Steven E. Canfield

EAU Guidelines on Renal Cell Carcinoma: 2014 Update.

CONTEXT The European Association of Urology Guideline Panel for Renal Cell Carcinoma (RCC) has prepared evidence-based guidelines and recommendations for RCC management. OBJECTIVES To provide an update of the 2010 RCC guideline based on a standardised methodology that is robust, transparent, reproducible, and reliable. EVIDENCE ACQUISITION For the 2014 update, the panel prioritised the following topics: percutaneous biopsy of renal masses, treatment of localised RCC (including surgical and nonsurgical management), lymph node dissection, management of venous thrombus, systemic therapy, and local treatment of metastases, for which evidence synthesis was undertaken based on systematic reviews adhering to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Relevant databases (Medline, Cochrane Library, trial registries, conference proceedings) were searched (January 2000 to November 2013) including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm. Risk of bias (RoB) assessment and qualitative and quantitative synthesis of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. EVIDENCE SYNTHESIS All chapters of the RCC guideline were updated. For the various systematic reviews, the search identified a total of 10,862 articles. A total of 151 studies reporting on 78,792 patients were eligible for inclusion; where applicable, data from RCTs were included and meta-analyses were performed. For RCTs, there was low RoB across studies; however, clinical and methodological heterogeneity prevented data pooling for most studies. The majority of studies included were retrospective with matched or unmatched cohorts based on single or multi-institutional data or national registries. The exception was for systemic treatment of metastatic RCC, in which several RCTs have been performed, resulting in recommendations based on higher levels of evidence. CONCLUSIONS The 2014 guideline has been updated by a multidisciplinary panel using the highest methodological standards, and provides the best and most reliable contemporary evidence base for RCC management. PATIENT SUMMARY The European Association of Urology Guideline Panel for Renal Cell Carcinoma has thoroughly evaluated available research data on kidney cancer to establish international standards for the care of kidney cancer patients.

Systematic review of oncological outcomes following surgical management of localised renal cancer.

CONTEXT Renal cell carcinoma (RCC) accounts for 2-3% of adult malignancies. There remain uncertainties over the oncological outcomes for the surgical management of localised RCC. OBJECTIVE Systematically review relevant literature comparing oncological outcomes of surgical management of localised RCC (T1-2N0M0). EVIDENCE ACQUISITION Relevant databases including Medline, Embase, and the Cochrane Library were searched up to October 2010, and an updated scoping search was performed up to January 2012. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The main outcomes were overall survival, cancer-specific survival, recurrence, and metastases. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). EVIDENCE SYNTHESIS A total of 4580 abstracts and 389 full-text articles were assessed. Thirty-four studies met the inclusion criteria (6 RCTs and 28 NRSs). Meta-analyses were planned but were deemed inappropriate due to data heterogeneity. There were high risks of bias and low-quality evidence across the evidence base. Open radical nephrectomy and open partial nephrectomy showed similar cancer-specific and overall survival, but when both open and laparoscopic approaches are considered together, the evidence showed improved survival for partial nephrectomy for tumours ≤4cm. The overall evidence suggests either equivalent or better survival with partial nephrectomy. Laparoscopic radical nephrectomy offered equivalent survival to open radical nephrectomy, and all laparoscopic approaches achieved equivalent survival. Open and laparoscopic partial nephrectomy achieved equivalent survival. The issue of ipsilateral adrenalectomy or complete lymph node dissection with radical nephrectomy or partial nephrectomy remains unresolved. CONCLUSIONS The evidence base suggests localised RCCs are best managed by nephron-sparing surgery where technically feasible. However, the current evidence base has significant limitations due to studies of low methodological quality marked by high risks of bias.

