Drug-Drug Interaction Between Capecitabine and PPIs Reduces Survival in GI Cancers

Drug-Drug Interaction Between Capecitabine and PPIs Reduces Survival in GI Cancers
Drug-Drug Interaction Between Capecitabine and PPIs Reduces Survival in GI Cancers

Patients receiving capecitabine for gastrointestinal cancers should avoid using proton pump inhibitors (PPIs) for gastric acid suppression or gastrointestinal bleeding, according to a study published in JAMA Oncology.1

Capecitabine is commonly prescribed for gastric cancer, and also has indications for colorectal and breast cancers. Proton pump inhibitors are commonly used to treat heartburn and gastrointestinal bleeding. PPIs are also available as over-the-counter remedies for heartburn and gastric acid suppression (eg, Nexium, Prevacid, and Protonix).

In a secondary analysis of TRIO-013 (ClinicalTrials.gov Identifier: NCT00680901), a phase 3 randomized trial with 545 patients with metastatic GEC (median age, 60 years; 74% [406] men) who received capecitabine and oxaliplatin and were randomized to treatment with or without lapatinib, researchers sought to determine if PPIs impair the efficacy of capecitabine in patients with metastatic gastroesophageal cancer (GEC).

For the study, use of proton pump inhibitors was confirmed by review of patients' medication records. Researchers compared progression-free survival and overall survival among patients who were treated with PPIs vs those who were not. Multivariate Cox proportional hazards modeling was used to account for younger age (younger than 60 years), Asian ethnicity, female sex, and disease stage (metastatic/advanced).

Of the patients included in this analysis, 229 received PPIs (42.0%) and were evenly distributed between the 2 treatment arms.

Among those who did not receive lapatinib (placebo arm), patients treated with PPIs had worse median progression-free survival (4.2 months vs 5.7 months; HR, 1.55; 95% CI, 1.29-1.81, P <.001), overall survival (9.2 months vs 11.3 months; HR, 1.34; 95% CI, 1.06-1.62; P =.04), and disease control rate (83% vs 72%; P =.02) compared with those patients who were not treated with PPIs.

Multivariate analysis demonstrated that progression-free survival (HR, 1.68; 95% CI, 1.42-1.94; P <.001) and overall survival (HR, 1.41; 95% CI, 1.11-1.71; P =.001) were worse in patients treated with proton pump inhibitors.

Among those patients in the lapatinib (treatment) arm, the effect of PPIs on progression-free survival (HR, 1.08; P =.54) and overall survival (HR, 1.26; P = .10) was less; however, overall survival was significantly different (HR, 1.38; 95% CI, 1.06-1.66; P =.03) in this group on multivariate analysis.

These results demonstrate that because proton pump inhibitors may raise gastric pH levels, use of these drugs has a negative effect on dissolution and absorption of capecitabine; however, their effect on lapatinib is unclear.

Results in previous studies with erlotinib and sunitinib were consistent with these findings. Because capecitabine is also used in the treatment of breast cancer and colon cancer, further studies are in process.

Reference

1. Chu MP, Hecht JR, Slamon D, et al. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: Secondary analysis of the TRIO-013/LOGiC randomized clinical trial. 2016 Oct 13. doi: 10.1001/jamaoncol.2016.3358. [epub ahead of print]

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