Citations

709 Background: Several immunotherapy (IMT) combinations either as an IMT doublet or IMT in combination with TKIs are now available for first-line therapy of metastatic renal cell carcinoma (mRCC). In the absence of head-to-head clinical trials, we performed an indirect comparison of frontline treatment options to provide clinical guidance. Methods: Medline, Embase and Cochrane Library were searched to identify relevant trials. Hazard ratios (HR) and confidence interval (CI) for primary outcome of progression-free survival (PFS) and secondary outcome of overall survival (OS) were abstracted. Network meta-analysis was performed using a multivariate, consistency model, random-effects meta-regression. Data on Grade 3 or higher AEs was abstracted and meta-analyzed. Pre-specified subgroup analyses were performed based on risk categories (high risk vs low and intermediate vs), history of prior nephrectomy, PD-L1 positivity, age and sex. Risk for bias(RoB) was assessed using the Cochrane Collaboration’s tool. Results: Nine studies were included for PFS analysis, and 6 studies for OS analysis. Avelumab-axitinib (AA) (HR 0.69, 0.48-0.96), and Pembrolizumab-Axitinib (PA) (HR 0.89, 0.50-0.96) significantly improved PFS, while there was no significant PFS benefit with atezolizumab-bevacizumab (AB) (HR 0.83, 0.62-1.13) and nivolumab-ipilimumab (NI) (HR 0.85, 0.63-1.15) as compared to Sunitinib. PA (HR 0.53, 0.38-0.75) and NI (HR 0.63, 0.44-0.90) significantly improved OS, while AB (HR 0.93, 0.75-1.12) showed no significant OS benefit as compared to Sunitinib. NI and AB had significantly fewer grade ≥3 AE than sunitinib. No significant interaction was found by risk group, age, sex or prior nephrectomy. Significant interaction was found by PD-L1 expression(p<0.001), with significant PFS improvement in PD-L1 positive (HR 0.62, 0.53-0.73) but not in PD-L1 negative patients (HR 0.92, 0.81-1.05). Overall, RoB was low amongst included studies. Conclusions: AA improved PFS, NI improved OS, whereas PA improve both PFS and OS as compared to sunitinib monotherapy. However, no IMT combination was superior to other combinations. Cost effectiveness analysis will be reported separately.

708 Background: Patients with high risk non-metastatic renal cell cancer (RCC) are at significant risk of recurrence following nephrectomy. Previously, we reported no benefit of adjuvant tyrosine kinase inhibitor (TKI) treatment in high-risk patients. Since our most recent publication, efficacy results from the multicenter double-blind SORCE trial have become available. We updated our meta-analysis to include these additional data and performed a cumulative meta-analysis. Methods: PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched to identify relevant RCTs. A generic variance-weighted random effects model was used to derive estimates for efficacy. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. The primary outcome was disease-free survival (DFS), defined as the interval between randomization and the first recurrence, the occurrence of metastasis or a secondary cancer, or death due to any cause. Statistical analysis was performed using Comprehensive Meta-Analysis version 3 (Biostat). Results: Five phase 3 trials were identified, enrolling 6531 patients. Two trials compared sunitinib with placebo (S-TRAC and ECOG-ACRIN), two compared sorafenib with placebo (ECOG-ACRIN and SORCE) and one trial each compared pazopanib (PROTECT) and axitinib (ATLAS) vs placebo. Cumulative evidence suggests that adjuvant therapy with TKIs showed no significant improvement in (DFS) hazard ratio [HR] of 0.93 (95% CI, 0.85-1.02), compared to placebo. There was no significant heterogeneity among included trials ( I2= 52%, P= .41). Overall, the trials were at low risk of bias. Conclusions: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve DFS as compared to placebo. Improved patient selection using better prognostic biomarkers or scoring systems may identify subsets of patients who can benefit from adjuvant treatments. Toxicity estimates will be updated as data from SORCE trial publication becomes available.

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.

Abstract Objective The objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the pharmacological management of osteoporosis in postmenopausal women using romosozumab. Conclusions We reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.

Abstract Objectives While anti-tumor necrosis factor alpha (anti-TNFa) therapies for Crohn disease (CD) were initially introduced in 1998 for biologic therapies are often introduced after a minimum of 6 years after diagnosis. The benefit of anti-TNFa early in the course of CD is still controversial, with some studies showing better outcomes but others not. To determine whether earlier introduction of anti-TNFa therapy improves efficacy in clinical trials or clinical series, we aimed to perform a meta-analysis comparing early vs late anti-TNFa use in the management of CD. Methods A comprehensive search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus was conducted from each database’s inception to November 3, 2019. We included comparative studies of early vs late use of anti-TNFa therapy in adult patients with CD. Results Eleven studies were included in the analysis, with a total of 2501 patients. Meta-analysis demonstrated that the early use of anti-TNFa was associated with a statistically significant decrease in the need for surgery (relative risk [RR] = 0.43; 95% confidence interval [CI], 0.26–0.69; I2 = 68%) and disease progression (RR = 0.51; 95% CI, 0.35–0.75; I2 = 61%). Early use also showed an increase in early remission (RR = 1.94; 95% CI, 1.54–2.46; I2 = 0%) and clinical response. There was no statistically significant difference in achieving late remission (RR = 1.39; 95% CI, 0.94–2.05; I2 = 65%) or mucosal healing (RR = 1.10; 95% CI, 0.63–1.91; I2 = 0%). Conclusion This systematic review suggests that using anti-TNFa earlier in the treatment of CD (within 3 years) may improve clinical outcomes compared to late administration in terms of achieving early clinical remission, clinical response, disease progression, and the need for surgery.

