Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study.

Hitoshi Kawazoe,Yoshihiro Yakushijin,Mamoru Tanaka,Akihiro Tanaka,Hiroaki Araki,Kenshi Takechi,Ryoji Ito,Hitoshi Katayama,Akiko Yano,Toshihide Moriguchi,Yuri Ishida,Aamir Ahmad

doi:10.1371/journal.pone.0171066

Abstract

PurposeAs the major toxicity induced by pemetrexed plus carboplatin is severe hematologic toxicities, the aim of this study was to determine the risk factors for severe hematologic toxicities in lung cancer patients.MethodsWe retrospectively investigated data from lung cancer patients who had received pemetrexed plus carboplatin, with or without bevacizumab. This observational study was carried out at Ehime University Hospital using electronic medical records dating from July 2009 to March 2015. Severe hematologic toxicities were defined as grade 3 or 4, according to the Common Terminology Criteria for Adverse Events, version 4.0.ResultsForty-two patients were included in the study. The incidence of grade 3 or 4 hematologic toxicities during the first cycle of chemotherapy and during all cycles was 19.0% and 16.1%, respectively. Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27–54.38; p = 0.03), whereas creatinine clearance of <45 mL/min was not significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted OR: 0.91, 95% CI: 0.25–3.34; p = 0.88).ConclusionsThe results suggest that severe hematologic toxicities in patients receiving carboplatin-based pemetrexed may be significantly induced by the inhibition of renal tubular pemetrexed secretion through drug–drug interactions between NSAIDs and pemetrexed rather than through glomerular filtration of pemetrexed, even with moderate to sufficient renal function.

Highlights

Lung cancer is the most commonly diagnosed type of cancer and the leading cause of cancerrelated mortality, both worldwide and in Japan
Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27–54.38; p = 0.03), whereas creatinine clearance of
NSAIDs and pemetrexed plus carboplatin-induced hematologic toxicities increased risk of severe hematologic toxicities during all cycles

Summary

Introduction

Lung cancer is the most commonly diagnosed type of cancer and the leading cause of cancerrelated mortality, both worldwide and in Japan. Pemetrexed in combination with platinum is standard first-line chemotherapy for these patients, and the leading therapy for prolonging survival and improving quality of life compared with third generation chemotherapeutic agents plus platinum. Cisplatin and carboplatin are traditional first and second generation platinum drugs, respectively. Cisplatin is associated with severe non-hematologic and mild hematologic toxicities, including nausea, vomiting, and renal disorder, and should be administered alongside the best available antiemetics [6] and adequate hydration [7]. Carboplatin produces fewer toxicities than cisplatin, even without the use of supportive therapies to address toxic effects. Carboplatin-based pemetrexed is widely used because of its lower toxicity and short infusion time, making it convenient for outpatient chemotherapy. The pharmacokinetics of pemetrexed depend upon the renal function of patients and concomitant administration of non-steroidal anti-inflammatory drugs (NSAIDs) [8,9,10]. Angiotensin-converting enzyme inhibitor (ACE) and angiotensin II receptor blocker (ARB) have been shown to have a renoprotective effect [11,12,13,14,15]

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