Targeted therapy for metastatic renal cell carcinoma.

BACKGROUND: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Bipolar versus monopolar transurethral resection of the prostate for lower urinary tract symptoms secondary to benign prostatic obstruction.

BACKGROUND: Transurethral resection of the prostate (TURP) is a well-established surgical method for treatment of men with lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO). This has traditionally been provided as monopolar TURP (MTURP), but morbidity associated with MTURP has led to the introduction of other surgical techniques. In bipolar TURP (BTURP), energy is confined between electrodes at the site of the resectoscope, allowing the use of physiological irrigation medium. There remains uncertainty regarding differences between these surgical methods in terms of patient outcomes. OBJECTIVES: To compare the effects of bipolar and monopolar TURP. SEARCH METHODS: A comprehensive systematic electronic literature search was carried out up to 19 March 2019 via CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, PubMed, and WHO ICTRP. Handsearching of abstract proceedings of major urological conferences and of reference lists of included trials, systematic reviews, and health technology assessment reports was undertaken to identify other potentially eligible studies. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared monopolar and bipolar TURP in men (> 18 years) for management of LUTS secondary to BPO. DATA COLLECTION AND ANALYSIS: Two independent review authors screened the literature, extracted data, and assessed eligible RCTs for risk of bias. Statistical analyses were undertaken according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions. The quality of evidence (QoE) was rated according to the GRADE approach. MAIN RESULTS: A total of 59 RCTs with 8924 participants were included. The mean age of included participants ranged from 59.0 to 74.1 years. Mean prostate volume ranged from 39 mL to 82.6 mL. Primary outcomes BTURP probably results in little to no difference in urological symptoms, as measured by the International Prostate Symptom Score (IPSS) at 12 months on a scale of 0 to 35, with higher scores reflecting worse symptoms (mean difference (MD) -0.24, 95% confidence interval (CI) -0.39 to -0.09; participants = 2531; RCTs = 16; I² = 0%; moderate certainty of evidence (CoE), downgraded for study limitations), compared to MTURP. BTURP probably results in little to no difference in bother, as measured by health-related quality of life (HRQoL) score at 12 months on a scale of 0 to 6, with higher scores reflecting greater bother (MD -0.12, 95% CI -0.25 to 0.02; participants = 2004; RCTs = 11; I² = 53%; moderate CoE, downgraded for study limitations), compared to MTURP. BTURP probably reduces transurethral resection (TUR) syndrome events slightly (risk ratio (RR) 0.17, 95% CI 0.09 to 0.30; participants = 6745; RCTs = 44; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 20 fewer TUR syndrome events per 1000 participants (95% CI 22 fewer to 17 fewer). Secondary outcomes BTURP may carry a similar risk of urinary incontinence at 12 months (RR 0.20, 95% CI 0.01 to 4.06; participants = 751; RCTs = 4; I² = 0%; low CoE, downgraded for study limitations and imprecision), compared to MTURP. This corresponds to four fewer events of urinary incontinence per 1000 participants (95% CI five fewer to 16 more). BTURP probably slightly reduces blood transfusions (RR 0.42, 95% CI 0.30 to 0.59; participants = 5727; RCTs = 38; I² = 0%; moderate CoE, downgraded for study limitations), compared to MTURP. This corresponds to 28 fewer events of blood transfusion per 1000 participants (95% CI 34 fewer to 20 fewer). BTURP may result in similar rates of re-TURP (RR 1.02, 95% CI 0.44 to 2.40; participants = 652; RCTs = 6; I² = 0%; low CoE, downgraded for study limitations and imprecision). This corresponds to one more re-TURP per 1000 participants (95% CI 19 fewer to 48 more). Erectile function as measured by the International Index of Erectile Function score (IIEF-5) at 12 months on a scale from 5 to 25, with higher scores reflecting better erectile function, appears to be similar (MD 0.88, 95% CI -0.56 to 2.32; RCTs = 3; I² = 68%; moderate CoE, downgraded for study limitations) for the two approaches. AUTHORS' CONCLUSIONS: BTURP and MTURP probably improve urological symptoms, both to a similar degree. BTURP probably reduces both TUR syndrome and postoperative blood transfusion slightly compared to MTURP. The impact of both procedures on erectile function is probably similar. The moderate certainty of evidence available for the primary outcomes of this review suggests that there is no need for further RCTs comparing BTURP and MTURP.