Ross J. Mason

Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis

While it has been demonstrated that receipt of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) improves survival compared to RC alone, the driving factor for this benefit may be from patients with ypT0 status at surgery. Meanwhile, the implications of having residual urothelial carcinoma of the bladder (rUCB) at RC after NAC are less clear. We therefore evaluated whether survival differed between patients with rUCB at RC after NAC and stage-matched controls who underwent RC alone. Patients who underwent NAC + RC (n = 180) were matched to controls who underwent RC alone (n=324) on the basis of pT and pN stage, margin status, and year of RC. The 5-yr recurrence-free survival (RFS; 90% vs 94%; p=1), cancer-specific survival (CSS; 82% vs 93%; p=0.4), and overall survival (OS; 82% vs 82%; p=0.5) were not significantly different between the NAC and control groups for patients with ypT0N0/pT0N0 disease (n=103). Conversely, among patients with rUCB at RC (n=401), patients who received NAC had significantly worse 5-yr RFS (50% vs 63%; p=0.01), CSS (40% vs 59%; p=0.003), and OS (33% vs 48%; p=0.02). On multivariable analysis for patients with rUCB, NAC receipt remained independently associated with worse RFS (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.28-2.66; p=0.001), CSS (HR 1.81, 95% CI 1.30-2.52; p<0.001), and OS (HR 1.57, 95% CI 1.18-2.08; p=0.002). Limitations include potential for selection bias owing to the retrospective observational design. Thus, while patients who achieve a complete response to NAC have excellent survival outcomes, those with rUCB after NAC have a worse prognosis compared to stage-matched controls undergoing RC alone. It may be worthwhile considering these patients for clinical trials evaluating the role of additional treatments after RC using newer agents while we await further research on predicting which patients achieve ypT0 status from NAC before RC. PATIENT SUMMARY On surgical removal of the bladder, patients without residual bladder cancer after neoadjuvant chemotherapy have excellent survival outcomes. However, patients with residual cancer after neoadjuvant chemotherapy and surgery have worse outcomes compared to patients undergoing surgery alone. These patients should therefore be considered for additional treatments after surgery using newer agents while we await further research on predicting which patients will benefit from neoadjuvant chemotherapy before bladder removal for cancer.

Impact of Radical Prostatectomy on Long-Term Oncologic Outcomes in a Matched Cohort of Men with Pathological Node Positive Prostate Cancer Managed by Castration

Purpose: Long‐term data supporting the role of primary tumor resection in node positive prostate cancer are lacking. We evaluated the impact of adding radical retropubic prostatectomy to surgical castration on long‐term oncologic outcomes in pathological node positive prostate cancer. Materials and Methods: We identified men who underwent pelvic lymphadenectomy and orchiectomy within 90 days for pathological node positive prostate cancer from 1966 to 1995. Men treated with radical retropubic prostatectomy in addition to orchiectomy were matched 1:1 to men who underwent orchiectomy alone based on age, year of surgery, clinical grade, clinical T stage, number of positive nodes and preoperative serum prostate specific antigen, the latter from 1987 and thereafter. Kaplan‐Meier and Cox regression analyses were done to compare cancer specific and overall survival. Results: The matched cohort included 158 men with 79 in each group. Of men who underwent orchiectomy alone 76 died, including 60 of prostate cancer. Of patients treated with radical retropubic prostatectomy plus orchiectomy 70 died, including 28 of prostate cancer. On Kaplan‐Meier analyses prostatectomy plus orchiectomy vs orchiectomy alone was associated with prolonged cancer specific survival (at 20 years 59% vs 18%, log rank p <0.001) and overall survival (at 20 years 22% vs 9%, log rank p <0.001). In Cox models prostatectomy plus orchiectomy vs orchiectomy alone was associated with improved cancer specific survival (HR 0.28, 95% CI 0.17–0.46, p <0.001) and overall survival (HR 0.48, 95% CI 0.34–0.66, p <0.001). Findings were similar in the subset with available preoperative prostate specific antigen values. Conclusions: With lifelong followup in nearly the entire cohort, this study demonstrates that adding radical retropubic prostatectomy to surgical castration for pathological node positive prostate cancer is associated with improved cancer specific and overall survival. When technically feasible in well selected patients, aggressive locoregional resection should be considered for node positive prostate cancer as part of a multimodal approach.

Comprehensive assessment of renal tumour complexity in a large percutaneous cryoablation cohort

To evaluate the association between renal tumour complexity and outcomes in a large cohort of patients undergoing percutaneous cryoablation (PCA).

