor size was found for mutations in BAP1 (q=0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 (q=0.004) and TP53 (q=0.001) were associated with decreased CSS in a multivariable model; only TP53 (q=0.005) remained significant when SSIGN score was included. SETD2 mutations (q=0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. CONCLUSIONS In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53. After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. PATIENT SUMMARY Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

Intravenous Mannitol Versus Placebo During Partial Nephrectomy in Patients with Normal Kidney Function: A Double-blind, Clinically-integrated, Randomized Trial

BACKGROUND Mannitol is currently used as a renal protective agent to mitigate the effects of renal ischemia during nephron-sparing surgery (NSS). This routine practice lacks rigorous methodological study. OBJECTIVE To assess the effect on renal function outcomes after surgery of mannitol infusion prior to renal ischemia during NSS. DESIGN, SETTING, PARTICIPANTS This prospective, randomized, placebo-controlled, double-blind trial included 199 patients with a preoperative estimated glomerular filtration rate (eGFR) >45ml/min/1.73m2 scheduled for NSS; the trial was conducted between July 2012 and July 2015. INTERVENTION Patients undergoing NSS were randomized to receive mannitol (12.5g) or placebo intravenously within 30min prior to renal vascular clamping. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the difference in eGFR (renal function) between the two groups at 6 mo following surgery assessed with an analysis of covariance model using preoperative eGFR, treatment group, and surgical approach as covariates. RESULTS AND LIMITATIONS At baseline, the median age of the patients was 58 yr, and the median eGFR was 88ml/min/1.73m2. Comparing placebo with mannitol infusion, the adjusted difference of 0.2 eGFR units at 6 mo was not significant (p=0.9), with the upper bound of the 95% confidence interval (-3.1 to 3.5) excluding a clinically relevant effect of mannitol. Limitations include evaluation of a single mannitol dose and patients all had excellent preoperative renal function. CONCLUSIONS Intraoperative 12.5g mannitol infusion during NSS has no demonstrable clinical benefit when compared with standardized fluid hydration in patients with normal preoperative renal function, and its use in this setting is not warranted. PATIENT SUMMARY In this randomized trial, patients with normal kidney function who received mannitol during surgery to remove part of their kidney had no better kidney function 6 mo after surgery than those who did not receive mannitol. We conclude that this routine practice should be discontinued.

The Prognostic Impact of a Positive Vascular Margin on pT3 Clear Cell Renal Cell Carcinoma

PURPOSE We examined the impact of positive vascular margins in patients with pT3 clear cell renal cell carcinoma. MATERIALS AND METHODS After excluding patients with nonvascular positive margins, metastasis, lymph node involvement, neoadjuvant therapy or nonclear cell histology, we identified 224 patients with venous tumor invasion through our institutional database from 1999 to 2013. Kaplan-Meier analysis and log rank tests were used to evaluate whether positive vascular margins were associated with progression-free survival or cancer specific survival. RESULTS There were 41 patients (18%) with a positive vascular margin. Margin status was directly related to the level of invasion (p <0.0001). Compared to the negative vascular margin group the positive group had a significantly worse progression-free survival (p=0.01) but not cancer specific survival (p=0.3). Similarly the level of vascular thrombus invasion was significantly associated with worse progression-free survival (p=0.02) but not cancer specific survival (p=0.4). The 3-year progression-free survival was worst with inferior vena cava invasion and best with segmental/muscular venous branch invasion (54%, 95% CI 34-70 vs 76%, 95% CI 64-85). Among patients with only main renal vein thrombus, vascular margin status was not associated with progression-free survival (p=0.5) or cancer specific survival (p=0.2). CONCLUSIONS In patients with pT3N0/XM0 clear cell renal cell carcinoma positive vascular margins are associated with risk of disease progression. However, the risk of relapse associated with positive vascular margins is driven by the extent of vascular thrombus invasion. These findings suggest that the clinical significance of vascular margin status as currently defined in pT3 clear cell renal cell carcinoma is minimal.

A Systematic Approach to Discussing Active Surveillance with Patients with Low-risk Prostate Cancer

