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Meta-Analysis
. 2020 Mar;69(3):343-354.
doi: 10.1007/s00262-019-02453-2. Epub 2019 Dec 21.

The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies

Brooke E Wilson  1   2 , Bertrand Routy  3   4 , Adnan Nagrial  5   6 , Venessa T Chin  7   8   9
Affiliations
Meta-Analysis

The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies

Brooke E Wilson et al. Cancer Immunol Immunother. 2020 Mar.

Abstract

Purpose: Pre-clinical and early clinical data suggests the microbiome plays an important role in oncogenesis and influences response to immune checkpoint blockade (ICB). The objective of this systematic review and meta-analysis was to determine whether antibiotics affect overall survival (OS) and progression free survival (PFS) in patients with solid malignancies treated with ICB.

Patients and methods: A systematic search of EMBASE, MEDLINE and conference proceedings was conducted for observational studies examining the effect of antibiotics on ICB. A random effects study-level meta-analysis was performed with pooling of the hazards ratio (HR) for OS and PFS. Meta-regression was used to determine the impact of the timing of antibiotic exposure on OS.

Results: 766 studies were identified, and 18 studies met the inclusion criteria. Of the 2889 patients included, 826 (28.6%) were exposed to antibiotics. The most common malignancies were lung (59%), renal cell carcinoma (RCC) or urothelial carcinoma (16.3%) and melanoma (18.7%). OS was prolonged in those without antibiotic exposure (pooled HR 1.92, 95% CI 1.37-2.68, p < 0.001). The effect of antibiotics on OS was greater in studies defining antibiotic exposure as 42 days prior to initiation of ICB (HR 3.43, 95% CI 2.29-5.14, p < 0.0001). PFS was also longer in patients who did not receive antibiotics (pooled HR 1.65, 95% CI 1.3-2.1, p < 0.0001).

Conclusion: In patients receiving ICB, OS and PFS are longer in patients who are not exposed to antibiotics. Antibiotic use in the 42 days before starting ICB appears to be most detrimental to outcome.

Keywords: Antibiotics; Cancer; Immune checkpoint blockade; Immunotherapy.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Search strategy
Fig. 2
Fig. 2
Definitions of antibiotic exposure by study relative to the initiation of immune checkpoint blockade at time 0. This figure demonstrates the various definitions of antibiotic exposure adopted in each study, relative to the initiation of ICB at time 0. Studies by Do [17], Kulkarni [15], Masini [18] and Hemadri [21] defined antibiotic exposure as any time during ICB, as illustrated with the arrow beyond 100 days
Fig. 3
Fig. 3
Pooled hazards ratio for overall survival among those exposed and unexposed to antibiotics stratified by antibiotic exposure definition. Group 1: cohorts defining antibiotic exposure as up to 42 days before initiation of ICB. Group 2: cohorts defining antibiotic exposure as 60 days before and 42 days after initiation of ICB. Group 3: cohorts defining antibiotic exposure as 60 days before and anytime during ICB
Fig. 4
Fig. 4
Pooled hazards ratio for progression free survival among those exposed and unexposed to antibiotics stratified by antibiotic exposure definition. Group 1: cohorts defining antibiotic exposure as 42 days before initiation of ICB. Group 2: cohorts defining antibiotic exposure as 60 days before and 42 days after initiation of ICB. Group 3: cohorts defining antibiotic exposure as 60 days before and anytime during ICB
See this image and copyright information in PMC

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