Broad-Spectrum Antibiotic Regimen Affects Survival in Patients Receiving Nivolumab for Non-Small Cell Lung Cancer

Geum, Min Jung; Kim, Chungsoo; Kang, Ji Eun; Choi, Jihyang; Kim, Jae Song; Son, Eun Sun; Lim, Sun Min; Rhie, Sandy Jeong

doi:10.3390/ph14050445

Cited by 13 publications

(12 citation statements)

References 42 publications

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“…Analysis of the antibiotic type, together with timing and duration of treatment, showed that β-lactamase inhibitors were the most deleterious, followed by uoroquinolones and cephalosporins. This con rms previous ndings (27). Another study showed that β-lactamase inhibitors, but not other antibiotics, adversely affected OS in lung cancer cases treated with immune checkpoint inhibitors (30).…”

Section: Discussionsupporting

confidence: 89%

Impact of antibiotic use before definitive concurrent chemoradiation in patients with locally advanced non-small cell lung cancer

Mei

et al. 2022

Strahlenther Onkol

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Purpose: The study evaluated whether antibiotic treatment before chemoradiotherapy in uenced outcomes in patients with locally advanced non-small cell lung cancer (LA-NSCLC).Methods: The records of LA-NSCLC patients treated with chemoradiotherapy between 2010 and 2017 at xxx were retrospectively examined together with their antibiotic use (antibiotic type, duration of treatment, and time between discontinuation and chemoradiotherapy). The in uence of antibiotics on progressionfree survival (PFS) and overall survival (OS) was evaluated with Kaplan-Meier curves and univariate and multivariate Cox regression.Results: Of 522 patients, 176 had received intravenous broad-spectrum antibiotics in the month before chemoradiotherapy. Antibiotic use was linked to both reduced PFS (7.9 vs. 13.4 mo, p<0.001) and OS (20.4 vs. 25.3 mo, p=0.049). Multivariate regression demonstrated that antibiotic treatment was an unfavorable independent prognostic factor for LA-NSCLC patients that received chemoradiotherapy (HR, 1.234; 95% CI, 1.019-1.494; p=0.031). Prognosis was also in uenced by the antibiotic type, length of treatment, and interval between discontinuation and start of chemoradiotherapy initiation. β-lactamase inhibitors were found to be the most harmful (median OS for β-lactamase inhibitors /Fluoroquinolones / Cephalosporins:16.5/19.9/25.9 mo, p=0.045). Cutoff values for interval and duration calculated by the Xtile procedure showed that intervals of 7-16 days or durations ≤6 days did not signi cantly affect OS relative to untreated patients (intervals: p=0.9, duration: p=0.93).Conclusions: Antibiotic treatment for longer than six days, especially with β-lactamase inhibitors, was associated with poor prognosis. Furthermore, delaying chemoradiotherapy for 7-16 days after antibiotic discontinuation may reduce these negative effects.

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Section: Discussionsupporting

confidence: 89%

Impact of antibiotic use before definitive concurrent chemoradiation in patients with locally advanced non-small cell lung cancer

Mei

et al. 2022

Strahlenther Onkol

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“…Intriguingly, we found that different antibiotic regimens were associated with different survival outcomes in individuals undergoing first‐line chemotherapy, consistent with previous ICI‐related reports 23–25 . For example, one analysis of the impact of broad‐spectrum antibiotics on nivolumab efficacy found β‐lactamase inhibitors to have the greatest impact on patient OS and PFS 26 . In another report, individuals undergoing fluoroquinolone antibiotic treatment exhibited a worse prognosis than individuals being treated with other broad‐spectrum antibiotics 24 .…”

Section: Discussionsupporting

confidence: 88%

“… 23 , 24 , 25 For example, one analysis of the impact of broad‐spectrum antibiotics on nivolumab efficacy found β‐lactamase inhibitors to have the greatest impact on patient OS and PFS. 26 In another report, individuals undergoing fluoroquinolone antibiotic treatment exhibited a worse prognosis than individuals being treated with other broad‐spectrum antibiotics. 24 In our study, we found that β ‐lactamase inhibitors and fluoroquinolones were associated with a more pronounced difference in survival outcomes among individuals undergoing chemotherapy as compared to cephalosporin treatment.…”

Section: Discussionmentioning

confidence: 99%

The impact of antibiotic selection and interval time among advanced non‐small cell lung cancer patients receiving prior antibacterial treatment and first‐line chemotherapy

