Error in Title of Letter to the Editor
Authors: Michael Chu, Michael Sawyer
Journal: JAMA Oncology (2017)

In Reply We thank these authors for their interest in our article.It is true that this definition of 20% or more concurrent overlap might have led to an apparent decrease in capecitabineproton pump inhibitor (PPI) effect, but we were more willing to accept finding a PPI effect and underestimating the interaction than to miss the interaction entirely, for 2 reasons.First, we do not believe that taking a PPI for 3 days (<20%) out of 14 days of capecitabine administration would have clinically meaningful effects.Furthermore, for brevity in the original article, we did not specify that almost all patients identified as having less than 20% concurrent PPI and capecitabine exposure had in fact never taken a PPI.Second, we have successfully used this definition of concurrent use for other PPIfocused oncology studies 1-3 -for continuity, we continued this definition in this study.We found similar concerning results with patients receiving concurrent PPIs and adjuvant capecitabine in patients with colon cancer, for whom 5-year recurrence-free survival was 74% vs 83% in those not receiving a PPI (P = .03). 3 In the absence of knowing the exact timing of PPI intake in relation to capecitabine and associated pharmacokinetics, we agree that we cannot rule out that it may be possible to dose capecitabine with an adequate interval between the PPI and capecitabine.Conversely, neither can we say that it is safe to space the dosing in this manner in the absence of a prospective study designed as such.A pharmacogenetic difference may exist between ethnic groups that affects tyrosine kinase inhibitor metabolism.Our data, however, may suggest that regional differences exist based on prescribing patterns.We originally investigated TRIO-013 because lapatinib has potential pH solubility issues. 4 Proton pump inhibitor effects on capecitabine (and oxaliplatin's requirement of having a concurrent fluoropyrimidine for activity) overshadowed any potential PPI effects on lapatinib.In TRIO-013, Asian patients were more commonly prescribed PPIs than western European patients (P < .001).Given lapatinib's potential pH-dependent solubility, future lapatinib pharmacogenetic studies between ethnic groups will have to take into consideration regional prescribing patterns.It is pragmatic to consider use of PPIs to be time independent in patients with gastric cancer because there are generally 3 reasons for them to take PPIs: (1) symptomatic bleeding, (2) endoscopic discovery of a large malignant ulcer, and (3) dyspepsia as an adverse effect from oral capecitabine therapy.Another factor that Hussaarts et al raise is whether once-daily PPI dosing may have less impact than twice-daily dosing.They also correctly identify that the specific PPI is important because they have differences in both degree of gastric pH change, as well as duration of activity.For example, esomeprazole and pantoprazole will typically lead to gastric pH changes for 80% and 50% of 12 hours, respectively. 5Many of these patients will present with either gastrointestinal bleeding or ulcerating tumors, necessitating maximal PPI treatment.With what limited data are available regarding prescribing habits (even in a noncancer population), PPIs tend to be propagated as originally prescribed in a majority of patients.