Concomitant use of capecitabine and proton pump inhibitors – Is it safe?

Cheng, Vian; Lemos, Mário L de; Hunter, Nicole; Badry, Nadine; Lemos, Jane de

doi:10.1177/1078155219846952

Cited by 16 publications

(30 citation statements)

References 18 publications

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“…Conversely, before our study, negative results regarding the use of PPIs and capecitabine were reported [ 19 , 20 , 21 ]. In a retrospective post hoc analyses of the TRIO-013/LOGiC study, the concomitant use of PPIs with capecitabine and oxaliplatin (CapeOx) with or without lapatinib was evaluated in patients with ERBB2/HER2-positive metastatic gastroesophageal cancer [ 20 ].…”

Section: Discussionmentioning

confidence: 56%

“…Interesting preclinical and clinical data pointed out the possibility to revert drug resistance of tumor cells by using high dose PPIs [ 4 , 5 , 6 , 7 , 8 , 9 ]. However, there were also recent data which reported negative retrospective results with the concurrent use of PPIs and capecitabine in different setting of patients affected with GI cancer [ 19 , 20 , 21 ]. Our study for the first time investigated in a randomized phase II trial the concurrent use of repurposed high-dose rabeprazole combined with low-dose metronomic capecitabine.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Roberto

Romiti

Mazzuca

et al. 2020

Cancers

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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.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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

Roberto

Romiti

Mazzuca

et al. 2020

Cancers

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“…Concomitant use of Maalox, an antacid containing magnesium hydroxide and aluminum hydroxide, did not significantly affect the extent and rate of absorption of capecitabine [16]. PPIs induce a stronger acid suppression than antacids, but the dissociation constant of capecitabine is 8.8, indicating that its absorption might be minimally affected in the elevated pH conditions (pH 3.5–4.9) induced by PPIs [7]. Therefore, drug‐drug interaction studies are warranted to understand the effect of PPIs on the pharmacokinetics of capecitabine.…”

Section: Discussionmentioning

confidence: 99%

“…The degree of absorption of orally administered anticancer agents such as capecitabine in the gastrointestinal tract could significantly affect the pharmacokinetic profile of those drugs and thereby their safety and efficacy. The bioavailability of tyrosine kinase inhibitors is reduced with the administration of proton pump inhibitors (PPIs) because the solubility of the drugs is decreased in conditions of elevated intragastric pH [7]. However, whether the acidic environment of the stomach influences the absorption of capecitabine remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT)

et al. 2021

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Background. Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the dataset from the AXEPT trial, a phase III randomized trial that demonstrated the non-inferiority of modified XELIRI (mXELIRI; capecitabine plus irinotecan) with FOLFIRI (leucovorin, fluorouracil, and irinotecan), both either with or without bevacizumab in patients with metastatic colorectal cancer. Patients and Methods. Out of the per-protocol set (n=620), patients with information on concomitant medications (n=482) were included in this post-hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors. Results. Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the non-users, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in non-users. Treatment-by-PPI-use interaction was significant for overall survival and progression-free survival. Conclusion. The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favourable option than capecitabine for patients with metastatic colorectal cancer using PPIs. The Oncologist 2021;9999:• • Implications for Practice: This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug-drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.

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“…[13][14][15][16][17][18] However, pharmacokinetic and in vitro studies have failed to identify the mechanisms of the interaction between PPIs and capecitabine. 19 Furthermore, it is unclear whether the potentially negative effects of PPIs might also involve intravenously administered cytotoxic agents.…”

Section: Introductionmentioning

confidence: 99%

Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy

Kichenadasse

Miners

Mangoni

et al. 2021

Journal of the National Comprehensive Cancer Network

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Background: Concomitant use of proton pump inhibitors (PPIs) may negatively affect the efficacy of anticancer drugs such as fluoropyrimidines in patients with colorectal cancer (CRC). The primary objective of this study was to assess whether there is an association between concomitant PPI use and survival outcomes in patients with CRC treated with a fluoropyrimidine-based chemotherapy. Patients and Methods: A secondary analysis of 6 randomized controlled clinical trials in patients with advanced CRC was conducted using individual patient data through data-sharing platforms. The outcome measures were progression-free survival and overall survival in PPI users and nonusers. Subgroup analysis included the type of chemotherapy, capecitabine versus 5-FU, line of therapy, and addition of a vascular endothelial growth factor receptor inhibitor. Overall pooled hazard ratios (HRs) with 95% confidence intervals were calculated using a random effects model. Results: A total of 5,594 patients with advanced CRC across 6 trials and 11 trial arms were included; 902 patients were receiving a PPI at trial entry and initiation of chemotherapy. PPI use was significantly associated with worse overall survival (pooled HR, 1.20; 95% CI, 1.03–1.40; P=.02; I2 for heterogeneity = 69%) and progression-free survival (overall pooled HR, 1.20; 95% CI, 1.05–1.37; P=.009; I2 = 65%) after adjusting for clinical covariates. Furthermore, the association between concomitant PPI use and survival outcomes was similar across most treatment subgroups. Conclusions: We speculate that alterations in the gut microbiome, altered immune milieu within the tumor, and interactions through transporters are potential mechanisms behind this association between PPI use and chemotherapy in patients with CRC, which warrant further study. Concomitant use of PPIs is associated with worse survival outcomes in patients with CRC treated with fluoropyrimidine-based chemotherapy. Clinicians should cautiously consider the concomitant use of PPIs in such patients.

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Concomitant use of capecitabine and proton pump inhibitors – Is it safe?

Cited by 16 publications

References 18 publications

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

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

Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT)

Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy

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