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Proton pump inhibitors lower capecitabine efficacy in gastroesophageal cancer
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Use of proton pump inhibitors reduced the efficacy of capecitabine in patients with advanced gastroesophageal cancer, according to an analysis of results from a randomized clinical trial.
Researchers attributed the reduced efficacy to a possible rise in gastric pH levels, which resulted in changes in the dissolution and absorption of capecitabine.
“These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving proton pump inhibitor (PPI) treatment and adjuvant capecitabine also experienced poorer RFS compared with patients not receiving a PPI,” Michael P. Chu, MD, assistant professor in the department oncology at Cross Cancer Institute in Canada, and colleagues wrote. “Taken together, this ad hoc analysis gives further support that a negative interaction exists between capecitabine and PPIs and warrants further investigation.”
Chu and colleagues used data from the randomized phase 3 TRIO-O13/LOGiC trial, which compared capecitabine and oxaliplatin with or without lapatinib (Tykerb, Novartis) in patients with ERBB2/HER-2–positive gastroesophageal cancer to determine whether PPIs hinder capecitabine efficacy.
All participants from the study’s intention-to-treat cohort (n = 545; 74% male; median age, 60 years) were included in the analysis, 96% of whom had metastatic disease. PFS and OS served as the primary outcome. Secondary outcomes included disease response rate and toxicity.
Forty-two percent of patients (n = 229) received PPIs (lapatinib, n = 110; control, n = 119).
Among patients who received capecitabine and oxaliplatin alone, those who received PPIs achieved shorter median PFS, (4.2 months vs. 5.7 months; HR = 1.55; 95% CI, 1.29-1.81) and shorter median OS (9.2 months vs. 11.3 months; HR = 1.34; 95% CI, 1.06-1.62).
A multivariate analysis that accounted for disease stage, race, sex and age also showed that patients who received PPIs achieved shorter PFS (HR = 1.68; 95% CI, 1.42-1.94) and OS (HR = 1.41; 95% CI, 1.11-1.71).
Among patients who received capecitabine, oxaliplatin and lapatinib, PPIs had less of an effect on PFS (HR = 1.08) and OS (HR = 1.26). However, multivariate analysis revealed a significant difference in OS (HR = 1.38; 95% CI, 1.06-1.66).
“This secondary analysis of TRIO-O13/LOGiC confirms previous retrospective data that concomitant use of gastric acid suppressants such as PPIs with capecitabine may lower the antitumor efficacy of capecitabine,” Chu and colleagues wrote. “However, this trial did not examine for pharmacokinetics and circulating drug levels, so a direct link with potential reduced capecitabine absorption cannot be made in this analysis.”
The development of oral chemotherapeutics makes this finding more concerning, according to the researchers.
“Other oral drugs … may suffer from the same drug interaction phenomenon,” Chu and colleagues wrote. “While stopping gastric acid suppressants may prove difficult, it may be possible to temporarily counteract a lowered absorption by using an acidic beverage for drug administration. Overall, more food-effect studies are warranted in the development of oral therapeutics, and our study draws to light the possibility that such an interaction may also affect more commonly used cytotoxic chemotherapeutics, such as capecitabine, used across tumor subtypes.” – by Andy Polhamus
Disclosure: Chu reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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