Izak Faiena

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials

Purpose We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. Materials and Methods We searched PubMed® for English language articles published through January 2017 using the keywords “renal cell carcinoma,” “kidney cancer,” “immunotherapy,” “targeted therapy” and “adjuvant therapy.” ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. Results Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon‐&agr; and high dose interleukin‐2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence‐free survival benefit of sorafenib or sunitinib over placebo, while S‐TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence‐free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. Conclusions Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S‐TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.

Role of surgical approach on lymph node dissection yield and survival in patients with upper tract urothelial carcinoma

OBJECTIVES With increasing utilization of robot-assisted surgery in urologic oncology, robotic nephroureterectomy (RNU) is becoming the surgical modality of choice for patients with upper tract urothelial carcinoma (UTUC). The role of surgical approach on lymph node dissection (LND) and lymph node (LN) yield is unclear, and potential therapeutic effects are unknown. Here we analyze the effects of surgical approach on LN yield, performance of LND, and overall survival (OS). METHODS AND MATERIALS Patients with UTUC who underwent nephroureterectomy from 2010 to 2013 were identified in the National Cancer Database. Outcomes of interest included rate of LND, LN yield, and OS. Logistic regression analyses were used to predict performance of LND. Negative binomial regression was used to derive incidence rate ratios for LN yield. Cox proportional hazards models were used to quantify survival outcomes. RESULTS A total of 3,116 patients met inclusion criteria. LND was performed in 41% (314/762) of RNU, 27% (380/1385) of LNU cases, and 35% (340/969) of ONU (P<0.001). Compared with an ONU, patients who underwent a LNU had significantly lower odds of receiving a LND (OR = 0.70, 95% CI: 0.55-0.87) and had fewer LNs removed (IRR = 0.69, 95% CI: 0.60-0.80), while RNU trended toward increased LN yield (IRR = 1.14, 95% CI: 0.98-1.33). In a Cox proportional hazards model, increasing LN yield was associated with improved OS in patients with pN0 disease (HR = 0.97 per 1 unit increase in LN yield, 95% CI: 0.95-0.99). CONCLUSIONS Compared with an ONU, RNU does not compromise performance of a LND and may be associated with improved LN yield. LNU is associated with the lowest rates of LND and LN yield. Increasing LN yield is associated with improved OS in patients with pN0 disease. Despite differential rates of LND and LN yield, surgical approach did not independently affect OS.

Overall survival in patients with residual disease after radical cystectomy and neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NAC) has been shown to improve survival in patients with urothelial carcinoma (UC). However, there are a subset of patients who do not respond or progress despite systemic treatment.MethodsData from the National Cancer Database on patients who underwent a radical cystectomy (RC) with or without NAC from 2006 to 2013 were abstracted. Covariates were balanced using inverse probability weighting methods. The primary outcome of overall survival in patients with residual disease by stage was evaluated using 90-day conditional landmark analysis and Cox proportional hazards modeling. Secondary outcome of predictors of residual disease was evaluated using multivariable logistic regression analysis.ResultsA total of 20,128 patients met our inclusion criteria; 16,058 patients underwent RC only (80%) and 4070 underwent RC with NAC (20%). Patients who received NAC were younger and healthier, treated at an academic center, and presented with higher stage. NAC was associated with improved overall survival amongst patients with cT3-4aN0 (HR 0.84 95% CI 0.73–0.97; p = 0.02) and cN+ (HR 0.70, 95% CI 0.58–0.86; p = 0.001). Predictors of no residual disease were NAC (OR 0.17, 95% CI 0.14–0.21; p < 0.001) and treatment at an academic facility (OR 0.47, 95% CI 0.37–0.60; p < 0.001). Patients with cT3-4a or cN+ had increased odds of having residual UC (OR 2.01, 95% CI 1.53–2.64; p < 0.001, and OR 2.14, 95% CI 1.43–3.21; p < 0.001, respectively) compared with cT2.ConclusionIn patients with residual UC, NAC is associated with a significant survival benefit in higher stage disease only. Furthermore, those treated with NAC or at an academic center were less likely to have residual disease. Given the toxicity of NAC, more prudent patient selection for NAC is warranted and requires further study.

