-
1.
Efficacy and Treatment Burden of Intravitreal Aflibercept Versus Intravitreal Ranibizumab Treat-and-Extend Regimens at 2 Years: Network Meta-Analysis Incorporating Individual Patient Data Meta-Regression and Matching-Adjusted Indirect Comparison.
Ohji, M, Lanzetta, P, Korobelnik, JF, Wojciechowski, P, Taieb, V, Deschaseaux, C, Janer, D, Tuckmantel, C
Advances in therapy. 2020;(5):2184-2198
-
-
Free full text
-
Abstract
PURPOSE To compare visual outcomes and treatment burden between intravitreally administered aflibercept (IVT-AFL) and ranibizumab (RBZ) treat-and-extend (T&E) regimens in patients with wet age-related macular degeneration (wAMD) at 2 years. METHODS A systematic literature review was carried out in Medline, EMBASE, and CENTRAL in October 2018. Matching-adjusted indirect comparison (MAIC) and/or individual patient data meta-regression was used to connect ALTAIR (assessing IVT-AFL T&E) with other studies, adjusting for between-trial differences in baseline visual acuity and age or baseline visual acuity, age, and polypoidal choroidal vasculopathy (PCV) status. Sensitivity analyses were conducted to test the robustness of the results, including direct MAIC between IVT-AFL T&E (ALTAIR) and RBZ T&E (CANTREAT and TREX-AMD trials). RESULTS Six randomized controlled trials (RCTs) (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX) were included in the analysis. IVT-AFL T&E was assessed in one study, ALTAIR (n = 255), while RBZ T&E was assessed in two trials (n = 327). At 2 years, the median difference (95% credibility interval) between IVT-AFL T&E and RBZ T&E regarding the numbers of Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained was not significant (M1: - 2.29 [- 8.10, 3.58]; M2: - 0.55 [- 6.34, 5.29]). IVT-AFL T&E was associated with significantly fewer injections than RBZ-T&E (M1: - 6.12 [- 7.60, - 4.65]; M2: - 5.93 [- 7.42, - 4.45]). Results of the sensitivity analyses were consistent with the main scenarios. CONCLUSION Patients with wAMD receiving an IVT-AFL T&E regimen achieved and maintained improvement in visual acuity with fewer injections over 2 years compared with RBZ T&E. IVT-AFL T&E may therefore serve as the optimal therapy for wAMD, as it was associated with clinical efficacy and minimized treatment burden.
-
2.
Efficacy of ranibizumab for the treatment of diabetic retinopathy: A protocol for systematic review of randomized controlled trial.
Ren, YB, Su, XJ, Qi, YX, Luan, HQ, Sun, Q
Medicine. 2019;(17):e15409
-
-
Free full text
-
Abstract
BACKGROUND Previous clinical trials have reported that ranibizumab can be used to treat diabetic retinopathy (DR) effectively. However, no study has been conducted to evaluate its efficacy for patients with DR systematically. Thus, this study will specifically and systematically assess the efficacy and safety of ranibizumab for DR. METHODS Cochrane Library, EMBASE, PUBMED, Web of Science, Google Scholar, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, and Chinese Biomedical Literature Database will be searched from inceptions to the March 20, 2019 for studies related to the topic. This study will only consider publicly released randomized controlled trials for evaluating the effect and safety of ranibizumab for DR. No language restrictions will be imposed for all databases search. Methodological quality of each included trial will be assessed by Cochrane risk of bias tool. Statistical analysis will be performed by Stata 12.0 software. RESULTS This study will provide recent summary evidence of ranibizumab for DR. Primary outcomes include percentages with retinopathy improvement, and cumulative probabilities for retinopathy worsening. Secondary outcome consist of visual function, best-corrected visual acuities, central subfield thickness, total macular volume, peripheral visual field loss, retinal neovascularization, and adverse events. CONCLUSION The findings of this study may provide theoretical basis for clinical practice refer and may benefit more patients with DR.
-
3.
Antivascular endothelial growth factor agents pretreatment before vitrectomy for complicated proliferative diabetic retinopathy: a meta-analysis of randomised controlled trials.