Outcomes After Cryoablation Versus Partial Nephrectomy for Sporadic Renal Tumors in a Solitary Kidney: A Propensity Score Analysis

BACKGROUND While partial nephrectomy (PN) is considered the standard approach for a tumor in a solitary kidney, percutaneous cryoablation (PCA) is emerging as an alternative nephron-sparing option. OBJECTIVE To compare outcomes between PCA and PN for tumors in a solitary kidney. DESIGN, SETTING, AND PARTICIPANTS Patients who underwent PCA or PN between 2005 and 2015 for a single primary renal tumor in a solitary kidney were identified using Mayo Clinic Registries. Exclusion criteria were inherited tumor syndromes and salvage procedures. INTERVENTION PCA and PN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS To achieve balance in baseline characteristics, we used inverse probability of treatment weighting (IPTW) based on propensity to receive treatment. The risk of having a post-treatment complication and percent drop in estimated glomerular filtration rate (eGFR), as well as the risks of local/ipsilateral recurrence, distant metastasis, and cancer-specific mortality, were compared between groups using logistic, linear, and Fine-and-Gray competing risk regression models. RESULTS AND LIMITATIONS The cohort included 118 patients (PCA: 54; PN: 64) with a median follow-up of 47 mo (interquartile range 18, 74). In unadjusted analyses, PCA was associated with a lower risk of complications (15% vs 31%; odds ratio [OR]=0.38; 95% confidence interval [CI] 0.15, 0.96; p=0.04). However, upon accounting for baseline differences with IPTW adjustment, there was no longer a significant difference in the risk of complications (28% vs 29%; OR=0.95; 95% CI 0.53, 1.69; p=0.9). There were no significant differences between PCA and PN in percentage drop in eGFR at discharge (mean: 11% vs 16%; β=-5%; 95% CI -13, 3; p=0.2) or at 3 mo (12% vs 9%; β=3%; 95% CI -3, 10; p=0.3). Likewise, no significant differences were noted in local recurrence (HR=0.87; 95% CI 0.38, 1.98; p=0.7), distant metastases (HR=0.60; 95% CI 0.30, 1.20; p=0.2), or cancer-specific mortality (HR=1.13; 95% CI 0.32, 3.98; p=0.8). Limitations include the sample size, given the relative rarity of renal masses in solitary kidneys. CONCLUSIONS Our study found no significant difference in complications, renal function outcomes, and oncologic outcomes between PN and PCA for patients with a tumor in a solitary kidney. Validation in a larger multi-institutional analysis may be warranted. PATIENT SUMMARY Partial nephrectomy (surgery) and percutaneous cryoablation are both options for treating a kidney tumor while preserving the normal portion of the kidney. In patients with a tumor in their only kidney, we found no difference in the risk of complications, kidney function outcomes, or cancer control outcomes between these two approaches.

Are We Using the Best Tumor Size Cut-Points for Renal Cell Carcinoma Staging?

OBJECTIVE To compare the predictive ability for oncologic outcomes among current tumor size cut-points and clinically relevant alternatives to determine which are optimal. METHODS Patients who underwent radical or partial nephrectomy between 1970 and 2010 for T1-2Nx/N0M0 renal cell carcinoma (RCC) were identified. Associations between tumor size and progression-free survival (PFS) and cancer-specific survival (CSS) were evaluated using Kaplan-Meier analyses and Cox models. Predictive ability was assessed using c-indexes. RESULTS The cohort included 3304 patients with a median age of 63 years (interquartile range 53, 70). Median follow-up among survivors was 9.9 years (interquartile range 6.9, 14.3). There were 536 patients who progressed and 354 who died from RCC. For RCC tumors ≤3.0 cm, 10-year PFS and CSS rates were 93%-95% and 97%-99%, respectively. For tumors >3.0-4.0 cm, PFS and CSS began to decline (91% and 95%, respectively), with further gradual declines in PFS and CSS with increasing tumor size. Plots of hazard ratios for progression and RCC death as a function of tumor size did not reveal major inflection points. Differences in discrimination based on various combinations of tumor-size cut-points for progression or RCC death were small, with c-indexes ranging between 0.691-0.704 and 0.734-0.750, respectively. CONCLUSION RCC tumors ≤3.0 cm in size are associated with favorable outcomes. Thereafter, risks of progression and RCC death increase gradually with tumor size, with no compelling biological reason to endorse a given cut-point over another.

