Antibiotic treatment and survival in non-small cell lung cancer patients receiving immunotherapy: a systematic review and meta-analysis

Introduction

Background

Lung cancer, diagnosed in around 230,000 Americans each year, is the leading cause of cancer death in males and the second leading cause in females (1). In non-small cell lung cancer (NSCLC), which includes adenocarcinoma, large cell carcinoma, and squamous cell carcinoma, immune checkpoint inhibitors (ICIs) offer a promising alternative to traditional chemotherapy. ICIs, which can target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), used alone or in combination, have been shown to improve survival in cases of advanced NSCLC when compared with chemotherapy alone (2,3).

Despite their general efficacy, the success of ICI treatment is variable and highly dependent on the individual, with research suggesting that the composition of the gut microbiome is an important contributor to response to treatment. Antibiotics reduce the diversity of gut microbiota and alter the abundance of specific microbial species, among other effects. They are frequently prescribed in NSCLC patients to reduce infection risk from various avenues, including immunosuppression resulting from treatment, lung obstruction, and indwelling catheters (4). Because the gut microbiome and immune system are intricately linked, it is likely that antibiotics’ modification of the gut microbiota affects the body’s innate immune system, and eventually ICI efficacy (5-7). A study by Liu and colleagues showed that lung cancer patients exhibit decreased intestinal microbial diversity even before antibiotic treatments are introduced, thus suggesting that lung cancer patients may be particularly vulnerable to the interaction between antibiotics and ICI (8). Studies on a variety of cancers have suggested a lower overall survival (OS) and progression-free survival (PFS) in patients treated with ICIs that have also been treated with antibiotics (9-12).

While an exact mechanism by which antibiotics modify the efficacy of ICI has not yet been identified, several meta-analyses have been conducted to explore the relationship between ICIs and antibiotics and the overall effect on clinical outcomes. Taken together, the results of published studies and meta-analyses point at antibiotics affecting ICI efficacy and clinical outcomes, but likely with differences and to varying degrees in different patients.

Rationale and knowledge gap

The published meta-analyses on NSCLC (Lurienne, Elkrief, Wilson, Jiang, and Crespin) have several shortcomings (13-17): the inclusion of unpublished work in the format of abstracts and posters, which could be responsible for the observed heterogeneity, the lack of a more comprehensive, standardized quality evaluation of the individual studies, and the outdated MEDLINE searches, even for the only meta-analysis published in 2023 (17). The current lack of meta-analysis of the adjusted survival estimates, to account for possible confounding, likewise remains an important limitation of the existing literature.

Objective

Here, we present an updated, comprehensive meta-analysis of peer-reviewed publications on NSCLC patients treated with antibiotics and ICI, stratified by studies with univariate vs. multivariate survival estimates. Findings of this systematic review and meta-analysis will fill in important research gaps regarding this emerging but highly clinically important topic. We present this article in accordance with the PRISMA reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-597/rc).

Methods

A systematic literature search was performed using MEDLINE (through PubMed) in order to retrieve all relevant studies published until June 30^th, 2023 which reported data on the associations between antibiotic use and lung cancer outcomes after treatment with anti-PD-(L)1-based treatments. In order to include the largest possible patient population, no filters for language or year of publication were applied. Keywords used were “immunotherapy” or “immune checkpoint inhibitor” or “PD-L1” or “PDL1” AND “antibiotics” AND “lung cancer”. In addition to the literature search, five previous meta-analyses (Crespin 2023, Jiang 2022, Lurienne 2020, Elkrief 2019, Wilson 2020) were manually reviewed to ensure that all published articles were included.

Study selection

Studies were included if they fulfilled the following criteria: (I) study included patients diagnosed with NSCLC and treated with anti-PD-(L)1 agents, either as monotherapy or in combination with other anticancer treatments; (II) patients received antibiotics before and/or during immunotherapy, regardless of antibiotics class, route of administration and duration of use; (III) inclusion of a control group who did not receive antibiotics within the defined timeframes; and (IV) availability of data on the associations between antibiotics and OS, PFS in the format of hazard ratios (HRs), or as patients at risk in a survival curve, so that HRs could be estimated (18). If studies were reporting on overlapping patient populations, the most recent study, or the study where OS and PFS were reported were selected for inclusion in the meta-analysis.

