Date Published: February 3, 2017
Publisher: Public Library of Science
Author(s): Hitoshi Kawazoe, Akiko Yano, Yuri Ishida, Kenshi Takechi, Hitoshi Katayama, Ryoji Ito, Yoshihiro Yakushijin, Toshihide Moriguchi, Mamoru Tanaka, Akihiro Tanaka, Hiroaki Araki, Aamir Ahmad.
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.
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.
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). The 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.
Lung cancer is the most commonly diagnosed type of cancer and the leading cause of cancer-related mortality, both worldwide and in Japan. Pemetrexed, a multitargeted antifolate, is a key drug for patients with non-squamous, non-small cell lung cancer (NSCLC) [1–5]. 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  and adequate hydration . In contrast, 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) [8–10]. Several drugs can induce nephrotoxicity, including NSAIDs, zoledronic acid (ZOL), radiocontrast agents, vancomycin, and fibrate-based medicines. On the other hand, angiotensin-converting enzyme inhibitor (ACE) and angiotensin II receptor blocker (ARB) have been shown to have a renoprotective effect [11–15].
Forty-two patients and 174 cycles of pemetrexed plus carboplatin were included in the study. Baseline patient characteristics are summarized in Table 1. The median dose of pemetrexed and carboplatin at first cycle was 495 mg/m2 [range 457–513 mg/m2] and AUC 5 [AUC 4–AUC 6], respectively. Median and range for the number of cycles of carboplatin-based pemetrexed were 4 and 1–8, respectively. The median values for white blood cell, neutrophil, HGB, and platelet counts; aspartate transaminase, alanine transaminase, and CCr at baseline were within the normal reference ranges of our institute.
There is little information available at present on the predictive risk factors for severe hematologic toxicities in patients receiving pemetrexed plus carboplatin in the clinical practice setting. This was a pilot research and the primary objective of this pilot research was to generate the hypotheses for future formal study. The present study showed that the incidence of grade 3 or 4 hematologic toxicities during the first cycle and during all cycles was 19.0% and 16.1%, respectively, figures lower than those observed in previous phase III trials (25.8–40.0%) [2, 4]. We used the time-depend GEE analysis to identify, for the first time, that regular use of NSAIDs was significantly associated with an increased risk of severe hematologic toxicities.