Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial.

IMPORTANCE: Capecitabine is an oral cytotoxic chemotherapeutic commonly used across cancer subtypes. As with other oral medications though, it may suffer from drug interactions that could impair its absorption. OBJECTIVE: To determine if gastric acid suppressants such as proton pump inhibitors (PPIs) may impair capecitabine efficacy. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of TRIO-013, a phase III randomized trial, compares capecitabine and oxaliplatin (CapeOx) with or without lapatinib in 545 patients with ERBB2/HER2-positive metastatic gastroesophageal cancer (GEC); patients were randomized 1:1 between CapeOx with or without lapatinib. Proton pump inhibitor use was identified by medication records. Progression-free survival (PFS) and overall survival (OS) were compared between patients treated with PPIs vs patients who were not. Specific subgroups were accounted for, such as younger age (<60 years), Asian ethnicity, female sex, and disease stage (metastatic/advanced) in multivariate Cox proportional hazards modeling. The TRIO-013 trial accrued and randomized patients between June 2008 and January 2012; this analysis took place in January 2014. INTERVENTIONS: Patients were divided based on PPI exposure. MAIN OUTCOMES AND MEASURES: Primary study outcome was PFS and OS between patients treated with PPIs vs patients who were not. Secondary outcomes included disease response rates and toxicities. RESULTS: Of the 545 patients with GEC (median age, 60 years; 406 men [74%]) included in the study, 229 received PPIs (42.0%) and were evenly distributed between arms. In the placebo arm, PPI-treated patients had poorer median PFS, 4.2 vs 5.7 months (hazard ratio [HR], 1.55; 95% CI, 1.29-1.81, P < .001); OS, 9.2 vs 11.3 months (HR, 1.34; 95% CI, 1.06-1.62; P = .04); and disease control rate (83% vs 72%; P = .02) vs patients not treated with PPIs. In multivariate analysis considering age, race, disease stage, and sex, PPI-treated patients had poorer PFS (HR, 1.68; 95% CI, 1.42-1.94; P < .001) and OS (HR, 1.41; 95% CI, 1.11-1.71; P = .001). In patients treated with CapeOx and lapatinib, PPIs had less effect on PFS (HR, 1.08; P = .54) and OS (HR, 1.26; P = .10); however, multivariate analysis in this group demonstrated a significant difference in OS (HR, 1.38; 95% CI, 1.06-1.66; P = .03). CONCLUSIONS AND RELEVANCE: Proton pump inhibitors negatively effected capecitabine efficacy by possibly raising gastric pH levels, leading to altered dissolution and absorption. These results are consistent with previous erlotinib and sunitinib studies. Whether PPIs affected lapatinib is unclear given concurrent capecitabine. Given capecitabine's prevalence in treatment breast cancer and colon cancer, further studies are under way. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00680901.

Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial.

PURPOSE: To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS: Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250 mg or placebo daily. Primary end point was overall survival (OS) in patients with centrally confirmed HER2 amplification in the primary efficacy population. RESULTS: A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. CONCLUSION: Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation.

Seasonal allergic rhinitis is associated with a detrimental effect on examination performance in United Kingdom teenagers: case-control study.

BACKGROUND: Seasonal allergic rhinitis is common globally, and symptoms have been shown to impair learning ability in children in laboratory conditions. Critical examinations in children are often held in the summer during the peak grass pollen season. OBJECTIVE: To investigate whether seasonal allergic rhinitis adversely impacts examination performance in United Kingdom teenagers. METHODS: Case-control analysis of 1,834 students (age 15-17 years; 50% girls) sitting for national examinations. Cases were those who dropped 1 or more grades in any of 3 core subjects (mathematics, English, and science) between practice (winter) and final (summer) examinations; controls were those whose grades were either unchanged or improved. Associations between allergic rhinitis symptoms, clinician-diagnosed allergic rhinitis, and allergic rhinitis-related medication use, recorded on examination days immediately before the examination, were assessed using multilevel regression models. RESULTS: Between 38% and 43% of students reported symptoms of seasonal allergic rhinitis on any 1 of the examination days. There were 662 cases (36% of students) and 1,172 controls. After adjustment, cases were significantly more likely than controls to have had allergic rhinitis symptoms during the examination period (odds ratio [OR], 1.4; 95% CI, 1.1-1.8; P = .002), to have taken any allergic rhinitis medication (OR, 1.4; 95% CI, 1.1-1.7; P = .01), or to have taken sedating antihistamines (OR, 1.7; 95% CI, 1.1-2.8; P = .03). CONCLUSION: Current symptomatic allergic rhinitis and rhinitis medication use are associated with a significantly increased risk of unexpectedly dropping a grade in summer examinations. CLINICAL IMPLICATIONS: This is the first time the relationship between symptomatic allergic rhinitis and poor examination performance has been demonstrated, which has significant implications for clinical practice.