Tian

Mei

et al. 2022

Cancer Medicine

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Background To determine whether antibiotic use before chemotherapy is associated with chemotherapy responses and patient outcomes among NSCLC patients and define the optimal interval between chemotherapy initiation and antibiotic treatment. Materials and methods One thousand four hundred and four advanced NSCLC patients receiving first‐line platinum‐based doublets therapy were retrospectively analyzed. Kaplan–Meier curve evaluated the impact of antibiotic use and type of antibiotics on the survival of patients. The factors affect the patient's prognosis were further confirmed by Cox regression. The optimal interval between antibiotic treatment and the initiation of chemotherapy was determined by the X‐tile program. Results NSCLC patients of 33.5% advanced underwent broad‐spectrum antibiotic treatment prior to chemotherapy. In the chemotherapy only (Chemo) and chemotherapy plus antiangiogenesis (Chemo‐angio) treatment groups, prior antibiotic treatment was associated with worse OS (Chemo: 13.8 vs. 17.6 months, p < 0.001; Chemo‐angio:11.9 vs. 18.1 months, p = 0.012) and PFS (Chemo: 3.7 vs. 5.8 months, p < 0.001; Chemo‐angio: 3.1 vs. 5.9 months, p < 0.001). Cox regression analysis revealed prior antibiotic administration as an independent predictor of OS and PFS (HR for PFS/OS: 1.925/1.452, both p < 0.001). Antibiotic usage duration (HR for PFS/OS: 1.030/1.036, p = 0.009/0.001) and type (PFS/OS: p < 0.001/p = 0.01) also showed significant association with patient prognosis, with calculated interval time cutoff values of 2, 4, and 2 days for fluoroquinolones, β‐lactamase inhibitors, and cephalosporins, respectively. Conclusion Antibiotic use before first‐line chemotherapy was associated with poor results in advanced NSCLC patients; treatment length and type being strongly correlated with patient outcomes. Appropriate prolongation of the time between two treatments may enhance patient survival. Further prospective research is however necessary.

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

Abdelhamid,

Tuminello,

Ivic-Pavlicic

et al. 2023

Transl Lung Cancer Res

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Background In patients with non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) are an effective mode of treatment. Despite their efficacy, responses to ICIs have been shown to differ based on several factors; for example, antibiotic use prior to and/or during immunotherapy has been associated with lower survival in NSCLC patients. The objective of this study is to provide an updated review of the literature and to fill in important knowledge gaps by accounting for potential confounding in the relationship between ICIs and survival. Methods We performed a systematic review and meta-analysis on peer-reviewed studies that examined the effects of antibiotic use on overall survival (OS) and progression-free survival (PFS) in NSCLC patients treated with ICIs. We searched MEDLINE for studies published up to June 30 th , 2023 that included NSCLC patients treated with anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) agents, who received antibiotics before and/or during immunotherapy, and included a control group who did not receive antibiotics and had available data on the associations between antibiotics and OS and PFS. We calculated aggregated crude OS and PFS for all studies, and only for studies that reported multivariable hazard ratios (HRs). Risk of bias was assessed using a funnel plot. All results were synthesized and displayed using the metaphor statistical package in R, version 4.2.1. Results Nineteen studies, conducted between 2017 and 2022, met the inclusion criteria, and included 2,932 patients with advanced and/or metastatic NSCLC. Compared to those who did not receive antibiotics, immunotherapy patients who did had a significantly reduced PFS (HR: 1.22, 95% CI: 1.03–1.44) and OS (HR: 1.56, 95% CI: 1.23–1.99). Adjusted HRs were even more pronounced (OS HR adj : 1.67, 95% CI: 1.23–2.27, PFS HR adj : 1.64, 95% CI: 1.16–2.32). Conclusions NSCLC patients treated with antibiotics have significantly lowered survival compared with patients not treated with antibiotics. These results support the hypothesis that antibiotic use in conjunction with ICI among NSCLC patients lowers survival. Limitations of this analysis include the use of studies available only on a single database, limiting the literature search to NSCLC patients, which may impact the generalizability of results to other cancer patient populations, and the inability to account for and adjust the estimates for the same variables (e.g., age, sex) across all studies. Nevertheless, our findings underscore the importance of taking antibiotic use into consideration when using ICIs to treat NSCLC and suggest that confounders should be taken into account when designing future similar studies.

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Broad-Spectrum Antibiotic Regimen Affects Survival in Patients Receiving Nivolumab for Non-Small Cell Lung Cancer

Cited by 13 publications

References 42 publications

Impact of antibiotic use before definitive concurrent chemoradiation in patients with locally advanced non-small cell lung cancer

Impact of antibiotic use before definitive concurrent chemoradiation in patients with locally advanced non-small cell lung cancer

The impact of antibiotic selection and interval time among advanced non‐small cell lung cancer patients receiving prior antibacterial treatment and first‐line chemotherapy

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

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