Proton pump inhibitors and colorectal cancer: A systematic review

Table 5 Summary of treatment studies

Author	Center	Study design	Cancer stage and type	Cancer treatment	PPI use (definition)	No. of patients	Results
Zhang et al[39] 2017	Guangzhou, China	R	Stage II-III Rectal cancer	LCRT (46 Gy, Oxaliplatin + Capecitabine (2 cycles)	EOU = OME: 20 mg PO, min. OD for 6 d / 40 mg IVI, daily). EOG = total OME dose ≥ 200 mg1	125	EOG vs non-EOG: 1DFS (3-year) = 77.1% vs 96.6%, P = 0.032, DFS (5-year) = 69.6% vs 46.7%, P = 0.032, OS (3-year) = 82.3% vs 96.6%, P = 0.092, OS (5-year) = 76.9% vs 89.5%, P = 0.092 EOU vs non-EOU: 1DFS (3-year) = 85.5% vs 77.8%, P = 0.658, DFS (5-year) = 75.6% vs 74.6%, P = 0.658, OS (3-year) = 90.3% vs 82.5%, P = 0.754, OS (5-year) = 82% vs 77.6%, P = 0.754
Sun et al[40] 2016	Edmonton, Canada	R	Stage I-III CRC	Adjuvant Capecitabine monotherapy	Any use during treatment (based on prescription data)	298	PPI-user vs non-users: RFS (5 years) = 74% vs 83%, P = 0.03; OS (5-year) = 81% vs 78%, P = 0.7. Multivariate RFS (5-year): HR (95%CI) = 1.65 (0.93-2.94), P = 0.09
Wong et al[41] 2019	Alberta, Canada	R	Stage II-III CRC	Adjuvant CapeOx or FOLFOX	Any use during treatment (based on prescription data)	389	PPI-users vs non-users, RFS (3-year): CapeOX = 69.5% vs 82.6%, P = 0.03; FOLFOX = 82.9% vs 61.7%, P = 0.7; Multivariate RFS: HR (95%CI) = 2.20 (1.14-4.25) P = 0.018; OS (3-year): CapeOX = 90.1% vs 91.2%, P = 0.345, FOLFOX = 77.4% vs 80.1%, P = 0.929
Kichenadasse et al[42] 2021	6 clinical trials	Retrospective post-hoc analysis of RCT	Stage IV CRC	Fluoropyrimidine-based chemotherapy (± additional agents). Regimens differed across included trials	Minimum 7 d of use during study period	5633	OS: Significantly worse in PPI-users [HR (95%CI) = 1.20 (1.03-1.40)], P = 0.02; PFS: Significantly worse in PPI-users [HR (95%CI) = 1.20 (1.05-1.37)], P = 0.009 Various treatment subgroups did not influence OS and PFS
Kim et al[43] 2021	China, Japan, South Korea (98 centers)	Retrospective post-hoc analysis of RCT	Stage IV CRC	mXELIRI or FOLFIRI (± Bevacizumab)	Use for ≥ 20% of study period	620	mXELIRI arm: No difference in OS or PFSFOLFIRI arm: Significantly better OS [HR (95%CI) = 0.5 (0.3-0.85), P = 0.11] and PFS [HR (95%CI) = 0.55 (0.33-0.91), P = 0.20] in PPI users

¹Definitions of EOU and EOG are stated in the results section. CapeOX: Capecitabine plus oxaliplatin; CRC: Colorectal cancer; CI: Confidence interval; DFS: Disease free survival; EOU: Eligible omeprazole users; EOG: Effective omeprazole group; FOLFOX: 5-Fluorouracil, leucovorin, and oxaliplatin; FOLFIRI: 5-Fluorouracil, leucovorin, and irinotecan; HR: Hazard ratio; LCRT: Long-course chemoradiotherapy; mXELIRI: Capecitabine plus irinotecan; OME: Omeprazole; OS: Overall survival; PPI: Proton pump inhibitors; PFS: Progression free survival; RFS: Recurrence free survival; R: Retrospective cohort study; RCT: Randomized controlled trials.