Combination Therapy of High-Dose Rabeprazole Plus Metronomic Capecitabine in Advanced Gastro-Intestinal Cancer: A Randomized Phase II Trial

Abstract

Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumor microenvironment acidification thus restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). Methods: A phase II study in which patients with gastrointestinal cancer, refractory to standard treatments, who had a life expectancy >3 months, were blind randomized 1:1 to mCAP, 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg bid, three days a week. The primary endpoint was 3-months progression-free survival (PFS). The secondary endpoints were clinical benefit (CB) and overall survival (OS). Safety and plasma concentrations of capecitabine and its metabolites (5′-DFUR and 5-FU) were also evaluated. Results: Sixty-seven (median age 69 years; 63% male; 84% colorectal cancer, 76% ECOG-PS £ 1; 84% pretreated with two or more lines of chemotherapy) out of 90 patients screened for eligibility, were randomized to receive mCAP+rabeprazole (n = 32) vs. mCAP (n = 35). All patients were evaluable for response. No significant difference between mCAP+rabeprazole vs. mCAP, in terms of 3-months PFS rate (HR = 1.43, 95%CI 0.53–3.85; p = 0.477), median PFS (HR = 1.22, 95%CI 0.75–2.00, p = 0.420), CB (RR = 0.85, 95%CI 0.29–2.44; p = 0.786) and median OS (HR = 0.89, 95%CI 0.54–1.48; p = 0.664) was observed. However, a 3-year OS rate of 10% and 12% was reported in the mCAP-rabeprazole and mCAP groups, respectively. Overall, no grade 3 or 4 toxicity occurred but grade 1 or 2 adverse event of any type were more frequently in the mCAP+rabeprazole group than in the mCAP (OR 2.83, 95%CI 1.03–7.79; p = 0.043). Finally, there was not statistically significant difference in the plasma concentration of capecitabine and its metabolites between the two groups. Conclusions: Although the adjunct of high dose rabeprazole to mCAP was not shown to affect mCAP activity, as PPI are being investigated worldwide as drugs to be repositioned in cancer treatment and also considering the limited sample size as well as the favorable safety profile of the combination in the present study, further clinical investigations are desirable.

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

“…However, two “infrequently mentioned” post hoc analyses of RCT, Yang et al (2017) and Roberto et al (2020) , demonstrated PPI use during the capecitabine treatment window was not associated with decreased efficacy in advanced gastric and gastrointestinal cancers, respectively. Such variations in conclusions between Chu et al (2017) and Yang et al (2017) and Roberto et al (2020) may have arisen due to the distinctive feature of the TRIO013 trial ( Hecht et al, 2016 ), which enrolled patients with HER-2 overexpression. Studies have recognized the pivotal role of ethnicity in responses to the treatment in HER-2 amplification ( Killelea et al, 2015 ; Yi et al, 2016 ) and convincing data has also suggested that the response to lapatinib, a tyrosine kinase inhibitor of HER-2, be different across ethnic groups ( Hecht et al, 2016 ).…”

“…This trial is considered a landmark study that supports the idea of detrimental effects of PPIs on capecitabine. However, two “infrequently mentioned” post hoc analyses of RCT, Yang et al (2017) and Roberto et al (2020) , demonstrated PPI use during the capecitabine treatment window was not associated with decreased efficacy in advanced gastric and gastrointestinal cancers, respectively. Such variations in conclusions between Chu et al (2017) and Yang et al (2017) and Roberto et al (2020) may have arisen due to the distinctive feature of the TRIO013 trial ( Hecht et al, 2016 ), which enrolled patients with HER-2 overexpression.…”

“…Thus, different treatment response due to ethnicity among the cohorts may have confounded the true influence of PPI on the efficacy of capecitabine. Of note, patients in Roberto et al (2020) were not limited to HER-2 amplification but, unfortunately, the detailed enrollment of Yang et al (2017) remains unknown as Yang et al (2017) was only presented as a conference abstract. Since every cancer type contains its own exclusive histopathologic profile and presents distinctive responses to chemotherapy, it is apparent that more studies are required to delve into this special population for a robust conclusion to be reached.…”

Proton Pump Inhibitors Reduce Survival Outcomes in Patients Treated with Capecitabine: Meta-analysis

“…In this systematic review, we have included a total of 17 studies out of the original 96 studies brought up from our searching keywords [4,8,12,[17][18][19][20][21][22][23][24][25][26][27][28][29][30]. These 17 studies were relevant and had su cient data, and were hence included in the review and meta-analysis.…”

“…In 2019, a systematic review was done by Viñal et al speci cally to assess the effect of PPIs on the e cacy on capecitabine [14], with most of the studies in the original review till 2019 being includedsave for one study that was excluded due to the non-speci cation of the type of acid-suppression therapy used. In addition, when it comes to the studies in the review reported to show signi cant results, one of the studies included as a conference [16], released the full trial paper in 2020 with additional study subjects [17]. This discrepancy in the results of the studies included in this review, the publishing of newer studies after that, as well as the absence of any meta-analysis studies on this particular interaction between both drugs has created a need for a wholesome review assessing not only the risks; but also the bene ts of PPIs on the use of capecitabine, has led to the birth of this systematic review and metaanalysis.…”