The PubMed literature search initially included 345 published texts and abstracts; one record was initially excluded for out-of-range publication date, as it was published after June 30^th, 2023, and 314 were excluded based on irrelevant title or abstract. Of the 30 remaining records, six were excluded because they were not conducted on NSCLC patients or because they did not include treatment with PD-L1 or PD-1, two were excluded because they did not include a control group without antibiotics, and three were excluded because they did not report the HR for OS or for PFS, and did not provide the survival curves with persons-at-risk for HR calculation. Ultimately, nineteen published articles from peer-reviewed journals were included in the meta-analysis (see Figure 1). The literature screening was independently conducted by two reviewers (E.T., A.A.) who consulted with a third author to resolve any discrepancy.

Figure 1 Meta-analysis study identification. PD-L1, programmed death-ligand 1; NSCLC, non-small cell lung cancer; PD-1, programmed cell death protein 1; HR, hazard ratio.

Data extraction

The following data were independently collected by the two reviewers on a spreadsheet from each of the included studies: first author’s name, publication year, country where the study was conducted, time frame of treatment, number of patients included, lung cancer stage, immunotherapy type, treatment scheme and line of treatment, antibiotics regimen, OS and progression free survival expressed as HRs and their 95% confidence intervals (CIs), variables used for adjustment, and adjusted results. When HR was not available, it was calculated from the survival curve using the person-at-risk reported in the figure (18). Additionally, multivariable HR estimates were used when univariate estimates were not reported or could not be calculated.

Quality assessment was completed by two reviewers (A.A., T.I.P.) using the 2018 Mixed Methods Appraisal Tool (MMAT) (19).

Statistical analysis

We summarized the HRs and their 95% CIs to assess the association between OS and PFS and use of antibiotics. A random effects model was used to pool HR estimates. Meta-analyses were stratified by univariate vs. multivariate survival estimates. Q and I² statistics were used to test heterogeneity across studies (20,21). For all tests, two-sided P values less than 0.05 were considered statistically significant. All analyses were performed using the metaphor statistical package in R, version 4.2.1 (22). Risk of publication bias was assessed using a funnel plot.

Results

There were nineteen studies, conducted between 2017 and 2022, that met all the inclusion criteria, with 2,932 patients with advanced and/or metastatic NSCLC. As the nineteen papers received a MMAT score of 4–5, indicating that 80–100% of the quality standards were met, all identified studies were included (Table S1). Patients were treated with immunotherapy according to various lines of treatment, from 1^st to all lines. The type of immunotherapy varied, or was not specified (Table 1). The antibiotic regimens also varied, but antibiotics were generally administered within two months before or after the start of immunotherapy. Two studies: Routy, 2018 and Derosa, 2018 reported on the same patient population (24,25). However, the population in the Derosa paper was the confirmation cohort used by Routy and colleagues (n=239), who had a separate discovery cohort (n=140). Therefore, only the discovery cohort (univariate analysis) from the Routy study was included in this meta-analysis, while the Derosa paper was included in its entirety. Additionally, no OS data was available in the Kaderbhai study, thus only PFS was used in this analysis (23).

Of the nineteen studies, eight showed worse OS and PFS in those NSCLC patients on ICI who were treated with antibiotics (Table 1) while four only showed worse OS, one only showed worse PFS, and six did not show a statistically significant difference in survival (23-41). Six of the eight studies showing worse OS and PFS at univariate analyses confirmed the results at multivariate analysis (23,27-29,32,34). Additionally, five studies confirmed worse OS only at multivariate analysis, one study confirmed worse PFS only, and one study did not include any multivariate analyses (24,31,33,36,37,39,41). Both univariate OS (pooled HR: 1.56, 95% CI: 1.23–1.99, Figure 2) and PFS (pooled HR: 1.22, 95% CI: 1.03–1.44, Figure 3) were significantly lower in patients receiving antibiotic treatment in conjunction with ICI when pooled estimates were calculated. The heterogeneity was low for OS (I²=27.30%) and PFS (I²=0.00%), and the Cochran’s Q statistic test for heterogeneity was not statistically significant in both cases.