Zhao, XY, Xia, S, Chen, YX
The British journal of ophthalmology. 2018;(8):1077-1085
-
-
Free full text
-
Abstract
BACKGROUND/AIMS: To evaluate the efficacy of antivascular endothelial growth factor (anti-VEGF) agents pretreatment before vitrectomy for patients with complicated proliferative diabetic retinopathy (PDR). METHODS The PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched up to June 2017 to identify related studies. The Peferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. The StataSE V.12.0 software was used to analyse the relevant data. The weighted mean difference, relative risk and their 95% CIs were used to assess the strength of the association. RESULTS 14 randomised controlled trials involving 613 patients were assessed, the anti-VEGF pretreatment group included 289 patients and the control group included 324 patients. Our analysis indicated that anti-VEGF pretreatment before vitrectomy for complicated PDR could facilitate much easier surgery regarding less intraoperative bleeding, less endodiathermy, shorter duration of surgery, less iatrogenic retinal breaks, less frequency of using silicone oil and relaxing retinotomy (P<0.05). Additionally, anti-VEGF pretreatment could also achieve better postoperative best-corrected visual acuity, less early recurrent vitreous haemorrhage (VH) and quicker absorption of recurrent VH (P<0.05). However, the incidence of late recurrent VH, recurrent retinal detachment or related secondary surgery could not be reduced (P>0.05). CONCLUSION The pretreatment of anti-VEGF agents before vitrectomy for patients with complicated PDR might facilitate much easier surgery and better visual rehabilitation, reduce the rate of early recurrent VH and accelerate its absorption. Moreover, future better-designed studies with larger sample sizes are required to further evaluate the efficacy of different anti-VEGF agents and reach a firmer conclusion.
-
4.
Aflibercept for neovascular age-related macular degeneration.
Sarwar, S, Clearfield, E, Soliman, MK, Sadiq, MA, Baldwin, AJ, Hanout, M, Agarwal, A, Sepah, YJ, Do, DV, Nguyen, QD
The Cochrane database of systematic reviews. 2016;(2):CD011346
-
-
Free full text
-
Abstract
BACKGROUND Central vision loss caused by age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Neovascular AMD is characterized by choroidal neovascularization (CNV). Growth of new blood vessels in patients with neovascular AMD is driven by a complex process that involves a signal protein called vascular endothelial growth factor A (VEGF-A). Anti-VEGF drugs that block this protein include ranibizumab, bevacizumab, and aflibercept. OBJECTIVES To assess and compare the effectiveness and safety of intravitreal injections of aflibercept versus ranibizumab, bevacizumab, or sham for treatment of patients with neovascular AMD. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (Issue 11, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched December 4, 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on November 30, 2015. SELECTION CRITERIA We included randomized controlled trials (RCTs) in which aflibercept monotherapy was compared with ranibizumab, bevacizumab, or sham for participants with neovascular AMD who were treatment-naive. DATA COLLECTION AND ANALYSIS We used standard methodological procedures of The Cochrane Collaboration for screening, data abstraction, and study assessment. Two review authors independently screened records, abstracted data, and assessed risk of bias of included studies; we resolved discrepancies by discussion or with the help of a third review author when needed. MAIN RESULTS We included two RCTs (total of 2457 participants, 2457 eyes). Trial participants had neovascular AMD with active subfoveal choroidal neovascular lesions. Both trials followed the same protocol and compared aflibercept at various doses versus ranibizumab, but they were carried out in different countries. One trial enrolled participants from the United States and Canada, and the second trial was conducted at 172 sites in Europe, Asia Pacific, Latin America, and the Middle East. The overall quality of the evidence was high, and included trials were at low risk for most bias domains assessed; however, both trials were funded by the manufacturers of aflibercept. For the purposes of analysis, we combined aflibercept groups regardless of dosing and analyzed them as a single group.Visual acuity outcomes were similar between aflibercept and ranibizumab groups; at one year, participants in the aflibercept groups showed mean change in best-corrected visual acuity (BCVA) from baseline similar to that of participants in the ranibizumab groups (mean difference (MD) -0.15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, 95% confidence