Comparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour types

Abstract

BackgroundIn solid tumours, antibiotic use during immune checkpoint inhibitor (ICI) treatment is associated with shorter survival. Following allogeneic haematopoietic cell transplantation (allo-HCT), antibiotic-induced gut microbiome alterations are associated with risk of relapse and mortality. These findings suggest that the gut microbiota can modulate antitumour immune response across tumour types, though it is not clear if the impact on outcomes is specific to immune therapy. An important limitation of previous studies is that the analysis combined all antibiotic exposures irrespective of the antibiotic spectrum of activity. Whether antibiotic exposure during induction chemotherapy in acute myeloid leukaemia (AML) affects risk of relapse is also unknown.Patients and methodsWe performed a single-centred retrospective analysis of antibiotic exposures in metastatic/advanced non-small cell lung cancer (NSCLC) and renal cell cancer (RCC) receiving ICI and newly diagnosed AML patients receiving induction chemotherapy achieving a complete remission 1. Antibiotic use within 4 weeks before and 6 weeks after the ICI initiation were included. In AML patients, antibiotic exposures between days 1 and 28 of induction were collected. Antibiotics were a priori stratified based on spectrum of activity. Primary outcomes of interest were progression-free survival (PFS), overall survival (OS) in NSCLC and RCC and relapse-free survival (RFS) in AML.Results140 patients with NSCLC, 55 with RCC and 143 with AML were included. In multivariable analysis, PFS and OS were shorter in NSCLC patients who received broad-spectrum anti-anaerobes (PFS, HR=3.2, 95% CI 1.6 to 6.2, p<0.01; OS, HR=1.7, 95% CI 0.8 to 3.6, p=0.19) or ‘other’ antibiotics (vancomycin-predominant) (PFS, HR=2.4, 95% CI 1.3 to 4.6, p<0.01; OS, HR=2.4, 95% CI 1.2 to 4.7, p=0.01). In RCC, patients who received penicillins/penicillin-class/early-generation cephalosporins had shorter PFS (HR=3.6, 95% CI 1.7 to 7.6, p<0.01) but similar OS (p=0.37). In the AML cohort, none of the exposures were associated with RFS.ConclusionIn contrast to AML, antibiotic exposures in solid tumours affected clinical outcomes. The presence of an allogeneic effect (allo-HCT) or an augmented immune system (checkpoint blockade) may be necessary for microbiota mediation of relapse risk.

The negative effect of antibiotics on RCC patients with immunotherapy: A systematic review and meta-analysis

“…For ATB types, β-lactam ± inhibitors were used most frequently, followed by quinolones (However, in Guven et al, 2021 ( 34 ), quinolones were the most frequently used antibiotics, accounted for 48.4%). Only Kulkarni et al, 2020 ( 33 ) reported the influence of antibiotic type on the clinical effect of ICIs treatment. The duration of ATB was grouped into short-term (≤7 days) and long-term (> 7 days) use, which did not show significant differences between the studies.…”

“…HR for OS was extracted from five studies ( 21 – 23 , 33 , 34 ) for meta-analysis, and one study was assessed using Kaplan–Meier curves. As shown in ( Figure 3 ), using the common effect model (I 2 = 25%, P=0.25), ATB exposure showed a significantly lower OS than no ATB exposure (pooled HR=1.69, 95%CI [1.34; 2.12]).…”

A new biological triangle in cancer: intestinal microbiota, immune checkpoint inhibitors and antibiotics

“…Moreover, previous pre-clinical evidence has revealed reduced response to ICIs in tumor-bearing mice following antibiotic pretreatment [ 74 ], but the underlying mechanisms of antibiotics and immunotherapy remain unclear. Currently, results from clinical trials and conventional treatment therapies have associated antibiotic exposure with low overall survival and response rates of patients undergoing immunotherapy [ 75 , 76 ]. Several studies have demonstrated a negative correlation between antibiotic exposure with outcomes in patients and advanced solid cancer who received ICIs [ 77 – 81 ].…”

Role of gut microbiome in the outcome of cancer immunotherapy

“…Penicillin, penicillin‐class or early generation cephalosporins affected the PFS of RCC patients 59 . Side effects of antibiotics on the efficacy of ICI treatment were observed in patients with advanced melanoma and acute myeloid leukemia 59,60 . In patients with advanced melanoma, the rate of antibiotic administration exceeded 13%.…”