Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour.

OBJECTIVE: Unbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments. DESIGN: Literature review, pooling analysis and correlation analysis. DATA SOURCES: PubMed, from 1 January 2010 to 30 June 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments. RESULTS: Of 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29). CONCLUSIONS: No systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.

White light, autofluorescence and narrow-band imaging bronchoscopy for diagnosing airway pre-cancerous and early cancer lesions: a systematic review and meta-analysis.

BACKGROUND: We aimed to summarize the diagnostic accuracy of white light bronchoscopy (WLB) and advanced techniques for airway pre-cancerous lesions and early cancer, such as autofluorescence bronchoscopy (AFB), AFB combined with WLB (AFB + WLB) and narrow-band imaging (NBI) bronchoscopy. METHODS: We searched for eligible studies in seven electronic databases from their date of inception to Mar 20, 2015. In eligible studies, detected lesions should be confirmed by histopathology. We extracted and calculated the 2×2 data based on the pathological criteria of lung tumor, including high-grade lesions from moderate dysplasia (MOD) to invasive carcinoma (INV). Random-effect model was used to pool sensitivity, specificity, diagnostic odds ratio (DOR) and the area under the receiver-operating characteristic curve (AUC). RESULTS: In 53 eligible studies (39 WLB, 39 AFB, 17 AFB + WLB, 6 NBI), diagnostic performance for high-grade lesions was analyzed based on twelve studies (10 WLB, 7 AFB, 7 AFB + WLB, 1 NBI), involving with totally 2,880 patients and 8,830 biopsy specimens. The sensitivity, specificity, DOR and AUC of WLB were 51% (95% CI, 34-68%), 86% (95% CI, 73-84%), 6 (95% CI, 3-13) and 77% (95% CI, 73-81%). Those of AFB and AFB + WLB were 93% (95% CI, 77-98%) and 86% (95% CI, 75-97%), 52% (95% CI, 37-67%) and 71% (95% CI, 56-87%), 15 (95% CI, 4-57) and 16 (95% CI, 6-41), and 76% (95% CI, 72-79%) and 82% (95% CI, 78-85%), respectively. NBI presented 100% sensitivity and 43% specificity. CONCLUSIONS: With higher sensitivity, advanced bronchoscopy could be valuable to avoid missed diagnosis. Combining strategy of AFB and WLB may contribute preferable diagnosis rather than their alone use for high-grade lesions. Studies of NBI warrants further investigation for precancerous lesions.