Research ArticleClinical Studies
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Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases

AKIHIDE KOBAYASHI, KENJI IKEMURA, ERI WAKAI, MASAYOSHI KONDO and MASAHIRO OKUDA
Anticancer Research December 2023, 43 (12) 5613-5620; DOI: https://doi.org/10.21873/anticanres.16764

Abstract

Background/Aim: Chemotherapy-induced peripheral neuropathy (CIPN) due to oxaliplatin (L-OHP) is a major clinical problem. Effective and safe preventive strategies for CIPN are urgently needed. Although proton pump inhibitors (PPIs) have various off-target effects, their clinical impact on L-OHP-induced CIPN remains unclear. In the present study, we investigated the effects of PPIs on L-OHP-induced CIPN in patients using two real-world clinical databases. Patients and Methods: We retrospectively analyzed the electronic medical records of Osaka University Hospital to examine the effect of PPIs on CIPN development in 217 patients who received XELOX (L-OHP plus capecitabine) therapy for colorectal cancer. In addition, the Japanese Adverse Drug Event Report (JADER) database was used to validate the effects of PPIs on L-OHP-induced CIPN. Results: The incidences of CIPN (grade ≥2) and discontinuation of L-OHP were significantly lower in patients with PPIs than in those without PPIs. Multivariate analysis showed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of grade ≥2 CIPN (odds ratio=0.054, p<0.001). Kaplan–Meier analysis showed that the time to onset of grade ≥2 CIPN was significantly prolonged in patients with PPIs without affecting the therapeutic efficacy of L-OHP (p=0.004). Moreover, JADER database analyses revealed that the reporting odds ratio of any PPI for L-OHP-induced CIPN was 0.485. Conclusion: Concomitant PPI use ameliorated L-OHP-induced CIPN in patients with colorectal cancer.

Key Words:

Oxaliplatin (L-OHP) is a platinum-based anticancer drug widely used to treat various cancers, including colorectal and gastric cancer (1). Chemotherapy-induced peripheral neuropathy (CIPN) is a major clinical problem associated with L-OHP owing to its high incidence (2). In particular, chronic peripheral neuropathy caused by L-OHP is dose limiting (3). Its onset significantly reduces the patient’s quality of life owing to physical discomfort, necessitating treatment modification or discontinuation (4). To date, both basic and clinical studies have investigated prophylaxis and/or therapy for CIPN; however, effective prevention strategies for CIPN remain to be established. Therefore, effective and safe preventive strategies for CIPN are urgently required.

L-OHP-induced CIPN underlying mechanism is known to involve the production of oxidative stress and neuroinflammation in the central and dorsal root ganglia (DRG) (5-7). Cytotoxicity in neurons is caused by the induction of demyelination, mitochondrial dysfunction, microtubular damage, and apoptosis through L-OHP-induced oxidative stress and neuroinflammation (8, 9). Moreover, L-OHP induces glial cell activation in the spinal cord (10). Activated glial cells are associated with the release of inflammatory cytokines, formation of free radicals, increased pain sensitivity, and development of L-OHP-induced neuropathy (11, 12). Inflammatory cytokines, such as interleukins (IL-1β and IL-6) and tumor necrosis factor-α (TNF-α) stimulate neurons and glial cells in the spinal cord, resulting in neuronal hyperexcitation in CIPN (13). These findings suggest that L-OHP-induced oxidative stress and neuroinflammation are important factors in CIPN development. Therefore, drugs with antioxidant and/or anti-inflammatory properties may serve as prophylactic and/or therapeutic agents for CIPN treatment.

Proton pump inhibitors (PPIs) are the most commonly prescribed drugs for the treatment of gastroesophageal hyperacidity (14). An estimated 20% of cancer patients are treated with PPIs to alleviate gastroesophageal reflux symptoms (15). In addition to the on-target inhibition of H+/K+-ATPase, PPIs are known to have several off-target effects, including antioxidant and anti-inflammatory (16-18). A recent study reported that omeprazole, a PPI, suppressed L-OHP-induced CIPN in mice (19). Additionally, database analysis of the FDA Adverse Event Reporting System (FAERS) showed that PPIs, such as pantoprazole and rabeprazole significantly decreased the reporting odds ratio of L-OHP-induced CIPN (19). Hence, PPIs are promising practical prophylactic agents against L-OHP-induced CIPN. However, the effect of PPIs on L-OHP-induced CIPN in the clinical setting remains unclear.

In the present study, the impact of concomitant PPIs on CIPN development in patients receiving L-OHP was examined using two real-world clinical databases: electronic medical records and the Japanese Adverse Drug Event Report (JADER) database.