Systematic Review and Meta-analysis of Diagnostic Accuracy of Percutaneous Renal Tumour Biopsy

CONTEXT The role of percutaneous renal tumour biopsy (RTB) remains controversial due to uncertainties regarding its diagnostic accuracy and safety. OBJECTIVE We performed a systematic review and meta-analysis to determine the safety and accuracy of percutaneous RTB for the diagnosis of malignancy, histologic tumour subtype, and grade. EVIDENCE ACQUISITION Medline, Embase, and Cochrane Library were searched for studies providing data on diagnostic accuracy and complications of percutaneous core biopsy (CB) or fine-needle aspiration (FNA) of renal tumours. A meta-analysis was performed to obtain pooled estimates of sensitivity and specificity for diagnosis of malignancy. The Cohen kappa coefficient (κ) was estimated for the analysis of histotype/grade concordance between diagnosis on RTB and surgical specimen. Risk of bias assessment was performed (QUADAS-2). EVIDENCE SYNTHESIS A total of 57 studies recruiting 5228 patients were included. The overall median diagnostic rate of RTB was 92%. The sensitivity and specificity of diagnostic CBs and FNAs were 99.1% and 99.7%, and 93.2% and 89.8%, respectively. A good (κ = 0.683) and a fair (κ = 0.34) agreement were observed between histologic subtype and Fuhrman grade on RTB and surgical specimen, respectively. A very low rate of Clavien ≥ 2 complications was reported. Study limitations included selection and differential-verification bias. CONCLUSIONS RTB is safe and has a high diagnostic yield in experienced centres. Both CB and FNA have good accuracy for the diagnosis of malignancy and histologic subtype, with better performance for CB. The accuracy for Fuhrman grade is fair. Overall, the quality of the evidence was moderate. Prospective cohort studies recruiting consecutive patients and using homogeneous reference standards are required. PATIENT SUMMARY We systematically reviewed the literature to assess the safety and diagnostic performance of renal tumour biopsy (RTB). The results suggest that RTB has good accuracy in diagnosing renal cancer and its subtypes, and it appears to be safe. However, the quality of evidence was moderate, and better quality studies are required to provide a more definitive answer.

Systematic Review of Perioperative and Quality-of-life Outcomes Following Surgical Management of Localised Renal Cancer

CONTEXT For the treatment of localised renal cell carcinoma (RCC), uncertainties remain over the perioperative and quality-of-life (QoL) outcomes for the many different surgical techniques and approaches of nephrectomy. Controversy also remains on whether newer minimally invasive nephron-sparing interventions offer better QoL and perioperative outcomes, and whether adrenalectomy and lymphadenectomy should be performed simultaneously with nephrectomy. These non-oncological outcomes are important because they may have a considerable impact on localised RCC treatment decision making. OBJECTIVE To review systematically all the relevant published literature comparing perioperative and QoL outcomes of surgical management of localised RCC (T1-2N0M0). EVIDENCE ACQUISITION Relevant databases including Medline, Embase, and the Cochrane Library were searched up to January 2012. Randomised controlled trials (RCTs) or quasi-randomised controlled trials, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The outcome measures were QoL, analgesic requirement, length of hospital stay, time to normal activity level, surgical morbidity and complications, ischaemia time, renal function, blood loss, length of operation, need for blood transfusion, and perioperative mortality. The Cochrane risk of bias tool was used to assess RCTs, and an extended version was used to assess nonrandomised studies (NRSs). The quality of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation. EVIDENCE SYNTHESIS A total of 4580 abstracts and 380 full-text articles were assessed, and 29 studies met the inclusion criteria (7 RCTs and 22 NRSs). There were high risks of bias and low-quality evidence for studies meeting the inclusion criteria. There is good evidence indicating that partial nephrectomy results in better preservation of renal function and better QoL outcomes than radical nephrectomy regardless of technique or approach. Regarding radical nephrectomy, the laparoscopic approach has better perioperative outcomes than the open approach, and there is no evidence of a difference between the transperitoneal and retroperitoneal approaches. Alternatives to standard laparoscopic radical nephrectomy (LRN) such as hand-assisted, robot-assisted, or single-port techniques appear to have similar perioperative outcomes. There is no good evidence to suggest that minimally invasive procedures such as cryotherapy or radiofrequency ablation have superior perioperative or QoL outcomes to nephrectomy. Regarding concomitant lymphadenectomy during nephrectomy, there were low event rates for complications, and no definitive difference was observed. There was no evidence to base statements about concomitant ipsilateral adrenalectomy during nephrectomy. CONCLUSIONS Partial nephrectomy results in significantly better preservation of renal function over radical nephrectomy. For tumours where partial nephrectomy is not technically feasible, there is no evidence that alternative procedures or techniques are better than LRN in terms of perioperative or QoL outcomes. In making treatment decisions, perioperative and QoL outcomes should be considered in conjunction with oncological outcomes. Overall, there was a paucity of data regarding QoL outcomes, and when reported, both QoL and perioperative outcomes were inconsistently defined, measured, or reported. The current evidence base has major limitations due to studies of low methodological quality marked by high risks of bias.