Radical prostatectomy then and now: Surgical overtreatment of prostate cancer is declining from 2009 to 2016 at a tertiary referral center

BACKGROUND In the era of increasing scrutiny of delivery of quality care, efforts to decrease surgical overtreatment of insignificant prostate cancer (iCaP) continue. OBJECTIVE To quantify the incidence of surgical overtreatment over time among a contemporary series of men diagnosed with CaP. METHODS We retrospectively reviewed the medical records and pathologic specimens for men with CaP who underwent radical prostatectomy between January 2009 and December 2016 at a tertiary referral center. Overtreatment, defined as presence of iCaP in radical prostatectomy specimens, was the primary endpoint. iCaP was defined as a tumor of Gleason score no more than 6 and a tumor diameter ≤10mm (volume <0.5 cc). Independent predictors of iCaP were determined using a multivariable model. RESULTS A total of 1,283 men were eligible for analysis. Overtreatment was found in 86 (6.7%) patients. The frequency of overtreatment significantly decreased from 15% (24/165) in 2009 to 3% (4/134) of patients in 2016 (P < 0.001). In the multivariable analysis, prostate-specific antigen density ≥0.15 vs. <0.15 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.15-0.64, P < 0.01), biopsy Gleason score 3+4 vs. 3+3 (OR 0.15, 95% CI 0.08-0.29, P < 0.01), African American vs. White ethnicity (OR 0.13, 95% CI 0.02-0.96, P = 0.045), and year of surgery (OR 0.88, 95% CI 0.77-0.99, P = 0.03) remained significant predictors of iCaP at surgery. Over the years of study, the odds of overtreatment decreased by 12% annually (OR 0.88, 95 CI 0.77-0.99, P = 0.03). At the same time, the pathological evidence of advanced disease at surgery (≥T3a with/without lymph node involvement) remained unchanged. COMMENT Surgical overtreatment of CaP has declined to a rate of approximately 3% at this tertiary referral center; further decline is likely. The decline probably has a multifactorial explanation: decreased rate of overdiagnosis, better patient selection for surgery, or change in the referral pattern.

PI-RADSv2 Category on 3 Tesla Multiparametric Prostate MRI Predicts Oncologic Outcomes in Gleason 3+4 Prostate Cancer on Biopsy