Figure 2 Meta-analysis of OS. *, multivariable HR estimate used. Studies are in temporal order of publication; a larger black box is indicative of a larger sample size. OS, overall survival; 95% CI, 95% confidence interval; HR, hazard ratio.

Figure 3 Meta-analysis of PFS. *, multivariable HR estimate used. Studies are in temporal order of publication; a larger black box is indicative of a larger sample size. PFS, progression-free survival; 95% CI, 95% confidence interval; HR, hazard ratio.

We next calculated pooled adjusted HRs for OS and PFS for the subset of studies reporting multivariate HR estimates (n=12 for OS, n=10 for PFS). When the adjusted survival estimates were considered, OS (pooled HR_adj: 1.67, 95% CI: 1.23–2.27, Figure 4) and PFS (pooled HR_adj: 1.64, 95% CI: 1.16–2.32, Figure 5) remained significantly lower in patients receiving antibiotic treatment.

Figure 4 Meta-analysis of multivariable OS. Studies are in temporal order of publication; a larger black box is indicative of a larger sample size. OS, overall survival; 95% CI, 95% confidence interval.

Figure 5 Meta-analysis of multivariable PFS. Studies are in temporal order of publication; a larger black box is indicative of a larger sample size. PFS, progression-free survival; 95% CI, 95% confidence interval.

Discussion

This meta-analysis of published, peer-reviewed studies on NSCLC patients treated with ICI, who received antibiotics before or after the start of ICI, indicates that those patients treated with antibiotics have significantly lower OS and PFS compared with patients not treated with antibiotics. The results show a low degree of heterogeneity, and it appears that there is no publication bias from the funnel plots (Figure 6); these observations strengthen and confirm the overall hypothesis of lower survival associated with antibiotic use in conjunction with ICI among NSCLC patients. Indeed, while many of the individual studies included in the analysis did not report statistically significant effects, probably because of small sample size and low power, the pooled HRs point to a clinically significant limitation in the effectiveness of ICIs in improving survival if antibiotic treatments are present. Moreover, these results are in keeping with the previous meta-analyses on this topic. Lurienne and colleagues’ meta-analysis in 2020 on 23 studies and 5,560 NSCLC patients drawn from publications, posters, and abstracts showed that antibiotic use was associated with lower OS (HR: 1.47, 95% CI: 1.12–1.9) as well as PFS (HR: 1.69, 95% CI: 1.25–2.29) in patients treated with ICIs, and that this effect was stronger when antibiotic use took place within 60 days of receiving ICI therapy (13). Elkrief et al.’s meta-analysis in 2019 was conducted on nine published studies of 1,057 NSCLC patients and three studies of other cancers (14). This study found a significant negative association between antibiotic use and survival in NSCLC patients treated with ICIs, though this effect was not quantified with a point estimate and CIs. In 2020, Wilson and colleagues looked at 2,889 patients with various solid malignancy types from eighteen papers and abstracts and found both lower OS (HR: 1.92, 95% CI: 1.37–2.68) and PFS (HR: 3.43, 95% CI: 2.29–5.14) with antibiotics in cancer patients treated with ICI (15). The meta-analysis by Jiang et al. in 2022 included four NSCLC studies and 974 patients, and also confirmed worse OS (point estimates not reported) and worse PFS (HR: 1.47, 95% CI: 1.11–1.95) in patients treated with antibiotics, particularly if treatment took place ~40 days before initiation of ICI treatment (16). In 2023, Crespin and colleagues obtained similar results from 47 studies on NSCLC, including posters and abstracts, and a total of 8,421 patients; OS (HR: 1.6, 95% CI: 1.4–1.83) and PFS (HR: 1.47, 95% CI: 1.27–1.7) were also lower in patients receiving antibiotic treatment (17). Of these five meta-analyses, three (Lurienne, Wilson, and Crespin) reported significant heterogeneity between studies despite the overall HRs being statistically significant. Our observed effect size (OS HR: 1.56, 95% CI: 1.23–1.99; PFS HR: 1.22, 95% CI: 1.03–1.44) was similar to what has been reported in the other meta-analyses (OS HR: 1.66; PFS HR: 1.57).

Figure 6 Funnel plots assessing publication bias using overall survival (A) and progression-free survival (B).

