Proton pump inhibitor concomitant use to prevent oxaliplatin-induced peripheral neuropathy: Clinical retrospective cohort study

Abstract

Background: Oxaliplatin-induced peripheral neuropathy (OIPN) is a major clinical challenge because it leads to discontinuation of chemotherapy. Omeprazole, a proton pump inhibitor (PPI), has been shown to prevent OIPN in a rat model. Therefore, we aimed to test whether the concomitant use of a PPI reduces oxaliplatin discontinuation due to OIPN.

Methods: This retrospective study used data from 1015 patients who started treatment with oxaliplatin and evaluated two cohorts (PPI vs. non-PPI). The primary outcome measure was oxaliplatin discontinuation due to OIPN. A Kaplan-Meier curve was generated for cumulative doses and evaluated using the log-rank test and Cox proportional hazards analysis.

Results: The log-rank test showed that the number of patients who discontinued oxaliplatin due to OIPN was significantly lower in the PPI group (p = 0.0264). Cox proportional hazards analysis incorporated and analyzed factors previously reported as potentially affecting neuropathy (sex, age, use of PPIs, calcium channel antagonists, opioids and adjuvant analgesics, and the CAPOX [capecitabine + oxaliplatin] regimen). The analysis suggested that the concomitant use of PPIs was a factor in reducing oxaliplatin discontinuation (adjusted hazard ratio [HR] = 0.568, 95% confidence interval [CI], 0.344-0.937, p = 0.0269). Since there were significant differences in some patient demographics between the two groups, propensity score matching was performed to align the patient demographics and then reanalyzed. After propensity score matching, the same analysis as above showed that oxaliplatin discontinuation due to OIPN was significantly less common in the PPI group (p = 0.0081); cox proportional hazards analysis showed that PPI use was a factor that significantly reduced oxaliplatin discontinuation due to OIPN (adjusted HR = 0.478, 95% CI, 0.273-0.836, p = 0.0096).

Conclusions: These results suggest that concomitant PPI use may reduce oxaliplatin discontinuation due to OIPN in patients receiving oxaliplatin.

Keywords: drug repositioning; oxaliplatin; peripheral nerve injuries; proton pump inhibitors; retrospective studies.

FIGURE 1

Classification of patients surveyed. The study included 1180 patients starting oxaliplatin‐related regimens. Of these, 165 were patients with diabetes and were excluded from subsequent analyses, leaving 1015 patients. Of the 1015 patients, 205 were in the proton pump inhibitor (PPI) group and 810 were in the no‐PPI group. Propensity score matching was performed, and 193 participants in the PPI group were matched with the corresponding 193 participants in the no‐PPI group.

FIGURE 2

Kaplan–Meier curves of cumulative incidence of oxaliplatin‐induced peripheral neuropathy (OIPN) (before propensity score matching). Kaplan–Meier curves were constructed with oxaliplatin discontinuation due to OIPN (A), incidence of OIPN (any grade) (B), ≥ Grade 2 (C), ≥ Grade 3 (D), and oxaliplatin dose reduction due to OIPN (E) on the y‐axis and the cumulative dose of oxaliplatin on the x‐axis. Differences in cumulative incidence between the proton pump inhibitor (PPI) and no‐PPI groups were analyzed using the log‐rank test.

FIGURE 3

Multivariate analysis of variables associated with oxaliplatin discontinuation due to oxaliplatin‐induced peripheral neuropathy (OIPN) (before propensity score matching). Cox proportional hazards analysis was then performed incorporating factors reported to influence OIPN (sex, regimen, age, use of proton pump inhibitors, use of opioids, use of adjuvant analgesics, and use of calcium channel blockers) as covariates.

FIGURE 4

Kaplan–Meier curves of cumulative incidence of oxaliplatin‐induced peripheral neuropathy (OIPN) (after propensity score matching). Kaplan–Meier curves were constructed with oxaliplatin discontinuation due to OIPN (A), incidence of OIPN (any grade) (B), ≥ Grade 2 (C), ≥ Grade 3 (D), and oxaliplatin dose reduction due to OIPN (E) on the y‐axis and the cumulative dose of oxaliplatin on the x‐axis. Differences in cumulative incidence between the proton pump inhibitor (PPI) and no‐PPI groups were analyzed using the log‐rank test.

FIGURE 5

Multivariate analysis of variables associated with oxaliplatin discontinuation due to oxaliplatin‐induced peripheral neuropathy (OIPN) (after propensity score matching). Cox proportional hazards analysis was then performed incorporating factors reported to influence OIPN (sex, regimen, age, use of proton pump inhibitors, use of opioids, use of adjuvant analgesics, and use of calcium channel blockers) as covariates.