Renal cell carcinoma with nodal metastases in the absence of distant metastatic disease (clinical stage TxN1-2M0): the impact of aggressive surgical resection on patient outcome.

PURPOSE Nodal disease in the setting of metastatic renal cell carcinoma is associated with poor prognosis. However, to our knowledge the biology of nodal metastases in the absence of metastatic disease is unknown. We reviewed our experience with treating this subset of patients with aggressive surgical resection. MATERIALS AND METHODS A total of 2,643 patients underwent nephrectomy at our institution between 1993 and 2003, including 40 with positive lymph nodes but no systemic metastases. All 40 patients underwent nephrectomy with extended retroperitoneal lymphadenectomy and they are the subjects of this study. Pathological characteristics and clinical outcomes were assessed. RESULTS Median patient age was 58 years and 62% of the patients were male. Median tumor size was 11 cm. Local stage was T1 in 3% of cases, T2 in 17%, T3a in 30%, T3b in 47% and T4 in 3%. Perinephric fat invasion was present in 77% of patients and positive margins were identified in 17%. Nodal status was N1 in 30% of patients and N2 in 70%, including 10 with masses of matted nodes. Histology was conventional in 63% of cases and papillary in 17%. The remaining 20% of patients had sarcomatoid dedifferentiation. Excluding the 10 patients with matted nodes the median number of nodes harvested per patient was 7 with a median of 2 that were positive. Extranodal extension was present in 70% of cases, while in 70% disease recurred at a median of 4.9 months. Median actuarial disease specific survival was 20.3 months. At a median followup of 17.7 months 30% of patients had no evidence of disease, 8% had disease and 62% had died. On multivariate analysis more than 1 positive node was predictive of decreased recurrence-free survival (HR 2.83, 95% CI 1.06 to 7.61, p = 0.039) and overall survival (HR 9.33, 95% CI 1.85 to 47.09, p = 0.007). CONCLUSIONS Nodal metastasis with renal cell carcinoma is an independent predictor of prognosis in patients with M0 disease. Even in the absence of distant metastatic disease patients with positive nodes should be targeted for aggressive surgical resection, followed by clinical trials of adjuvant therapy to improve the outcome.

Local treatments for metastases of renal cell carcinoma: a systematic review

Local treatment of metastases such as metastasectomy or radiotherapy remains controversial in the treatment of metastatic renal cell carcinoma. To investigate the benefits and harms of various local treatments, we did a systematic review of all types of comparative studies on local treatment of metastases from renal cell carcinoma in any organ. Interventions included metastasectomy, radiotherapy modalities, and no local treatment. The results suggest that patients treated with complete metastasectomy have better survival and symptom control (including pain relief in bone metastases) than those treated with either incomplete or no metastasectomy. Nevertheless, the available evidence was marred by high risks of bias and confounding across all studies. Although the findings presented here should be interpreted with caution, they and the identified gaps in knowledge should provide guidance for clinicians and researchers, and directions for further research.

Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy

The European Association of Urology renal cancer guidelines have been updated to recommend nivolumab and cabozantinib over the previous standard of care in patients who have failed one or more lines of VEGF targeted therapy.

The impact of minimally invasive surgeries for the treatment of symptomatic benign prostatic hyperplasia on male sexual function: a systematic review.