Purpose: Three Tesla multiparametric magnetic resonance imaging with PI-RADS™ (Prostate Imaging Reporting and Data System) version 2 scoring is a common tool in prostate cancer diagnosis which informs the likelihood of a cancerous lesion. We investigated whether PI-RADS version 2 also predicts adverse pathology features mainly in patients with biopsy Gleason score 3 + 4 disease. Materials and Methods: We reviewed the records of 326 consecutive men with a preoperative template and/or magnetic resonance imaging-ultrasound fusion biopsy Gleason score of 6-7 from a prospectively maintained database of men who underwent robotic radical prostatectomy. The primary analysis was done in patients with biopsy Gleason score 3 + 4 to assess the primary outcome of adverse pathology features on univariate and multivariate logistic regression. The secondary outcome was biochemical recurrence-free survival using the Kaplan-Meier method. Similar analysis was done in patients with a biopsy Gleason score of 6-7. Results: Of men with Gleason score 3 + 4 findings 27%, 15%, 36% and 23% showed a PI-RADS version 2 score of 0-2, 3, 4 and 5, respectively. On univariate analysis PI-RADS version 2 category 5 predicted adverse pathology features vs categories 0-2 (OR 10.7, 95% CI 3.7–31, p ⩽0.001). On multivariate analysis the PI-RADS version 2 category 5 was associated with adverse pathology when adjusting for preoperative magnetic resonance imaging targeted biopsy (OR 11.4, 95% CI 3.7–35, p ⩽0.0001). In men with a targeted biopsy Gleason score of 3 + 4 prostate cancer PI-RADS version 2 category 5 was associated with adverse pathology (OR 14.7, 95% CI 1.5–146.9, p = 0.02). Of men with biopsy Gleason score 3 + 4 disease 92% and 58% with a PI-RADS version 2 score of 4 and 5, respectively, had 2-year biochemical recurrence-free survival. Conclusions: A PI-RADS version 2 category 5 lesion in patients with a biopsy Gleason score 3 + 4 lesion predicted adverse pathology features and biochemical recurrence-free survival. These findings suggest that preoperative 3 Tesla multiparametric magnetic resonance imaging may serve as a prognostic marker of treatment outcomes independently of biopsy Gleason score or biopsy type.PURPOSE Three Tesla multiparametric magnetic resonance imaging with PI-RADS™ (Prostate Imaging Reporting and Data System) version 2 scoring is a common tool in prostate cancer diagnosis which informs the likelihood of a cancerous lesion. We investigated whether PI-RADS version 2 also predicts adverse pathology features mainly in patients with biopsy Gleason score 3 + 4 disease. MATERIALS AND METHODS We reviewed the records of 326 consecutive men with a preoperative template and/or magnetic resonance imaging-ultrasound fusion biopsy Gleason score of 6-7 from a prospectively maintained database of men who underwent robotic radical prostatectomy. The primary analysis was done in patients with biopsy Gleason score 3 + 4 to assess the primary outcome of adverse pathology features on univariate and multivariate logistic regression. The secondary outcome was biochemical recurrence-free survival using the Kaplan-Meier method. Similar analysis was done in patients with a biopsy Gleason score of 6-7. RESULTS Of men with Gleason score 3 + 4 findings 27%, 15%, 36% and 23% showed a PI-RADS version 2 score of 0-2, 3, 4 and 5, respectively. On univariate analysis PI-RADS version 2 category 5 predicted adverse pathology features vs categories 0-2 (OR 10.7, 95% CI 3.7-31, p ≤0.001). On multivariate analysis the PI-RADS version 2 category 5 was associated with adverse pathology when adjusting for preoperative magnetic resonance imaging targeted biopsy (OR 11.4, 95% CI 3.7-35, p ≤0.0001). In men with a targeted biopsy Gleason score of 3 + 4 prostate cancer PI-RADS version 2 category 5 was associated with adverse pathology (OR 14.7, 95% CI 1.5-146.9, p = 0.02). Of men with biopsy Gleason score 3 + 4 disease 92% and 58% with a PI-RADS version 2 score of 4 and 5, respectively, had 2-year biochemical recurrence-free survival. CONCLUSIONS A PI-RADS version 2 category 5 lesion in patients with a biopsy Gleason score 3 + 4 lesion predicted adverse pathology features and biochemical recurrence-free survival. These findings suggest that preoperative 3 Tesla multiparametric magnetic resonance imaging may serve as a prognostic marker of treatment outcomes independently of biopsy Gleason score or biopsy type.

Trends in usage of cytoreductive partial nephrectomy and effect on overall survival in patients with metastatic renal cell carcinoma

PURPOSE Cytoreductive radical nephrectomy (cRN) improves survival in select patients with metastatic renal cell carcinoma (mRCC). It is unclear, however, whether cytoreductive partial nephrectomy (cPN) compromises oncologic efficacy. We evaluated trends in utilization of cPN and compared overall survival (OS) in patients who underwent cRN or cPN for mRCC. MATERIALS AND METHODS We queried the National Cancer Database from 2006 to 2013 and identified patients who underwent cPN and cRN for mRCC. We analyzed rates of cPN over time. Logistic regression identified predictors of cPN. We matched patients based on propensity score for treatment. We used matched Kaplan-Meier survival analyses to compare OS, stratified by tumor size. We used multivariable Cox proportional hazards models to determine the effect of cPN and cRN on OS. RESULTS A total of 10,144 patients met inclusion criteria, with 9,764 (96.2%) undergoing cRN and 381 (3.8%) undergoing cPN. Rates of cPN increased over time from 1.8% to 4.3% over the study period. Treatment at an academic/research facility, papillary and chromophobe histology, and more recent year of treatment were associated with increased odds of cPN. In a matched survival analysis, cPN was associated with improved OS compared with cRN (log rank, P = 0.001). This effect was limited to primary tumors<4cm. In a propensity-score adjusted multivariable Cox model, cPN was associated with improved OS (hazard ratio = 0.81; 95% CI: 0.71-0.93; P = 0.002). CONCLUSIONS The use of cPN in patients with mRCC is increasing. cPN is associated with improved OS in patients with mRCC, although this effect is limited to patients with primary tumors<4cm.