Assessing Taxane-Associated Adverse Events Using the FDA Adverse Event Reporting System Database
Taxanes, including paclitaxel, docetaxel, and nab-paclitaxel, are a critical class of antineoplastic agents widely used in the treatment of various cancers, such as breast cancer and lung cancer. These agents interfere with microtubule function, leading to altered mitosis and cellular death. Despite their efficacy, taxanes are associated with significant adverse events, including hypersensitivity reactions, bone marrow toxicity, and peripheral neuropathy, which can lead to chemotherapy discontinuation. This study aimed to evaluate the safety profile of taxanes in real-world settings by analyzing data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2004 to December 2019.
Introduction
Taxanes are a cornerstone in cancer chemotherapy, with paclitaxel initially extracted from the Pacific yew tree (Taxus brevifolia) and docetaxel developed from the European yew tree (Taxus baccata) due to paclitaxel scarcity. Paclitaxel is formulated with Cremophor EL and ethanol, while nab-paclitaxel is a solvent-free, albumin-bound nanoparticle formulation. Despite their therapeutic benefits, taxanes are known to cause hypersensitivity reactions, bone marrow toxicity, and peripheral neuropathy, which can significantly impact patient outcomes and treatment continuity.
Methods
The study utilized the FAERS database, the largest pharmacovigilance system for adverse drug events reported by healthcare professionals, consumers, and manufacturers. The database includes demographic and administrative information, drug and reaction details, patient outcomes, and report sources. The deduplication process followed FDA recommendations, selecting the latest report for identical case IDs. Adverse events were identified using the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms.
Four statistical procedures were employed for data mining: reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN). These algorithms were used to identify associations between taxanes and specific adverse events. The time to onset of adverse events was calculated as the interval between the event date and the start date of taxane administration. Death outcomes were assessed by dividing the number of lethal adverse events by the total number of reported adverse events.
Results
Clinical Characteristics
The study analyzed 8,721 reports of hypersensitivity reactions, 4,964 reports of bone marrow toxicity, and 1,374 reports of peripheral neuropathy. Most hypersensitivity reactions and peripheral neuropathy reports were associated with paclitaxel (52.07% and 41.41%, respectively), while most bone marrow toxicity reports were linked to docetaxel (46.15%). Adverse events were predominantly reported by healthcare professionals, with female patients experiencing more adverse events.
Signal Detection
Paclitaxel exhibited a positive signal in ROR for hypersensitivity reactions, while docetaxel and nab-paclitaxel showed negative signals. Nab-paclitaxel had the highest signal for bone marrow toxicity and peripheral neuropathy, with ROR values of 6.45 (95% CI: 6.05–6.88) and 12.78 (95% CI: 11.55–14.14), respectively. All taxanes showed positive signals in ROR, PRR, BCPNN, and MGPS for bone marrow toxicity and peripheral neuropathy.
Time to Onset
The time to onset of hypersensitivity reactions with nab-paclitaxel (45.91 days) was significantly later than with docetaxel (35.10 days) and paclitaxel (23.76 days). Similarly, the time to onset of bone marrow toxicity with nab-paclitaxel (46.54 days) was later than with docetaxel (40.20 days) and paclitaxel (45.32 days). Peripheral neuropathy with nab-paclitaxel (91.49 days) had a significantly later onset compared to docetaxel (34.82 days) and paclitaxel (61.19 days).
Outcome Analysis
Paclitaxel showed a lower death rate (9.77%) for hypersensitivity reactions but required more interventions to prevent permanent impairment (4.35%). Nab-paclitaxel had a higher death rate (31.05%) for peripheral neuropathy. Death outcomes were more frequent with nab-paclitaxel for bone marrow toxicity (31.11%) and peripheral neuropathy (31.05%) compared to paclitaxel and docetaxel.
Discussion
This study provides a comprehensive analysis of taxane-associated adverse events using real-world data from the FAERS database. The findings highlight that bone marrow toxicity and peripheral neuropathy are major adverse events induced by taxanes, with nab-paclitaxel showing the highest potential for these adverse events. The late onset of adverse events with nab-paclitaxel suggests the need for prolonged monitoring and management strategies.
Contrary to previous beliefs, the study found no strong positive signal for hypersensitivity reactions with taxanes, likely due to the widespread use of premedication protocols. However, the higher death rates associated with nab-paclitaxel for bone marrow toxicity and peripheral neuropathy indicate that this formulation may not be as safe as previously thought. These findings underscore the importance of further research to understand the safety profile of nab-paclitaxel and optimize its clinical use.
Limitations
The study has several limitations. The FAERS database primarily includes reports from Europe and North America, potentially missing data from other regions. Additionally, the spontaneous reporting system may underreport adverse events, and the data mining techniques used cannot establish causality. Despite these limitations, the study provides valuable insights into the safety profile of taxanes in real-world settings.
Conclusions
The analysis of the FAERS database identified significant associations between taxanes and adverse events such as bone marrow toxicity and peripheral neuropathy. Nab-paclitaxel showed the highest signal for these adverse events, with a later onset compared to paclitaxel and docetaxel. The study emphasizes the need for further research to explain the safety of nab-paclitaxel and improve the management of taxane-associated adverse events in clinical practice.
doi.org/10.1097/CM9.0000000000001562
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