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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose As 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. Methods We 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. Results Forty-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). Conclusions The results suggest that severe hematologic toxicities in patients receiving carboplatinbased 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.

Original languageEnglish
Article numbere0171066
JournalPLoS One
Volume12
Issue number2
DOIs
Publication statusPublished - 2017 Feb 1
Externally publishedYes

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Pemetrexed
nonsteroidal anti-inflammatory agents
Carboplatin
lung neoplasms
cohort studies
Toxicity
Lung Neoplasms
Cohort Studies
Anti-Inflammatory Agents
Retrospective Studies
toxicity
Pharmaceutical Preparations
odds ratio
Odds Ratio
confidence interval
Confidence Intervals
Kidney
Electronic Health Records
drug interactions
Drug interactions

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin : A retrospective cohort study. / Kawazoe, Hitoshi; Yano, Akiko; Ishida, Yuri; Takechi, Kenshi; Katayama, Hitoshi; Ito, Ryoji; Yakushijin, Yoshihiro; Moriguchi, Toshihide; Tanaka, Mamoru; Tanaka, Akihiro; Araki, Hiroaki.

In: PLoS One, Vol. 12, No. 2, e0171066, 01.02.2017.

Research output: Contribution to journalArticle

Kawazoe, H, Yano, A, Ishida, Y, Takechi, K, Katayama, H, Ito, R, Yakushijin, Y, Moriguchi, T, Tanaka, M, Tanaka, A & Araki, H 2017, 'Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study', PLoS One, vol. 12, no. 2, e0171066. https://doi.org/10.1371/journal.pone.0171066
Kawazoe, Hitoshi ; Yano, Akiko ; Ishida, Yuri ; Takechi, Kenshi ; Katayama, Hitoshi ; Ito, Ryoji ; Yakushijin, Yoshihiro ; Moriguchi, Toshihide ; Tanaka, Mamoru ; Tanaka, Akihiro ; Araki, Hiroaki. / Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin : A retrospective cohort study. In: PLoS One. 2017 ; Vol. 12, No. 2.
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abstract = "Purpose As 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. Methods We 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. Results Forty-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). Conclusions The results suggest that severe hematologic toxicities in patients receiving carboplatinbased 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.",
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AU - Kawazoe, Hitoshi

AU - Yano, Akiko

AU - Ishida, Yuri

AU - Takechi, Kenshi

AU - Katayama, Hitoshi

AU - Ito, Ryoji

AU - Yakushijin, Yoshihiro

AU - Moriguchi, Toshihide

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AU - Tanaka, Akihiro

AU - Araki, Hiroaki

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N2 - Purpose As 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. Methods We 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. Results Forty-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). Conclusions The results suggest that severe hematologic toxicities in patients receiving carboplatinbased 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.

AB - Purpose As 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. Methods We 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. Results Forty-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). Conclusions The results suggest that severe hematologic toxicities in patients receiving carboplatinbased 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.

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