Patients and Methods

Patients. Data from 343 patients who received chemotherapy with XELOX (L-OHP plus capecitabine) for the first time for colorectal cancer between April 2013 and January 2022 were extracted from the electronic medical records of the Osaka University Hospital. Eligible patients received a 2 h intravenous infusion of L-OHP 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2/day for 14 days. The XELOX regimen was repeated four to eight times every 3 weeks. Patients were excluded if: they had missing data; previously received L-OHP; had a history of peripheral neuropathy associated with other anticancer agents or diseases; received a XELOX regimen of one cycle or less; or had a history of use of antidepressants, anticonvulsants, or other neuropathic pain medications. Patients receiving PPIs were defined as those who continued PPIs treatment during XELOX therapy. In addition, the periodic co-administration of drugs and medical history, which may affect the development and severity of CIPN, were investigated. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethical review board of Osaka University Hospital (No. 16002-13). Informed consent was obtained from all patients via an opt-out from the website.

Assessment. The severity of adverse events was evaluated by physicians according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CIPN that developed during XELOX therapy was evaluated in accordance with the following criteria: Peripheral sensory neuropathy was classified as follows: grade 1, loss of deep tendon reflexes or paresthesia; grade 2, limited instrumental activities of daily living (ADL); and grade 3, limited self-care ADL. The primary endpoint was the rate of grade ≥2 CIPN. The secondary endpoints were the severity of CIPN, incidence of other adverse events leading to discontinuation of XELOX therapy, rates of dose withdrawal due to CIPN, and time to treatment failure (TTF) of XELOX therapy. TTF was defined as the time from the initiation of XELOX therapy to treatment discontinuation.

JADER database analyses. Data on patient demographics (DEMO), drugs received (DRUG), adverse events (REAC), and primary diseases (HIST) from April 2004 to December 2022 were obtained from the JADER database released by the PMDA. The data associated with L-OHP were extracted. Disease names were defined using the Medical Dictionary for Regulatory Activities (MedDRA/J) version 26.0. The preferred term of “Neuropathy peripheral” was used for searching CIPN associated L-OHP. The effect of PPIs on L-OHP-associated CIPN was evaluated using reporting odds ratios (ROR). To calculate the ROR, CIPN-associated with L-OHP and all other reported adverse events associated with L-OHP were defined as “cases” and “non-cases”, respectively. RORs were calculated from two-by-two contingency tables of counts with or without PPI. RORs were expressed as point estimates with 95% confidence intervals (CI).

Statistical analyses. Statistical comparisons between the two groups were performed using the Mann–Whitney U-test and Fisher’s exact test for continuous and categorical variables, respectively. The incidences of CIPN and TTF were analyzed using the Kaplan–Meier curve method and log-rank test. Multivariate logistic regression analysis was performed to identify the effect of concomitant PPIs on the development of grade ≥2 CIPN following XELOX therapy. The logistic regression model was adjusted for the following potential confounding factors: age, male, body mass index, total L-OHP dose, baseline albumin level, estimated glomerular filtration rate, hemoglobin level, diabetes mellitus, and concomitant use of statins and neuropathic pain agents. Statistical analyses were performed using JMP® Pro version 16.2.0 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at two-tailed p<0.05, and the confidence level was set to 95%.

Results

After considering the inclusion and exclusion criteria, 217 of 343 patients were enrolled in the present study using electronic medical records. Patient characteristics are summarized in Table I. Thirty-eight patients (18%) received PPIs, while 179 patients (82%) did not receive PPIs. Patients treated with PPIs were prescribed the following: lansoprazole 15 mg/day (n=10) or 30 mg/day (n=8); esomeprazole 10 mg/day (n=3) or 20 mg/day (n=12); rabeprazole 10 mg/day (n=5). The median hemoglobin level was significantly lower in patients with PPIs than in those without PPIs (p<0.001), whereas the rates of diabetes mellitus and concomitant statin use were significantly higher in patients with PPIs than in those without PPIs (34% vs. 17%, p=0.023, 32% vs. 14%, p=0.016, respectively). No significant differences were observed in other patient characteristics between patients treated with and without PPIs.

View this table:
Table I.

Patient characteristics.

The incidence of CIPN and other adverse events following XELOX therapy is shown in Table II. Although all patients developed CIPN (grade ≥1), the ratios of grade ≥2 CIPN and discontinuation of L-OHP due to CIPN in patients with PPIs were markedly lower than those in patients without PPIs (3% vs. 26%, p=0.001, 3% vs. 20%, p=0.008, respectively). Moreover, severe CIPN (grade ≥3) was not observed in patients treated with PPIs. In contrast, there were no significant differences in the incidence of other XELOX-induced adverse events between the patients treated with and without PPIs.

View this table:
Table II.

Incidence of CIPN and other adverse events following XELOX therapy.