Comparative Survival following Initial Cytoreductive Nephrectomy versus Initial Targeted Therapy for Metastatic Renal Cell Carcinoma

Purpose: The optimal sequence of cytoreductive nephrectomy and targeted therapy of metastatic renal cell carcinoma is unclear. We compared overall survival between patients with metastatic renal cell carcinoma treated with initial cytoreductive nephrectomy with or without subsequent targeted therapy vs initial targeted therapy with or without subsequent cytoreductive nephrectomy. Materials and Methods: We evaluated the records of cases in the National Cancer Database diagnosed with metastatic renal cell carcinoma between 2006 and 2013 who were treated with cytoreductive nephrectomy and/or targeted therapy. Receipt of targeted therapy after initial cytoreductive nephrectomy and cytoreductive nephrectomy after initial targeted therapy were evaluated on competing risks analyses. To account for treatment selection bias, inverse probability of treatment weighting was performed based on the propensity to receive initial cytoreductive nephrectomy or initial targeted therapy. Overall survival was compared between the groups by Kaplan‐Meier analysis and Cox proportional hazards regression. Results: Of the 15,068 patients included in study 6,731 underwent initial cytoreductive nephrectomy and 8,337 received initial targeted therapy. Six months after initial cytoreductive nephrectomy 48.0% of patients received targeted therapy, of whom 15.3% died after initial cytoreductive nephrectomy prior to targeted therapy. Six months after initial targeted therapy 4.7% of patients underwent cytoreductive nephrectomy, of whom 44.9% died after initial targeted therapy prior to cytoreductive nephrectomy. Initial cytoreductive nephrectomy (OR 2.02, 95% CI 1.69–2.43, p <0.001) and cytoreductive nephrectomy after initial targeted therapy (HR 2.6, 95% CI 1.69–4.01, p <0.001) were more likely to be performed at academic vs community institutions. On inverse probability of treatment weighting analysis initial cytoreductive nephrectomy was associated with improved overall survival compared to initial targeted therapy (median 16.5 vs 9.2 months, HR 0.61, 95% CI 0.59–0.64, p <0.001). Conclusions: Given the greater likelihood of receiving multimodal therapy and the associated overall survival benefit, these data support cytoreductive nephrectomy as the initial approach to metastatic renal cell carcinoma in appropriate surgical candidates. Continued efforts are warranted to establish the optimal multimodal approach in these patients.

Independent Validation of the American Joint Committee on Cancer 8th Edition Prostate Cancer Staging Classification

Purpose: We sought to independently validate the AJCC (American Joint Committee on Cancer) 8th edition prostate cancer staging classification, which includes the elimination of pT2 subcategories and the reclassification of patients with prostate specific antigen 20 ng/ml or greater and Gleason Grade Group 5 as stage groups III‐A and III‐C, respectively. Materials and Methods: We identified 13,839 men who underwent radical prostatectomy at Mayo Clinic between 1987 and 2011 from our institutional registry. Outcomes included biochemical recurrence‐free, metastasis‐free and cancer specific survival. Kaplan‐Meier analyses and Cox regression models with the c‐index were used. Results: Median followup was 10.5 years (IQR 7.1–15.3). Among patients with pT2 prostate cancer the subclassification demonstrated limited discrimination for biochemical recurrence‐free, metastasis‐free and cancer specific survival (c‐index 0.531, 0.545 and 0.525, respectively). At the same time patients with 7th edition stage group II prostate cancer and prostate specific antigen 20 ng/ml or greater had significantly worse 15‐year biochemical recurrence‐free survival (42.2% vs 58.8%), metastasis‐free survival (78.2% vs 88.8%) and cancer specific survival (88.0% vs 94.4%, all p <0.001) than patients with 7th edition stage group II prostate cancer and prostate specific antigen less than 20 ng/ml. However, patients with 7th edition stage group II prostate cancer and prostate specific antigen 20 ng/ml or greater had significantly better 15‐year biochemical recurrence‐free survival (42.2% vs 31.3%, p = 0.007), metastasis‐free survival (78.2% vs 68.0%, p <0.001) and cancer specific survival (88.0% vs 83.4%, p = 0.01) than patients with 7th edition stage group III. Also, patients with 7th edition stage group II prostate cancer and Gleason Grade Group 5 had significantly worse 15‐year biochemical recurrence‐free survival (37.1% vs 57.9%, p <0.001), metastasis‐free survival (63.8% vs 88.5%, p <0.001) and cancer specific survival (73.0% vs 94.3%, p <0.001) than patients with 7th edition stage group II prostate cancer and Gleason Grade Group 1‐4 as well as worse 15‐year cancer specific survival (73.0% vs 83.4%, p = 0.005) than patients with 7th edition stage group III prostate cancer. Conclusions: Our data support the changes in the new AJCC classification.

Renal functional outcomes in patients undergoing percutaneous cryoablation or partial nephrectomy for a solitary renal mass

To compare renal functional changes after percutaneous cryoablation (PCA) or partial nephrectomy (PN).

