Effects of Proton Pump Inhibitors Intake During Chemoradiotherapy for Rectal Cancer: a Retrospective Cohort Study

Do proton pump inhibitors affect the effectiveness of chemotherapy in colorectal cancer patients? A systematic review with meta-analysis

“…Two post hoc analyses ( Kichenadasse et al, 2021 ; Kim et al, 2021 ) were included for quantitative analysis, while the RCTs ( Hurwitz et al, 2004 ; Saltz et al, 2008 ; Schmoll et al, 2012 ; Van Cutsem et al, 2012 ; Carrato et al, 2013 ; Tabernero et al, 2015 ; Xu et al, 2018 ) were included for qualitative analysis. Five studies ( Sun et al, 2016 ; Zhang et al, 2017 ; Wong et al, 2019 ; Bridoux et al, 2022 ; Kitazume et al, 2022 ) enrolled early-stage patients, 8 studies ( Hurwitz et al, 2004 ; Saltz et al, 2008 ; Schmoll et al, 2012 ; Van Cutsem et al, 2012 ; Carrato et al, 2013 ; Tabernero et al, 2015 ; Wang et al, 2017 ; Xu et al, 2018 ) investigated end-stage patients, and 1 study ( Rhinehart et al, 2019 ) included patients of all stages. Of note, the population enrolled in AXEPT ( Xu et al, 2018 ) trial was Asian only, and included patients from China, Japan, and Korea.…”

“…A total of 8,118 patients (PPI = 1,789; non-PPI = 6,329) 295 enrolled between 2000 and 2022 were included in the present 296 study ( Table 1 ). Seven are retrospective studies ( Sun et al, 2016 ; Wang et al, 2017 ; Zhang et al, 2017 ; Rhinehart et al, 2019 ; Wong et al, 2019 ; Bridoux et al, 2022 ; Kitazume et al, 2022 ), Kim et al (2021) is a post hoc analyses of AXEPT ( Xu et al, 2018 ) trial, and Kichenadasse et al (2021) is another post hoc analysis of 6 trials, including HORIZON III ( Schmoll et al, 2012 ), N016966 ( Saltz et al, 2008 ), Carrato 2013 ( Carrato et al, 2013 ), VELOUR ( Van Cutsem et al, 2012 ), RAISE ( Tabernero et al, 2015 ), and AVF2107g ( Hurwitz et al, 2004 ). Two post hoc analyses ( Kichenadasse et al, 2021 ; Kim et al, 2021 ) were included for quantitative analysis, while the RCTs ( Hurwitz et al, 2004 ; Saltz et al, 2008 ; Schmoll et al, 2012 ; Van Cutsem et al, 2012 ; Carrato et al, 2013 ; Tabernero et al, 2015 ; Xu et al, 2018 ) were included for qualitative analysis.…”

“…Of note, the population enrolled in AXEPT ( Xu et al, 2018 ) trial was Asian only, and included patients from China, Japan, and Korea. Regarding the chemotherapeutic regimens, 9 studies ( Saltz et al, 2008 ; Sun et al, 2016 ; Wang et al, 2017 ; Zhang et al, 2017 ; Rhinehart et al, 2019 ; Wong et al, 2019 ; Kim et al, 2021 ; Bridoux et al, 2022 ; Kitazume et al, 2022 ) investigated capecitabine-based regimens, of which, 3 studies ( Sun et al, 2016 ; Rhinehart et al, 2019 ; Kitazume et al, 2022 ) examined capecitabine monotherapy, and a total of 7 studies ( Saltz et al, 2008 ; Wang et al, 2017 ; Zhang et al, 2017 ; Xu et al, 2018 ; Wong et al, 2019 ; Bridoux et al, 2022 ; Kitazume et al, 2022 ) investigated capecitabine combination therapy, including regimens of capecitabine plus oxaliplatin (CapeOx), CapeOx plus bevacizumab (BEV), and capecitabine plus irinotecan (mXELIRI). There were another 9 studies ( Hurwitz et al, 2004 ; Saltz et al, 2008 ; Schmoll et al, 2012 ; Van Cutsem et al, 2012 ; Carrato et al, 2013 ; Tabernero et al, 2015 ; Wang et al, 2017 ; Xu et al, 2018 ; Wong et al, 2019 ) that concentrated on fluorouracil-based regimens, with 4 studies ( Saltz et al, 2008 ; Schmoll et al, 2012 ; Wang et al, 2017 ; Wong et al, 2019 ) investigating FOLFOX-based regimens, another 4 studies ( Van Cutsem et al, 2012 ; Carrato et al, 2013 ; Tabernero et al, 2015 ; Xu et al, 2018 ) examining regimens of leucovorin plus continuous infusion of fluorouracil plus irinotecan, with or without ramucirumab (FOLFIRI-based regimens), and one other study ( Hurwitz et al, 2004 ) that delved into regimens of irinotecan plus leucovorin plus bolus injection of fluorouracil, with or without BEV (IFL-based regimen).…”

Re-thinking the possible interaction between proton pump inhibitors and capecitabine

“…In a study of locally advanced rectal cancer ( n = 149, 15% of whom were on PPI) receiving capecitabine-based neoadjuvant chemoradiotherapy (NARCT) the complete pathological response rate was lower (8.7% versus 19%) in the PPI group. However, this was not statistically significant and there was also no significant difference in the recurrence-free rate or overall survival in the patients who used PPI during treatment [ 13 ]. Importantly, this study focussed on neoadjuvant capecitabine chemoradiotherapy and did not consider assessment of the effect of PPI on the subgroups of patients who then received either 5-FU-based ( n = 53) versus or capecitabine based ( n = 34) chemotherapy.…”

“…The inconsistency between studies described above, was highlighted in a systematic review [ 2 ], which included nine of the fourteen studies listed above, but did not include more recent publications [ 7 , 8 , 10 , 11 , 13 ]. We have briefly summarised the outcomes reported in these twelve studies for either capecitabine or 5-FU (Table 1 ).…”