interval (95% CI) -1.47 to 1.17; high-quality evidence). At two years, the mean change in BCVA from baseline was 7.2 ETDRS letters for aflibercept groups versus 7.9 for ranibizumab groups. Sufficient data were not available for calculation of confidence intervals.The proportion of participants who gained 15 or more letters of BCVA by one year of follow-up was approximately 32% for both aflibercept and ranibizumab (RR 0.97, 95% CI 0.85 to 1.11; high-quality evidence), and by two years of follow-up was approximately 31% (RR 0.98, 95% CI 0.85 to 1.12; high-quality evidence). Similar small proportions of participants in the aflibercept and ranibizumab groups lost 15 or more letters of BCVA at one year (RR 0.89, 95% CI 0.61 to 1.30; high-quality evidence); this outcome was not reported for two-year follow-up. Data were not reported on the proportion of participants with BCVA worse than 20/200 at one- or two-year follow-up.Participants treated with aflibercept or ranibizumab showed similar improvement in morphological outcomes, as assessed from images (central retinal thickness and CNV size). At one year, the proportion of eyes that achieved dry retina was similar between aflibercept and ranibizumab groups (absence of cystic intraretinal fluid and subretinal fluid on optical coherence tomography (OCT); RR 1.06, 95% CI 0.98 to 1.14; high-quality evidence). In addition, investigators reported no difference in reduction of CNV area between aflibercept- and ranibizumab-treated eyes at one year (MD -0.24 mm(2), 95% CI -0.78 to 0.29; high-quality evidence). Data were not reported for the proportion of eyes with absence of leakage on fluorescein angiography at one- or two-year follow-up.Overall, occurrence of serious systemic adverse events was similar and comparable in aflibercept- and ranibizumab-treated groups at one year (RR 0.99, 95% CI 0.79 to 1.25). Risk of any serious ocular adverse event was lower in the aflibercept group than in the ranibizumab group, but the risk estimate is imprecise (RR 0.62, 95% CI 0.36 to 1.07). As the result of imprecision, we graded the quality of evidence for all adverse events as moderate. AUTHORS' CONCLUSIONS Results of this review document the comparative effectiveness of aflibercept versus ranibizumab for visual acuity and morphological outcomes in eyes with neovascular AMD. Current available information on adverse effects of each medication suggests that the safety profile of aflibercept is comparable with that of ranibizumab; however, the number of participants who experienced adverse events was small, leading to imprecise estimates of absolute and relative effect sizes. The eight-week dosing regimen of aflibercept represents reduced treatment requirements in comparison with monthly dosing regimens and thus has the potential to reduce treatment burden and risks associated with frequent injections.
-
5.
METAANALYSIS OF REAL-WORLD OUTCOMES OF INTRAVITREAL RANIBIZUMAB FOR THE TREATMENT OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.
Kim, LN, Mehta, H, Barthelmes, D, Nguyen, V, Gillies, MC
Retina (Philadelphia, Pa.). 2016;(8):1418-31
-
-
Free full text
-
Abstract
PURPOSE To report the efficacy and safety of intravitreal ranibizumab for neovascular age-related macular degeneration (nAMD) in real-world practice. METHODS Metaanalysis of ∼26,360 patients from 42 real-world observational studies reporting outcomes of intravitreal ranibizumab for nAMD published between 2007 and 2015. Baseline demographics, lesion type, and visual acuity (VA) were recorded. The weighted mean was calculated for change in VA and frequency of injections and visits during year 1, year 2, and ≥3 years. Local and systemic adverse events were recorded. RESULTS The mean change in VA for patients receiving a treat-and-extend regimen was +8.8 (95% confidence interval [CI]: 5.8 to 11.8), +6.7 (95% CI: 3.2 to 10.1), and +5.4 (95% CI: -4.1 to 14.9) Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 1 year (n = 1,539), 2 years (n = 2,521), and ≥3 years (n = 1,298), in comparison with +3.5 (95% CI: 2.0 to 5.0), +1.3 (95% CI: -1.6 to 4.2), and -1.9 (95% CI: -9.8 to 6.0) ETDRS letters for pro re nata at 1 year (n = 20,247), 2 years (n = 14,408), and ≥3 years (n = 11,714). Treat-and-extend patients received on average more injections (6.9 vs. 4.7) but had fewer visits (7.6 vs. 9.2) in the first year. Baseline characteristics were similar between the regimens. The reported rate of endophthalmitis was 17 of 66,176 intravitreal injections (0.026%). CONCLUSION Intravitreal ranibizumab for nAMD prevents severe visual loss in real-world practice. Patients can achieve visual gain from baseline, but the extent to which these are maintained in the long term may depend on the frequency of injections.