Multivariate logistic regression analysis was performed to evaluate the impact of concomitant PPI use on the development of grade ≥2 CIPN in patients who underwent XELOX therapy (Table III). Among the potential clinical prognostic factors, multivariate analysis showed that concomitant PPI use was the only significant factor that affected the incidence of grade ≥2 CIPN (odds ratio=0.054, p<0.001). In contrast, the other investigated variables had no significant influence on the development of grade ≥2 CIPN following XELOX therapy.

View this table:
Table III.

Multivariate analysis for CIPN (grade ≥2) following XELOX therapy.

Using Kaplan-Meier analysis, we evaluated the impact of concomitant PPI use on grade ≥2 CIPN (Figure 1A) and TTF (Figure 1B) following XELOX therapy in patients treated with and without PPIs. As shown in Figure 1, the rate of grade ≥2 CIPN following XELOX therapy in patients treated with PPIs was significantly prolonged (p=0.004, log-rank test) in comparison with patients without PPIs. In contrast, there were no significant differences in the TTF following XELOX therapy between patients treated with and without PPIs (Figure 1B).

Figure 1.
Figure 1.

Kaplan–Meier analysis of chemotherapy-induced peripheral neuropathy (CIPN) (A) and time to treatment failure (TTF) (B) following XELOX therapy in patients treated with proton pump inhibitors (PPIs) (n=38) and without PPIs (n=179).

A total of 817,162 reports from the JADER database from April 2004 to December 2022 were analyzed. A total of 614 CIPN cases were identified among the 14,131 patients who received L-OHP. The results of the reporting ratio of CIPN associated with L-OHP and RORs with 95%CI in patients receiving L-OHP are summarized in Figure 2. The ROR (95%CI) for each PPI was as follows:0.502 (0.267-0.945, p=0.031) for lansoprazole, 0.280 (0.070-1.133, p=0.072) for omeprazole, 0.474 (0.195-1.154, p=0.105) for esomeprazole, and 0.594 (0.279-1.265, p=0.220) for rabeprazole. In addition, the reporting ratio of CPIN in patients with any PPI (2.2%) was significantly lower than that in patients without PPIs (4.5%; p<0.001).

Figure 2.
Figure 2.

Analyses on the effect of proton pump inhibitors (PPIs) on chemotherapy-induced peripheral neuropathy (CIPN) in patients treated with L-OHP using the JADER database. Reporting rate of CIPN (any grade) in patients with L-OHP is presented as cases/(cases + non-cases) (%). Fisher’s exact test was performed.

Discussion

Little is known about the effects of PPIs on the development of L-OHP-induced CIPN in the clinical setting. To the best of our knowledge, this is the first study to report the preventive effects of concomitant PPI use on the development of L-OHP-induced CIPN in the clinical setting.

In the present study using electronic medical records, the incidence of grade ≥2 CIPN and L-OHP discontinuation in patients treated with PPIs was significantly lower than that in patients without PPIs (Table II). Moreover, multivariate analysis showed that concomitant PPI use was an independent factor that significantly contributed to the prevention of grade ≥2 CIPN (Table III). Moreover, analyses using the JADER database revealed that the CIPN reporting rate in patients receiving any PPI was significantly lower than that in patients without PPIs (Figure 2). These findings suggest that concomitant PPI use should ameliorate CIPN associated with L-OHP in the clinical settings. Our findings are consistent with the results of a previous study using the FAERS database analysis and in vivo studies using mice (19).

As shown in Figure 1A, Kaplan–Meier analysis showed that the time to onset of grade ≥2 CIPN in patients with PPIs was significantly longer than that in patients without PPIs. Tanishima et al. (20) reported that L-OHP-induced CIPN is cumulatively toxic, and that the early occurrence of CIPN increases the risk of serious CIPN. In patients treated with PPIs, the incidence of grade ≥2 CIPN was only 3%, and severe CIPN (grade ≥3) was not observed (Table II). These findings indicate that PPIs could suppress CIPN exacerbation by delaying its onset.

However, no significant differences were observed between the incidence of other adverse events, excluding CIPN (Table II) and TTF of XELOX therapy (Figure 1B), in patients with and without PPIs. L-OHP is mainly eliminated from the kidney, and organic cation transporter 2 (OCT2) expressed in renal proximal tubules is responsible for the urinary secretion of L-OHP (21). Because PPIs have OCT2 inhibitory effects as off-target effect (22), it is possible that elevated blood levels of L-OHP caused by concomitant PPI use may influence the toxicity and efficacy of L-OHP. However, it has been reported that the plasma concentration of L-OHP is not altered by OCT2 knockout in mice (23). In addition, omeprazole was reported to have no effect on the suppression of tumor growth by L-OHP in tumor-bearing mice (19). Accordingly, these findings suggest that loss of function or inhibition of OCT2 could have little impact on the pharmacokinetics and pharmacodynamics of L-OHP. However, additional investigations are required to confirm the altered pharmacokinetics of L-OHP during the co-administration of PPI because the plasma concentration of L-OHP was not determined in the present study.

