Dataset Information

Safety and Efficacy of Programmed Cell Death 1 and Programmed Death Ligand-1 Inhibitors in the Treatment of Cancer: An Overview of Systematic Reviews

ABSTRACT:

Background

An influx of systematic reviews (SRs) of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in cancer treatment with or without meta-analysis and with different methodological quality and inconsistent results have been published, confusing clinical decision making. The aim of this study was to comprehensively evaluate and summarize the current evidence of PD-(L)1 inhibitors in the treatment of cancer.

Methods

A comprehensive search of SRs, which included meta-analyses of PD-(L)1 inhibitors on cancer, was performed on eight databases with a cutoff date of 1 January 2022. Two authors independently identified SRs, extracted data, assessed the report quality according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, evaluated the methodological quality by the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2), and appraised the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE).

Results

A total of 172 SRs with meta-analysis met the inclusion criteria. The report quality of included SRs was quite good, with 128 (74.42%) SRs of high quality and 44 (25.58%) of moderate quality. The methodological quality was alarming, as only one (0.58%) SR had high quality, five (2.91%) SRs had low quality, and the other 166 (96.51%) SRs had critically low quality. For GRADE, 38 (3.77%) outcomes had high-quality evidence, 288 (28.57%) moderate, 545 (54.07%) low, and 137 (13.59%) critically low-quality evidence. Current evidence indicated that treatment with PD-(L)1 inhibitors were significantly effective in non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, malignant melanoma, renal cell carcinoma, and urothelial carcinoma, breast cancer, and head and neck squamous cell carcinoma with PD-L1 expression level≥1%, whereas the evidence in gastroesophageal and colorectal tumors is still controversial. Monotherapy with PD-(L)1 inhibitors was associated with a lower frequency of any grade and high-grade adverse events (AEs). The incidence of any grade and high-grade AEs caused by PD-(L)1 inhibitors in combination with other therapies was no lower than the controls. However, PD-(L)1 inhibitors were associated with a higher frequency of any grade and high-grade immune-related AEs.

Conclusions

PD-(L)1 inhibitors appeared to be effective and safe for cancer treatment, except for gastrointestinal tumors; however, the quality of the evidence is not convincing. Future studies should improve methodological quality and focus on the sequential trial analysis of subgroups and safety.

Systematic Review Registration

http://www.crd.york.ac.uk/prospero, identifier CRD42020194260.

SUBMITTER: Ou S

PROVIDER: S-EPMC9326177 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings.MethodsExtensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis.ResultsTen nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1-21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3-14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9-27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5-2.9 vs. 2.0-2.7 months and 7.9-18.2 vs. 15.9 months) and second-line chemotherapy (3.3-4.0 months and 7.4-8 months). Odds of achieving ORR was 0.10 (95% CI 0.03-0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19-0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible.ConclusionsPD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.

Project description:BACKGROUND:Qigong, as one of the essential elements of Traditional Chinese exercises, has been used to improve physical and psychological health and combat diseases in China for thousands of years. In recent years, the beneficial effects of Qigong on different medical conditions are becoming more accepted by both patients and health care providers. Although it is a common impression that Qigong and related therapies are generally safe procedures, but the current understanding of its adverse events is fragmented. Thus, we conducted this overview to synthesize comprehensively existing systematic reviews on adverse events associated with Qigong and related therapies, and our findings can be used to informing clinicians, Qigong practitioner, and patients alike on applying such treatments or interventions in clinical treatment and daily life training mindful manner, and provide a guideline for researchers in future. METHODS:A systematic review of reviews will be performed. A literature search strategy designed by a number of specialists in the fields of Traditional Chinese Medicine (TCM), sports medicine, health information, and Qigong training will be carried out in relevant English and Chinese electronic database. The date range of search will start from inception to the search date. Two reviewers will identify relevant studies, extract data information, and then assess the methodical quality by Assessment of Multiple Systematic Reviews (AMSTAR) tool. Any types of systematic review that summarized adverse effects related to Qigong and related therapies in human will be included. Any safety-related outcomes will be considered as the primary outcomes of this overview. Where objectives from 2 or more reviews overlap, we will assess the causes of any noted discrepancies between reviews. An overall summary of results will be performed using tabular and graphical approaches and will be supplemented by narrative description. RESULTS:This overview will identify any adverse events associated with nonstandardized Qigong and related therapies procedures based on current relevant literature evidence of safety for Qigong. CONCLUSION:Our overview will provide evidence to help synthesize the broad degree of information available on furthering the knowledge, safety, and application of Qigong. ETHICS AND DISSEMINATION:Formal ethical approval is not required, as this study is an overview based on the published systematic reviews. The result of this overview of systematic reviews will be published in a peer-reviewed journal or disseminated at national and international conferences. PROSPERO REGISTRATION NUMBER:PROSPERO CRD42018109409.

Project description:BackgroundInhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have represented a novel approach for the management of advanced non-small cell lung cancer (NSCLC). In this study, we aimed to estimate five anti-PD-1/L1 agents (nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) using network meta-analyses (NMAs) and the Bayesian method to provide suggestions for advanced NSCLC treatments.MethodsWe searched PubMed, Web of Science, Embase, and the Wiley Online Library for eligible studies published up to March 2020. Both pairwise analyses and NMAs were conducted with clinical outcomes, including overall survival (OS), progression-free survival (PFS), objective response rate, and the incidences of adverse events. Results were presented in several patient populations according to treatment lines and PD-L1 status.ResultsNineteen randomized clinical trials (RCTs) involving 11,456 patients were included in our study. PD-1/L1 inhibitors showed significant benefits over chemotherapies in OS regardless of tumor PD-L1 status [first-line settings: OS =0.85, 95% CI (0.77, 0.94), I2=37%; second- or further-line settings: OS =0.77, 95% CI (0.71, 0.84), I2=37%]. The combined regimen of pembrolizumab and chemotherapy stood out to be the most effective and safest for patients in the first-line settings. Pembrolizumab monotherapy was showed to be the best especially for patients with PD-L1 ≥50%. In the subsequent-line settings, nivolumab ranked the best in improving the survival of patients, and durvalumab had the greatest effect in tumor shrinkage. Atezolizumab, followed by nivolumab, ranked the safest in reducing adverse events, whereas durvalumab was showed with the largest side effects among the five inhibitors.ConclusionsThe combination of pembrolizumab with chemotherapy is suitable for advanced NSCLC patients who have not received any systematic treatments before, and pembrolizumab monotherapy should also be considered, especially for patients with highly-expressed PD-L1 (≥50%). Nivolumab is the best option for patients with advanced NSCLC whose tumors have progressed following chemotherapies or combined modalities of treatments including chemotherapy. However, our results need to be further validated in future head-to-head clinical trials.