-
6.
A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer.
Heinemann, V, Rivera, F, O'Neil, BH, Stintzing, S, Koukakis, R, Terwey, JH, Douillard, JY
European journal of cancer (Oxford, England : 1990). 2016;:11-20
Abstract
BACKGROUND Head-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). METHODS A PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point. RESULTS Three trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68-0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/'other' RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab. CONCLUSIONS This meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.
-
7.
Anti-vascular endothelial growth factor for diabetic macular oedema.
Virgili, G, Parravano, M, Menchini, F, Evans, JR
The Cochrane database of systematic reviews. 2014;(10):CD007419
-
-
Free full text
-
Abstract
BACKGROUND Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO, or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities is used to try to improve vision in people with DMO. OBJECTIVES To investigate the effects in preserving and improving vision and acceptability, including the safety, compliance with therapy and quality of life, of antiangiogenic therapy with anti-VEGF modalities for the treatment of DMO. SEARCH METHODS We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment or no treatment in people with DMO. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by The Cochrane Collaboration. The risk ratios (RR) for visual loss and visual gain of three or more lines of logMAR visual acuity were estimated at one year of follow-up (plus or minus six months) after treatment initiation. MAIN RESULTS Eighteen studies provided data on four comparisons of interest in this review. Participants in the trials had central DMO and moderate vision loss.Compared with grid laser photocoagulation, people treated with antiangiogenic therapy were more likely to gain 3 or more lines of vision at one year (RR 3.6, 95% confidence interval (CI) 2.7 to 4.8, 10 studies, 1333 cases, high quality evidence) and less likely to lose 3 or more lines of vision (RR 0.11, 95% CI 0.05 to 0.24, 7 studies, 1086 cases, high quality evidence). In meta-analyses, no significant subgroup difference was demonstrated between bevacizumab, ranibizumab and aflibercept for the two primary outcomes, but there was little power to detect a difference. The quality of the evidence was judged to be high, because the effect was large, precisely measured and did not vary across studies, although some studies were at high or unclear risk of bias for one or more domains. Regarding absolute benefit, we estimated that 8 out of 100 participants with DMO may gain 3 or more lines of visual acuity using photocoagulation whereas 28 would do so with antiangiogenic therapy, meaning that 100 participants need to be treated with antiangiogenic therapy to allow 20 more people (95% CI 13 to 29) to markedly improve their vision after one year. People treated with anti-VEGF on average had 1.6 lines better vision (95% CI 1.4 to 1.8) after one year compared to laser photocoagulation (9 studies, 1292 cases, high quality evidence). To achieve this result, seven to nine injections were delivered in the first year and three or four in the second, in larger studies adopting either as needed regimens with monthly monitoring or fixed regimens.In other analyses antiangiogenic therapy was more effective than sham (3 studies on 497 analysed participants, high quality evidence) and ranibizumab associated with laser was more effective than laser alone (4 studies on 919 participants, high quality evidence).Ocular severe adverse events, such as endophthalmitis, were rare in the included studies. Meta-analyses conducted for all antiangiogenic drugs compared with either sham or photocoagulation did not show a significant difference regarding serious systemic adverse events (15 studies, 441 events in 2985 participants, RR 0.98, 95% CI 0.83 to 1.17), arterial thromboembolic events (14 studies, 129 events in 3034 participants, RR 0.89, 95% CI 0.63 to 1.25) and overall mortality (63 events in 3562 participants, RR 0.88, 95% CI 0.52 to 1.47). We judged the quality of the evidence on adverse effects as moderate due to partial reporting of safety data and the exclusion of participants with previous cardiovascular events in some studies. AUTHORS' CONCLUSIONS There is high quality evidence that antiangiogenic drugs provide a benefit compared to current therapeutic options for DMO, that is grid laser photocoagulation, in clinical trial populations at one or two years. Future research should investigate differences between drugs, effectiveness under real-world monitoring and treatment conditions, and safety in high-risk populations, particularly regarding cardiovascular risk.
