title: Efficacy of antineoplastic treatment is associated with the use of antibiotics that modulate intestinal microbiota.
abstract: Reduced anticancer efficacy of cyclophosphamide and platinum salts has been reported in animals treated with anti-Gram-positive antibiotics. These effects were related to translocation of Gram-positive bacteria during mucositis with subsequent induction of cytotoxic oxygen reactive species and tumor invasion by pathogenic Th17 cells. To assess these hypotheses in a clinical setting, we identified patients receiving cyclophosphamide for chronic lymphocytic leukemia (CLL) and cisplatin for relapsed lymphoma. Data originated from the CLL8 trial (NCT00281918) and the Cologne Cohort of Neutropenic Patients (NCT01821456). Relevant antibiotics were defined as compounds with primary activity against Gram-positive bacteria. We evaluated their impact on response, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier methodology and Cox proportional hazards regression analysis. Among 800 available CLL patients, those receiving anti-Gram-positive antibiotics (n = 45/800) achieved a significantly lower overall response rate (OR 74.3% vs. 90.2%, p = 0.007). Patients with anti-Gram-positive antibiotics progressed significantly earlier, had a reduced OS (median PFS 14.1 vs. 44.1 mo, p < 0.001; median OS 56.1 vs. 91.7 mo, p < 0.001) and multivariate analysis showed that administration of anti-Gram-positive antibiotic treatment was independently associated with reduced PFS (Hazard ratio (HR) 2.090, p = 0.001) and OS (HR 2.966, p < 0.001). Of 122 patients with relapsed lymphoma, those treated with anti-Gram-positive antibiotics (n = 21/122) achieved a significantly lower OR rate (70.3% vs. 42.9%, p = 0.016). Patients with anti-Gram-positive antibiotics progressed significantly earlier than others (median PFS 2.3 vs. 11.5 mo, p = 0.001). As for multivariate analysis, the use of anti-Gram-positive antibiotics was independently associated with reduced PFS (HR 2.237, p = 0.012) and OS (HR 7.831, p < 0.001). Our data supports a potential negative impact of anti-Gram-positive antibiotics on the anticancer activity of cyclophosphamide and cisplatin in a clinical setting.
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Natali
authors.initials: N
authors.lastname: Pflug
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kluth
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Vehreschild
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bahlo
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tacke
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Biehl
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Eichhorst
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Cramer
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Fink
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne , Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: von Bergwelt-Baildon
authors.affiliation: Department of Internal Medicine III, University of Ulm , Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German CLL Study Group (GCLLSG), Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Clinical Trials Center Cologne, ZKS Köln, University of Cologne, Cologne, Germany.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Cornely
authors.affiliation: 1st Department of Internal Medicine and Center for Integrated Oncology CIO Köln/Bonn, University Hospital of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Partner site Bonn-Cologne, Cologne, Germany.
authors.forename: Maria J G T
authors.initials: MJ
authors.lastname: Vehreschild
keywords: Antibiotics; chemotherapy; cisplatin; cyclophosphamide; microbiota