title: Association of Proton Pump Inhibitors and Capecitabine Efficacy in Advanced Gastroesophageal Cancer: Secondary Analysis of the TRIO-013/LOGiC Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Patients were divided based on PPI exposure.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00680901.
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Chu
authors.affiliation: Jonsson Comprehensive Cancer Center, Department of Clinical and Translational Research, University of California-Los Angeles, Los Angeles.
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
authors.affiliation: Jonsson Comprehensive Cancer Center, Department of Clinical and Translational Research, University of California-Los Angeles, Los Angeles.
authors.forename: Dennis
authors.initials: D
authors.lastname: Slamon
authors.affiliation: Jonsson Comprehensive Cancer Center, Department of Clinical and Translational Research, University of California-Los Angeles, Los Angeles.
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: Instituto do Cancer do Estado de Sao Paulo, Universidade de Sao Paolo, Sao Paolo, Brazil.
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Hoff
authors.affiliation: IRCCS Ospedale San Martino IST, Medical Oncology, Largo Benzi 10 Genova, 16132, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Sobrero
authors.affiliation: Department of Oncology, The 81 Hospital of the Chinese People's Liberation Army, Nanjing, China.
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.affiliation: Project Management, Translational Research in Oncology (TRIO), Paris, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Afenjar
authors.affiliation: Department of Biostatistics, TRIO, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Houe
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: King
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Koski
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Mulder
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Julie Price
authors.initials: JP
authors.lastname: Hiller
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Scarfe
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Spratlin
authors.affiliation: Department of Research and Development Projects, Clinical Platforms and Sciences, GlaxoSmithKline (GSK), Middlesex, United Kingdom.
authors.forename: Yingjie J
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Department of Research and Development Projects, Clinical Platforms and Sciences, GlaxoSmithKline (GSK), Middlesex, United Kingdom.
authors.forename: Saba
authors.initials: S
authors.lastname: Khan-Wasti
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: Chua
authors.affiliation: Cross Cancer Institute, Department of Oncology, Edmonton, Alberta, Canada.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sawyer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine / Q000008:administration & dosage; D004347:Drug Interactions; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D054328:Proton Pump Inhibitors / Q000009:adverse effects*; D011799:Quinazolines / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D054328:Proton Pump Inhibitors; D011799:Quinazolines; D000077150:Oxaliplatin; D000077341:Lapatinib; D000069287:Capecitabine