-
8.
Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies.
Duffy, A, Wilkerson, J, Greten, TF
Hepatology (Baltimore, Md.). 2013;(3):1068-77
-
-
Free full text
-
Abstract
UNLABELLED The presence of cirrhosis increases the potential risk of hemorrhage for patients with hepatocellular carcinoma (HCC). We evaluated the relative risk for hemorrhage in patients with HCC treated with antiangiogenic agents. We performed a systematic review and meta-analysis of antiangiogenic studies in HCC from 1995 to 2011. For nonrandomized studies we compared bleeding risk with other HCC single-arm studies that did not include an antiangiogenic agent. To separate disease-specific factors we also performed a comparison analysis with renal cell cancer (RCC)) studies that evaluated sorafenib. Sorafenib was associated with increased bleeding risk compared to control for all grade bleeding events (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.04, 3.0) but not grade 3-5 events in both HCC and RCC (OR 1.46; 95% CI 0.9, 2.36; P=0.45). When comparing the risk of bleeding in single-arm phase 2 studies evaluating antiangiogenic agents, this risk for all events (OR 4.34; 95% CI 2.16, 8.73) was increased compared to control. CONCLUSION This analysis of both randomized and nonrandomized studies evaluating an antiangiogenic agent in HCC showed that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower-grade events and similar in magnitude to the risk encountered in RCC.
-
9.
A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy.
Zhao, LQ, Zhu, H, Zhao, PQ, Hu, YQ
The British journal of ophthalmology. 2011;(9):1216-22
-
-
Free full text
-
Abstract
AIMS: To examine possible benefits of intravitreal bevacizumab (IVB) pretreatment in vitrectomy for severe diabetic retinopathy. METHODS A comprehensive literature search was performed using the Cochrane Collaboration methodology to identify randomised controlled trials and comparative studies of vitrectomy with or without IVB pretreatment for severe or complicated diabetic retinopathy. Meta-analyses were performed for intraoperative (including intraoperative bleeding, endodiathermy, iatrogenic retinal tears and mean surgical time) and postoperative outcome parameters (including best-corrected visual acuity, recurrent vitreous haemorrhage, reabsorption time of blood and other complications). RESULTS Six randomised controlled trials and one comparative study were identified and used for comparing vitrectomy alone (142 eyes, control group) with vitrectomy with IVB pretreatment (139 eyes). The intraoperative findings showed that the incidence of intraoperative bleeding and frequency of endodiathermy were statistically significantly less in the IVB pretreatment group (p<0.01) than in the vitrectomy alone group. The IVB pretreatment group took significantly less surgical time than the control group (p=0.003). Postoperative results indicated that reabsorption time of blood was significantly shorter (p=0.04), incidence of recurrent VH was almost significantly less (p=0.05), and final best-corrected visual acuity was significantly better (p=0.003) in the IVB group than in the control group. Other complications, including final retinal detachment, and reoperation, were statistically insignificant. CONCLUSION IVB pretreatment in vitrectomy can achieve excellent clinical outcomes for severe diabetic retinopathy. It potentially facilitates surgeons' manoeuvres and reduces intra- and postoperative complications.
-
10.
Metastatic renal cell cancer treatments: an indirect comparison meta-analysis.
Mills, EJ, Rachlis, B, O'Regan, C, Thabane, L, Perri, D
BMC cancer. 2009;:34
Abstract
BACKGROUND Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field. METHODS We conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis. RESULTS We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-alpha as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38-0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60-0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52-1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58-1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57-0.85). CONCLUSION New interventions for mRCC offer a favourable PFS for mRCC compared to interferon-alpha and placebo.