Survival of Patients Treated with Antibiotics and Immunotherapy for Cancer: A Systematic Review and Meta-Analysis

Abstract

Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumors treated with ICIs. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with a worse outcome in ABs users compared to no-ABs users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; P<.01). Similarly, PFS was inferior in ABs users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p<.01). In cancer patients treated with ICIs, AB use significantly reduces OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

Effect of Antacid Use on Immune Checkpoint Inhibitors in Advanced Solid Cancer Patients: A Systematic Review and Meta-analysis

“…In recent years, the influence of concomitant medications and gut microbiota on ICI therapies has received increasing attention. 12,14 Concomitant medications, such as antacids, including proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs), [15][16][17] systemic antibiotics, 18,19 steroids, 20 anticoagulants, 21 and opioids, 22 have been postulated to modulate the tumor microenvironment (TME) to affect clinical outcomes from ICI therapy. 17,23,24 The use of ICIs and concomitant medications may cause an imbalance in the gut microbiome, 14 and dysbacteriosis may lead to tumor resistance to ICIs and worse survival outcomes.…”

The Association Between Antibiotic Use and Outcome Among Metastatic Melanoma Patients Receiving Immunotherapy

“…The current body of knowledge derived from observational studies converges towards poorer prognosis among patients exposed to antibiotics in all cancers treated with ICI. 5,[8][9][10]15,43,44 The association was often strong but the data were heterogeneous, mixing different treatment lines, different ICIs or even different types of cancer within the same studies. Relevant confounders could not be appropriately taken into account in most studies, due to small sample sizes and heterogeneity.…”

“…7,44 The number of antibiotic-exposed patients in our study was similar to the number in meta-analyses mixing studies on all cancer types, treatment lines and antibiotic timeframes. 6,[8][9][10]43 In addition, the exhaustiveness of the database, with no loss to follow-up, protected from selection and attrition bias. Fourth, as there is no underlying rationale for antibiotics to impact the efficacy of targeted therapy, using the targeted therapy cohort as a negative control was an original and relevant approach to address our question.…”

“…One of the most disturbing findings that has emerged in the past 3 years is the suspected detrimental effect of antibiotics: across several cancers, antibiotics administered before ICI have been associated with shorter progression-free and overall survival. [5][6][7][8][9][10][11] Because the role of the gut microbiota in response to ICI has been substantiated by experimental data in mice, 12 the hypothesis of an impairment of ICI efficacy consecutive to antibiotic-induced gut dysbiosis has been raised. 13 Among patients receiving ICI, dysbiosis could consecutively lead to cancer progression and death.…”

Antibiotic resistance in the patient with cancer: Escalating challenges and paths forward

“…[128][129][130] Dysbiosis in the gut microbiota can increase the risk for resistance bacteria in the microbiota, 131 invasive infections, 50 post-transplant complications (such as graftversus-host disease in those who undergo hematopoietic stem cell transplantation), 132 and reduced efficacy in patients who have cancer treated with immunotherapy. 133 Monitoring gut microbiota for its composition, administering protective commensal bacteria to reduce antibioticresistant infections, and promoting a healthy microbiome could be promising approaches for preventing antibiotic resistance, minimizing antibiotic use, and leading to positive outcomes in these patients. [134][135][136] Another area of concern for patients with cancer is the recognition that there is geographical variability in antibiotic resistance.…”