BACKGROUND Physicians report difficulty convincing patients with prostate cancer about the merits of active surveillance (AS); as a result, a majority of patients unnecessarily choose to undergo radical treatment. OBJECTIVE To develop and evaluate a systematic approach for physicians to counsel patients with low-risk prostate cancer to increase acceptance of AS. DESIGN, SETTING, AND PARTICIPANTS A systematic counseling approach was developed and piloted in one clinic. Then five surgeons participated in a 1-h training session in which they learned about the approach. A total of 1003 patients with Gleason 3+3 prostate cancer were included in the study. We compared AS rates for 761 patients who were counseled over a 24-mo period before the training intervention with AS rates for 242 patients who were counseled over a 12-mo period afterwards, controlling for temporal trends and case mix. INTERVENTION A systematic approach for communicating the merits of AS using appropriate framing techniques derived from principles studied by negotiation scholars. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The rate of AS acceptance by patients for management of low-risk prostate cancer. RESULTS AND LIMITATIONS In the pilot phase, 81 of 86 patients (94%) accepted AS after counseling by the physician who developed the counseling approach. In the subsequent study, the cohort for the training intervention comprised 1003 consecutive patients, 80% of whom met the Epstein criteria for very low-risk disease. The proportion of patients who selected AS increased from 69% before the training intervention to 81% afterwards. After adjusting for time trends and case mix, the rate of AS after the intervention was 9.1% higher (95% confidence interval -0.4% to 19.4%) than expected, a relative reduction of approximately 30% in the risk of unnecessary curative treatment. CONCLUSIONS A systematic approach to counseling can be taught to physicians in a 1-h lecture. We found evidence that even this minimal intervention can decrease overtreatment. Our novel approach offers a framework to help address cancer screening-related overtreatment that occurs across medicine. PATIENT SUMMARY In this study, we evaluated the impact of teaching physicians how to better communicate the benefits and risks of prostate cancer treatments on the willingness of patients to choose active surveillance. Decisions related to cancer are often guided by emotions and biases that lead most patients to seek radical treatment; however, we demonstrated that if discussions are framed differently, these biases can be overcome and more patients will choose active surveillance.

The difficulty in selecting patients for cytoreductive nephrectomy: An evaluation of previously described predictive models ☆

PURPOSE To externally evaluate a preoperative points system and a preoperative nomogram, both created to assess time to death after cytoreductive nephrectomy (CN). MATERIALS AND METHODS We identified 298 patients who underwent CN at our institution, a tertiary cancer center, between 1989 and 2015. To validate the points system, we compared reported overall survival (OS) for each criterion to observed OS in our cohort. To evaluate the nomogram, we prognosticated risk of death at 6 months after surgery for 280 patients with sufficient follow-up in our cohort and evaluated discrimination using area under the curve (AUC) and calibration. Decision curve analysis was performed to assess clinical utility of the nomogram. RESULTS Significant differences in OS were observed between patients with and without 5 of 7 criteria on univariate analysis: low albumin (P<0.0001), high lactate dehydrogenase (P = 0.002), liver metastasis (P = 0.004), retroperitoneal lymphadenopathy (P = 0.002), and supradiaphragmatic lymphadenopathy (P = 0.019). Discrimination from the preoperative model, predicting death within 6 months of surgery was lower in our cohort (AUC = 0.65, 95% CI: 0.52-0.79) than the original publication (AUC = 0.76). Decision curve analysis demonstrated little benefit for applicability. CONCLUSIONS Five previously defined risk factors are predictive of decreased OS after CN in our cohort. We found lower discrimination using the preoperative model and minimal clinical utility according to decision analysis in our study cohort. These findings suggest the need for improved models to aid patient stratification and consequent treatment choice.

Genomic alterations as predictors of survival among patients within a combined cohort with clear cell renal cell carcinoma undergoing cytoreductive nephrectomy

PURPOSE To establish prognostic genomic biomarkers for patients with metastatic clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS We identified 60 patients who presented with metastatic ccRCC at our institution between 2001 and 2015 and had genomic sequencing on their primary tumor. We pooled these patients with 107 other patients with the same inclusion criteria from three well-known public databases. Five commonly mutated genes were chosen for analysis: VHL, PBRM1, BAP1, SETD2, and KDM5C. Overall survival (OS) was estimated using the Kaplan-Meier method and the log-rank test was used for comparisons between groups. RESULTS Median OS in the cohort was 2.5 years. Higher Fuhrman grade was associated with decreased median OS (P<0.001). Mutations in SETD2 (P = 0.027) and KDM5C (P = 0.019) were associated with reduced risk of death (hazard ratio [HR] = 0.58 [95% CI: 0.35-0.94] and HR = 0.43 [95% CI: 0.22-0.85], respectively). BAP1 mutations (P = 0.008) were associated with increased risk of death (HR = 1.81 [95% CI: 1.16-2.83]). There were significantly more female patients with a BAP1 mutation than females in the overall cohort (P = 0.001). CONCLUSIONS Mutations in BAP1 negatively affected OS, whereas SETD2 and KDM5C mutations were associated with prolonged OS in our pooled cohort of 167 patients with metastatic ccRCC. Our results expand upon efforts at understanding genomic biomarkers in localized disease. Those efforts set the stage for our novel investigation examining associations of select recurrent somatic mutations in stage IV patients with ccRCC.