A systematic review of randomized controlled trials and cohort studies was conducted to evaluate data for the effects of minimally invasive procedures for treatment of symptomatic benign prostatic hyperplasia (BPH) on male sexual function. The studies searched were trials that enrolled men with symptomatic BPH who were treated with laser surgeries, transurethral microwave therapy (TUMT), transurethral needle ablation of the prostate (TUNA), transurethral ethanol ablation of the prostate (TEAP) and high-intensity frequency ultrasound (HIFU), in comparison with traditional transurethral resection of the prostate (TURP) or sham operations. A total of 72 studies were identified, of which 33 met the inclusion criteria. Of the 33 studies, 21 were concerned with laser surgeries, six with TUMT, four with TUNA and two with TEAP containing information regarding male sexual function. No study is available regarding the effect of HIFU for BPH on male sexual function. Our analysis shows that minimally invasive surgeries for BPH have comparable effects to those of TURP on male erectile function. Collectively, less than 15.4% or 15.2% of patients will have either decrease or increase, respectively, of erectile function after laser procedures, TUMT and TUNA. As observed with TURP, a high incidence of ejaculatory dysfunction (EjD) is common after treatment of BPH with holmium, potassium-titanyl-phosphate and thulium laser therapies (> 33.6%). TUMT, TUNA and neodymium:yttrium aluminum garnet visual laser ablation or interstitial laser coagulation for BPH has less incidence of EjD, but these procedures are considered less effective for BPH treatment when compared with TURP.

Assessment of the Methodological Quality of Systematic Reviews Published in the Urological Literature From 1998 to 2008

PURPOSE Well done systematic reviews provide the highest quality evidence for clinical questions of therapeutic effectiveness. We assessed the methodological quality of systematic reviews in the urological literature. MATERIALS AND METHODS We systematically investigated all systematic reviews published in 4 major urological journals from 1998 to 2008. Studies were identified using a predefined search strategy in PubMed and confirmed by a hand search of journal tables of contents. A validated 11-point instrument to assess the methodological quality of systematic reviews was applied by 2 independent reviewers after a pilot testing phase. Disagreements were discussed and resolved by consensus. RESULTS The systematic literature search identified 217 individual systematic reviews, of which 57 ultimately met study eligibility criteria. Ten (17.5%), 20 (35.1%) and 27 (47.4%) systematic reviews were published in 1998 to 2001, 2002 to 2005 and 2006 to 2008, respectively. Using the measurement tool to assess systematic reviews the mean +/- SD score was 4.8 +/- 2.0 points. Fewer than half of all systematic reviews performed a systematic literature search that included at least 2 databases (49.1%) or unpublished studies (31.6%), or provided a list of included and excluded studies (45.6%). Of the systematic reviews 63.2% assessed and documented the methodological quality of included studies. Systematic reviews with The Cochrane Collaboration authorship affiliation had a higher mean score than those with no such reported affiliation (6.5 +/- 1.2 vs 4.4 +/- 1.9 points, p <0.001). CONCLUSIONS Results suggest that an increasing number of systematic reviews are published in the urological literature. However, many systematic reviews fail to meet established methodological standards, raising concerns about validity. Increased efforts are indicated to promote quality standards for performing systematic reviews among the authors and readership of the urological literature.

Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells

Bortezomib (PS-341, Velcade) is a peptide boronate inhibitor of the 20S proteasome that is currently being combined with taxanes in several clinical trials in patients with prostate cancer. Here, we report that bortezomib inhibited docetaxel-induced M-phase arrest and apoptosis in androgen-dependent LNCaP-Pro5 cells. Direct analysis of kinase activity in immune complex kinase assays revealed that docetaxel activated cyclin-dependent kinase (CDK) 1 (CDC2) and that bortezomib blocked this activation. The effects of bortezomib were associated with accumulation of p21 and mimicked by chemical CDK inhibitors or by transfecting cells with a small interfering RNA construct specific for CDK1. Transient transfection with p21 also inhibited docetaxel-induced apoptosis; conversely, p21 silencing reversed the antagonistic effects of bortezomib on docetaxel-induced apoptosis. Together, our data show that bortezomib interferes with docetaxel-induced apoptosis via a p21-dependent mechanism that is associated with CDK1 inhibition. These observations may have important implications for the ongoing bortezomib-docetaxel combination trials as well as trials using bortezomib and other cell cycle–sensitive agents. [Mol Cancer Ther 2006;5(8):2043–50]