The present meta-analysis, however, has several unique strengths in comparison to previously conducted meta-analyses. First, we included only peer-reviewed studies. This criterion ensured that the analyzed studies exhibit high-quality methodology and well-reported results, reducing heterogeneity between studies. In addition, we applied the MMAT scoring system to ensure the quality of the included studies; compared to the Newcastle-Ottawa Quality Assessment Scale, used by Lurienne [2020], Jiang [2022], and Crespin [2023], the MMAT covers additional criteria and subjects studies to more rigorous scrutiny (13,16,17). Additionally, we considered the effect of confounders on the reported effect sizes by calculating separate pooled HRs for multivariable analyses. This independent multivariable analysis is unique to this meta-analysis and demonstrated that the negative effect of antibiotics on survival of NSCLC patients treated with ICIs is greater when accounting for confounders. Finally, most of the studies included here (fifteen out of nineteen) were observational studies, and only four studies re-analyzed data from randomized clinical trials (Derosa 2018, Zhao 2019, Tinsley 2020, Castello 2021) (24,29,32,37). We also had the opportunity to include the most recent observational studies (as of June 2023). Therefore, the present meta-analysis includes patients who are more representative of the general population of real-world NSCLC cases, rather than selected patients involved in randomized clinical trials, thus strengthening the external validity of the results we report here.

This meta-analysis has some limitations. We included studies available only on a single database. Additionally, limiting the literature search to NSCLC patients may impact the applicability of results to other cancer patient populations, as lung cancer may affect the gut microbiome uniquely, independent of antibiotic use. The generalizability of the results to other lung cancer types, including small cell lung cancer, warrants further studies. Finally, as included studies collected different information and adjusted for different variables, this meta-analysis could not account and adjust the estimates for the same variables [e.g., age, sex, Eastern Cooperative Oncology Group (ECOG) performance status] across all studies. One surprising aspect is that none of the studies collected and/or analyzed information on race, despite the fact that the interaction between ICI and antibiotics could differ according to race. Although all the included studies contained a sizable number of female patients, none of the studies reported data separately by sex, even though the efficacy of immunotherapy has been reported to differ with sex (42-44). It is important to note that though most of the included studies adjusted for performance status or comorbidities and most still found antibiotics to be an independent predictor of OS and PFS even after adjusting for these factors, it is still difficult to determine whether baseline health status differences have fully been accounted for in these patient populations. It is documented that patients who develop an infection following immunotherapy treatment may present with distinct clinical characteristics that predict their infection risk, indicating that there may be key baseline differences in patients who are treated with antibiotics versus those who are not (45). Furthermore, evidence suggests that even among those who are treated with antibiotics, OS is better among those with multidisciplinary management of their infections, compared to those without (46).

Among the other understudied clinical factors that deserve future research are the fact that patients may experience delays in their cancer treatment due to infection, which may contribute to poorer survival, the lack of information on the outcome of the infection following the antibiotic treatment, the type of changes in microbiota associated with survival, the lack of information on cancer-specific survival (47). All of these are important considerations for future research studies. As immunotherapy becomes more widely practiced as a treatment for NSCLC and study numbers increase, a larger, future meta-analysis can attempt to take these and other important clinical factors into account.

Conclusions

Given the relative novelty of ICI treatment in cancer and the complexity of the gut microbiome, much remains unknown about their interaction in the bodies of cancer patients. Thus, while our results support an association between antibiotic use and decreased immunotherapy efficacy among NSCLC patients, the exact biological mechanisms will need to be elucidated in the future. Individual-level immunotherapy sensitivity is driven by a combination of both host and tumor-related factors, including the tumor immune microenvironment, systemic immunity, and the gut microbiome. Some have hypothesized that metabolites of gut microbiota impact antitumor immunity and, consequently, immunotherapy response. However, specifics of these mechanisms and networks remain unclear (48). As the results of newer research studies become available, the observed decrease in survival in patients treated with antibiotics may be explained by a well-understood mechanism.

According to the National Cancer Institute, current guidelines for health professionals do not consider antibiotic use when suggesting treatment of NSCLC with ICIs (49). As the findings of this and other meta-analyses point to significantly lower survival when NSCLC patients receive antibiotics just prior to or concurrently with immunotherapy, the guidelines may need to be updated to include possible restrictions in the use of antibiotics together with ICIs.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-597/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-597/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-597/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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