Background Smoking adversely impacts pain-related outcomes of spinal cord stimulation (SCS). However, the proportion of SCS patients at risk of worse outcomes is limited by an incomplete knowledge of smoking prevalence in this population. Thus, the primary aim of this systematic review is to determine the prevalence of smoking in adults with chronic pain treated with SCS. Methods A comprehensive search of databases from 1 January 1980 to 3 January 2019 was conducted. Eligible study designs included (1) randomized trials; (2) prospective and retrospective cohort studies; and (3) cross-sectional studies. The risk of bias was assessed using a tool specifically developed for prevalence studies. A total of 1619 records were screened, 19 studies met inclusion criteria, and the total number of participants was 10 838. Results Thirteen studies had low or moderate risk of bias, and six had a high risk of bias. All 19 studies reported smoking status and the pooled prevalence was 38% (95% CI 30% to 47%). The pooled prevalence in 6 studies of peripheral vascular diseases was 56% (95% CI 42% to 69%), the pooled prevalence of smoking in 11 studies of lumbar spine diagnoses was 28% (95% CI 20% to 36%) and the pooled prevalence in 2 studies of refractory angina was 44% (95% CI 31% to 58%). Conclusions The estimated prevalence of smoking in SCS patients is 2.5 times greater than the general population. Future research should focus on development, testing and deployment of tailored smoking cessation treatments for SCS patients.

Introduction Physical activity can prevent a wide range of diseases, including highly prevalent conditions such as heart disease, diabetes and associated cardiometabolic disorders. Numerous guidelines for the prescription of physical activity and exercise to promote general health and prevent disease are released each year, but the quality of these guidelines is currently unknown. This systematic review and critical appraisal of physical activity and exercise guidelines aims to summarise the current status and quality of these guidelines to provide suggestions to improve the development of future guidelines in this area. Methods and analysis We will conduct a systematic review of guidelines in Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews and Scopus databases published from database 2000 through 23 October 2019, written in English for the use of physical activity and exercise for the prevention of cardiometabolic disease and related risk factors in otherwise healthy individuals. We will also search the grey literature for additional eligible documents. We will use the Appraisal of Guidelines for Research and Evaluation II tool to assess the quality of eligible recommendations from all included guidelines, as well as perform exploratory analyses on guideline development variables. Ethics and dissemination As a protocol for the review and critical appraisal of published documents, no potential ethical considerations are discussed. The protocol will guide the development of the review, which will be disseminated to relevant journals for publication. PROSPERO registration number CRD42019126364

Objective To investigate the effect of therapies on radiographic progression in patients with axial spondyloarthritis (SpA). Methods A comprehensive database search for studies assessing radiographic progression in axial SpA (particular treatment versus no treatment of interest) was performed. Study‐specific standardized mean differences in treatment outcomes at 2 and ≥4 years were estimated and combined using random‐effects models. Results Twenty‐four studies in patients with axial SpA were identified, of which 18 involved tumor necrosis factor inhibitors ( TNF i), 8 involved nonsteroidal antiinflammatory drugs ( NSAID s), and 1 involved secukinumab. Spinal radiographic progression, as measured by the modified Stoke Ankylosing Spondylitis Spine Score ( mSASSS ), was not significantly different between TNF i‐treated and biologics‐naive patients at 2 years ( mSASSS difference −0.73 [95% confidence interval (95% CI ) −1.52, 0.12], I 2 = 28%) and ≥4 years ( mSASSS difference −2.03 [95% CI −4.63, 0.72], I 2 = 63%). Sensitivity analyses restricted to studies with a low risk of bias showed a significant difference in spinal radiographic progression between TNF i‐treated and biologics‐naive patients at ≥4 years ( mSASSS difference −2.17 [95% CI −4.19, −0.15]). No significant difference in spinal radiographic progression was observed between NSAID ‐treated and control patients ( mSASSS difference −0.30 [95% CI −2.62, 1.31], I 2 = 71%) or between secukinumab‐treated and biologics‐naive patients ( mSASSS difference −0.34 [95% CI −0.85, 0.17]). With regard to treatment differences in patients with nonradiographic axial SpA or in patients with radiographic progression measured using the sacroiliac joint score, an insufficient number of studies were available for analysis. Conclusion Although no significant protective effect of TNF i treatment on spinal radiographic progression was seen over the course of 2 years or ≥4 years in patients with axial SpA, our analysis restricted to studies with a low risk of bias showed a protective effect of TNF i after ≥4 years. Therefore, long‐term TNF i exposure might confer beneficial effects on spinal radiographic progression in axial SpA. No difference in radiographic progression at 2 years was seen in either the NSAID or secukinumab treatment groups compared to their controls. Future studies should explore the effects of biologic treatment on radiographic progression, as well as the effects of long‐term biologics exposure, in patients with early axial SpA or those with nonradiographic axial SpA.