Antibacterial use is associated with an increased risk of hematologic and gastrointestinal adverse events in patients treated with gemcitabine for stage IV pancreatic cancer
Background
Pre-clinical evidence has demonstrated that common intra-tumor bacteria metabolize the chemotherapeutic drug gemcitabine. The significance of this bacterial metabolism pathway, relative to the known metabolic pathways by host enzymes, is not known. We hypothesized that bacterial metabolism is clinically significant and that “knock down” by antibacterial therapy has the unintended effect of increasing the effective dose of gemcitabine, thereby increasing the risk for gemcitabine-associated toxicities.
Materials and Methods
We reanalyzed the comparator arm of the MPACT trial (NCT01442974), made available through Project DataSphere®. In this arm, 430 patients with metastatic pancreatic adenocarcinoma were treated with gemcitabine. We used the Anderson-Gill survival model to compare the risk of developing an adverse event after antibacterial prescription to time unexposed to antibacterials. Adverse events of grade three and greater were considered at three levels of granularity: all aggregated into one endpoint, aggregated by class, and taken individually. Antibiotic exposures were analyzed in aggregate as well as by class.
Results
Antibacterial exposure was associated with an increased risk of adverse events (HR = 1.77, CI = [1.46, 2.14]), any hematologic adverse event (HR = 1.64, CI = [1.26, 2.13]), and any gastrointestinal adverse event (HR = 2.14, CI = [1.12, 4.10] ), but not a constitutional (HR = 1.33, CI = [0.611, 2.90] ) or hepatologic adverse event (HR = 0.99, CI = [0.363, 2.71]). Among specific adverse events, antibacterial exposure was associated with an increased risk of anemia (HR = 3.16, CI = [1.59, 6.27] ), thrombocytopenia (HR = 2.52, CI = [1.31, 4.85]), leukopenia (HR =3.91, CI = [1.46, 10.5]), and neutropenia (HR = 1.53, CI = [1.07, 2.17]), but not any other specific adverse events.
Conclusion
Antibacterial exposure was associated with an increased risk of gemcitabine-associated, dose-limiting adverse events, including aggregate hematologic and gastrointestinal events, as well as four specific hematologic adverse events, suggesting that intra-tumor bacteria may be responsible for a clinically-significant portion of gemcitabine metabolism. Alternative avenues of evidence will be necessary to confirm this preliminary finding and assess its generalizability. There is plentiful opportunity for similar analyses on other clinical trial datasets, where gemcitabine or other bio-mimetic small molecules were used.