Interestingly, it is known that OCT2 is also expressed in the DRG and is involved in the accumulation of L-OHP in DRG neurons and development of neuropathy (24). A previous study reported that dasatinib, a tyrosine kinase inhibitor, inhibits OCT2-mediated accumulation of L-OHP in DRGs and alleviates neuropathic pain in mice (25). Moreover, cimetidine, a competitive OCT2 inhibitor, ameliorated L-OHP-induced sensitivity to cold at concentrations much higher than the clinical dose (24). Thus, inhibition of OCT2-mediated transport of L-OHP by PPIs in the DRG may contribute to the prevention of L-OHP-induced neurotoxicity. However, the inhibitory effect of PPI on L-OHP-induced neurotoxicity via OCT2 has not been fully elucidated, and further studies are needed to evaluate the mechanism of action of L-OHP-induced CIPN.

PPIs are widely used for gastrointestinal disorders and are recognized as relatively safe drugs. In addition, they are known to have a variety of off-target effects, including antioxidant and anti-inflammatory effects (17). The pathogenesis of L-OHP-induced CIPN is mainly related to inflammation and oxidative stress (5-7). Therefore, the antioxidant and anti-inflammatory effects of PPIs could contribute to the prevention of L-OHP-induced CIPN. Moreover, our recent clinical study demonstrated that PPIs could ameliorate capecitabine-induced hand-foot syndrome associated with inflammation (26). Thus, it is possible that PPIs may have applications in other diseases and adverse events caused by inflammation and/or oxidative stress.

A recent retrospective study of patients receiving L-OHP demonstrated that the incidence of CIPN (grade ≥1) in statin users (65%) was significantly lower than that in non-statin users (88%) (27). Because the CIPN (grade ≥1) was observed in all patients enrolled in the present study, we could not evaluate the effect of concomitant statin use on the development of CIPN (grade ≥1). Since dose interruption and dose reduction are recommended for patients who develop grade ≥2 CIPN but not grade ≥1 CIPN, avoiding the development of CIPN (grade ≥2) could be beneficial to patients. Thus, we evaluated the effect of concomitant agents on CIPN (grade ≥2) using multivariate analysis. The results showed that concomitant PPI use but not statin use was an independent factor that significantly contributed to the prevention of L-OHP-induced grade ≥2 CIPN (Table III). Therefore, we believe that PPIs could be superior to statins in preventing grade ≥2 CIPN.

Study limitations. First, this study included patients from a single institution, and the possibility of a selection bias could not be ruled out. Furthermore, the retrospective nature of this study made it difficult to examine potential confounders. Therefore, future large-scale, multicenter prospective studies should be conducted to evaluate the effects of PPIs on the safety, efficacy, and pharmacokinetics of L-OHP. Second, the external validity of this study may not apply to other cancers and other cancer chemotherapies, including L-OHP, as we focused on patients with colorectal cancer receiving XELOX therapy in the present study. Finally, the JADER database contains biases in reporting rates due to under- and over-reporting. However, the findings of the JADER database analysis were consistent with those of the present retrospective study. Further in vitro and in vivo studies are required to elucidate the detailed mechanisms underlying the amelioration of L-OHP-induced CIPN by PPIs.

Conclusion

In conclusion, this study is the first to demonstrate that concomitant PPI use ameliorates L-OHP-induced CIPN in patients with colorectal cancer without affecting the therapeutic efficacy of L-OHP. The present findings provide important information for establishing novel protective approaches to minimize CIPN.

Acknowledgements

The Authors would like to thank Editage (www.editage.jp) for the English language editing.

Footnotes

  • Authors’ Contributions

    All the Authors have read and approved the final version of the manuscript. A.K., K.I., and M.O. contributed to study conception and design. Material preparation, data collection, and analyses were performed by A.K., K.I., E.W., and M.K. The first draft of the manuscript was written by A.K. and K.I. All Authors commented on the previous versions of the manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Funding

    This work was supported by JSPS KAKENHI Grant Numbers JP23K06210, JP23H05316.

  • Received October 20, 2023.
  • Revision received November 14, 2023.
  • Accepted November 15, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases
AKIHIDE KOBAYASHI, KENJI IKEMURA, ERI WAKAI, MASAYOSHI KONDO, MASAHIRO OKUDA
Anticancer Research Dec 2023, 43 (12) 5613-5620; DOI: 10.21873/anticanres.16764
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