The Probability of Aggressive Versus Indolent Histology Based on Renal Tumor Size: Implications for Surveillance and Treatment

BACKGROUND While the probability of malignant versus benign histology based on renal tumor size has been described, this alone does not sufficiently inform decision-making in the modern era since indolent malignant tumors can be managed with active surveillance. OBJECTIVE To characterize the probability of aggressive versus indolent histology based on radiographic tumor size. DESIGN, SETTING, AND PARTICIPANTS We evaluated patients who underwent radical or partial nephrectomy at Mayo Clinic for a pT1-2, pNx/0, M0 solid renal tumor between 1990 and 2010. Pathology was reviewed by one genitourinary pathologist. High-grade clear-cell renal cell carcinoma (RCC), high-grade papillary RCC, collecting duct RCC, translocation-associated RCC, hereditary leiomyomatosis RCC, unclassified RCC, and malignant non-RCC tumors were all considered aggressive, as well as any tumors demonstrating coagulative necrosis (except low-grade papillary RCC) or sarcomatoid differentiation. The remaining benign and malignant tumors were considered indolent. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cancer-specific survival (CSS) was estimated using the Kaplan-Meier method. Logistic regression models were used to estimate the probability of malignant and aggressive histology based on tumor size. Sex-stratified analyses were also performed. RESULTS AND LIMITATIONS Of the 2650 patients included, there were 1860 patients with indolent tumors (300 benign; 1560 malignant) and 790 with aggressive tumors. The 10-yr CSS was 96% for indolent malignant tumors and 81% for aggressive malignant tumors. The predicted percentages of any malignant histology as well as aggressive histology increased with tumor size. Specifically, 2cm, 3cm, and 4cm tumors have an estimated 84%, 87%, and 88% likelihood of malignancy, respectively, and an 18%, 24%, and 29% likelihood of aggressive histology, respectively. For any given tumor size, men had a greater chance of aggressive histology than women. Potential limitations of this observational surgical cohort include selection bias. CONCLUSIONS We present tumor size-based estimates of the probability of aggressive histology for renal masses. This information should be useful for initial patient counseling and management. PATIENT SUMMARY Active surveillance is an option for kidney masses, even if they are malignant. Beyond knowing whether the mass is benign or cancer, it is important to know whether or not it is an aggressive tumor. This study presents tumor size-specific and sex-specific estimates of the probability of cancer overall and aggressive cancer among patients with a kidney mass in order to aid with initial decision-making.

Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma

CONTEXT The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial. OBJECTIVE To assess if CN versus no CN is associated with improved overall survival (OS) in patients with mRCC treated in the TT era and beyond, characterize the morbidity of CN, identify prognostic and predictive factors, and evaluate outcomes following treatment sequencing. EVIDENCE ACQUISITION Medline, EMBASE, and Cochrane databases were searched from inception to June 4, 2018 for English-language clinical trials, cohort studies, and case-control studies evaluating patients with mRCC who underwent and those who did not undergo CN. The primary outcome was OS. Risk of bias was evaluated using the Cochrane Collaborative tools. EVIDENCE SYNTHESIS We identified 63 reports on 56 studies. Risk of bias was considered moderate or serious for 50 studies. CN was associated with improved OS among patients with mRCC in 10 nonrandomized studies, while one randomized trial (CARMENA) found that OS with sunitinib alone was noninferior to that with CN followed by sunitinib. The risk of perioperative mortality and Clavien ≥3 complications ranged from 0% to 10.4% and from 3% to 29.4%, respectively, with no meaningful differences between upfront CN or CN after presurgical systemic therapy (ST). Notably, 12.9-30.4% of patients did not receive ST after CN. Factors most consistently prognostic of decreased OS were progression on presurgical ST, high C-reactive protein, high neutrophil-lymphocyte ratio, poor International Metastatic renal cell carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) risk classification, sarcomatoid dedifferentiation, and poor performance status. At the same time, good performance status and good/intermediate IMDC/MSKCC risk classification were most consistently predictive of OS benefit with CN. In a randomized trial investigating the sequence of CN and ST (SURTIME), an OS trend was observed with CN after a period of ST in patients without progression compared with upfront CN. However, the study was underpowered and results are exploratory. CONCLUSIONS Currently, ST should be prioritized in the management of patients with de novo mRCC who require medical therapy. CN maintains a role in patients with limited metastatic burden amenable to surveillance or metastasectomy, and may potentially be considered in patients with favorable response after initial ST or for symptoms palliation. PATIENT SUMMARY In the contemporary era, receiving systemic therapy is the priority in metastatic kidney cancer. Nephrectomy still has a role in patients with limited burden of metastases, well-selected patients based on established prognostic and predictive factors, and patients with a favorable response after initial systemic therapy.