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

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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.

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Most cited references 37

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Author and article information

Contributors

Shun-Long Ou: URI : https://loop.frontiersin.org/people/1834164

Jing Luo: URI : https://loop.frontiersin.org/people/1557518

Hua Wei: URI : https://loop.frontiersin.org/people/916505

Xiao-Li Qin: URI : https://loop.frontiersin.org/people/1845450

Su-Ya Du: URI : https://loop.frontiersin.org/people/1889257

Song Wang: URI : https://loop.frontiersin.org/people/1889258

Qian Jiang: URI : https://loop.frontiersin.org/people/812406

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 13 July 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 953761

Affiliations

[1] ¹ Department of Pharmacy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Centre, School of Medicine, University of Electronic Science and Technology of China , Chengdu, China

[2] ² School of Medicine, University of Electronic Science and Technology of China , Chengdu, China

[3] ³ Department of Pharmacy, Dujiangyan People’s Hospital, Dujiangyan Medical Center , Dujiangyan, China

[4] ⁴ Department of Pharmacy, Chengdu Third People’s Hospital , Chengdu, China

Author notes

Edited by: Maurizio Chiriva-Internati, University of Texas MD Anderson Cancer Center, United States

Reviewed by: Devis Benfaremo, Marche Polytechnic University, Italy; Insoon Chang, UCLA Health System, United States

*Correspondence: Qian Jiang, jiangqian_3805.student@ 123456sina.com

This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2022.953761

PMC ID: 9326177

PubMed ID: 35911744

SO-VID: f9720c10-6e53-4207-a192-ef9e0736df09

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 26 May 2022

Date accepted : 17 June 2022

Page count

Figures: 3, Tables: 1, Equations: 0, References: 37, Pages: 9, Words: 4479

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

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Abstract

Background

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Results

Conclusions

Systematic Review Registration

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Cancer Immunotherapy

Most cited references 37

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.

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Cited by 9

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