Prostate magnetic resonance imaging findings in patients treated for testosterone deficiency while on active surveillance for low-risk prostate cancer

OBJECTIVE To investigate the multiparametric prostate magnetic resonance imaging (mpMRI) findings in patients treated with testosterone replacement therapy (TRT) while on active surveillance for low-risk prostate cancer. METHODS We retrospectively reviewed 12 patients who underwent mpMRI before and after TRT while on active surveillance. Changes in serum testosterone level, prostate-specific antigen (PSA), prostate biopsy findings, prostate volume, and Prostate Imaging Reporting and Data System Version 2 (PI-RADSv2) score before and after TRT were summarized. RESULTS After TRT, there was a significant increase in serum testosterone (516.5ng/dl vs. 203.0ng/dl), PSA (4.2ng/ml vs. 3.3ng/ml), and prostate volume (55.2cm3 vs. 39.4cm3). In total, 2 patients had biopsy progression during the study period. The PI-RADSv2 scores before and after TRT were unchanged in 10/12 patients; none of these demonstrated biopsy progression on post-TRT. The PI-RADSv2 scores increased after TRT in 2/12 patients; both showed Gleason score upgrade on follow-up biopsy. Of these 2 patients, 1 patient underwent radical treatment due to clinical progression. The area under the curve for detecting biopsy progression calculated from PI-RADSv2 score after TRT was 0.90, which was better than that calculated from post-TRT PSA level (0.48). CONCLUSIONS After TRT, mpMRI findings remained stable in patients without biopsy progression, whereas PI-RADSv2 score increase was identified in patients with Gleason score upgrade on follow-up biopsy.

Is restaging transurethral resection necessary in patients with non-muscle invasive bladder cancer and limited lamina propria invasion?

OBJECTIVES To evaluate the influence of lamina propria invasion type at initial transurethral resection (TUR) on restaging pathology. MATERIALS AND METHODS We reviewed prospectively maintained records of all patients with a high-grade pT1 nonmuscle invasive bladder cancer who underwent both initial and restaging TUR within 6 weeks at our center between 2001 and 2016. The pathology of second TUR specimens was analyzed with regard to the characteristics of lamina propria invasion found at initial resection. RESULTS We included 198 patients, with a median age of 70 years (interquartile range: 63-79). Muscle was present in the initial TUR specimen in 107 patients (54%). Pathology restaging was pT0 in 73 patients (37%), pTis in 44 (22%), pTa in 27 (14%), pT1 in 50 (25%), and pT2 in 4 (2%). Eighty-seven patients (44%) had tumors with minimal lamina propria invasion at initial TUR: 53 specimens (27%) had focal invasion (few malignant cells in the lamina propria); 15 specimens (7.6%) had superficial invasion (invasion of the lamina propria to the level of the muscularis mucosae [T1a]); and 19 specimens (10%) had multifocal superficial invasion (multiple areas of T1a). Of the patients with minimal lamina propria invasion, residual disease was found in 54 patients (62%). However, none of those patients had T2 disease. CONCLUSIONS A significant number of patients with T1 tumors have residual disease at restaging TUR as do patients with minimal lamina propria invasion. The extent of T1 invasion does not eliminate the need for repeat TUR.

The Impact of Plasmacytoid Variant Histology on the Survival of Patients with Urothelial Carcinoma of Bladder after Radical Cystectomy

BACKGROUND The clinical significance of the plasmacytoid variant (PCV) in urothelial carcinoma (UC) is currently lacking. OBJECTIVE To compare clinical outcomes of patients with any PCV with that of patients with pure UC treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS We identified 98 patients who had pathologically confirmed PCV UC and 1312 patients with pure UC and no variant history who underwent RC at our institution between 1995 and 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariable and multivariable Cox regression and Cox proportional hazards regression to determine if PCV was associated with overall survival (OS). RESULTS AND LIMITATIONS Patients with PCV UC were more likely to have advanced tumor stage (p=0.001), positive lymph nodes (p=0.038), and receive neoadjuvant chemotherapy than those with pure UC (46% vs 22%, p<0.0001). The rate of positive soft tissue surgical margins was over five times greater in the PCV UC group compared with the pure UC group (21% vs 4.1%, respectively, p<0.0001). Median OS for the pure UC versus the PCV patients were 8 yr and 3.8 yr, respectively. On univariable analysis, PCV was associated with an increased risk of overall mortality (hazard ratio=1.34, 95% confidence interval: 1.02-1.78, p=0.039). However, on multivariable analysis adjusted for age, sex, neoadjuvant chemotherapy received, lymph node status, pathologic stage, and soft margin status, the association between PCV and OS was no longer significant (hazard ratio=1.06, 95% confidence interval: 0.78, 1.43, p=0.7). This retrospective study is limited by the lack of pathological reanalysis, and the impact of other concurrent mixed histology cannot be determined in this study. CONCLUSIONS Patients with PCV features have a higher disease burden at RC compared with those with pure UC. However, PCV was not an independent predictor of survival after RC on multivariable analysis, suggesting that PCV histology should not be used as an independent prognostic factor. PATIENT SUMMARY Plasmacytoid urothelial carcinoma is a rare and aggressive form of bladder cancer. Patients with plasmacytoid urothelial carcinoma had worse adverse pathologic features, but this was not associated with worse overall mortality when compared with patients with pure urothelial carcinoma.