Concomitant Use Of Proton Pump Inhibitors Research Articles

Proton Pump Inhibitors Ameliorate Capecitabine-induced Hand-Foot Syndrome in Patients With Breast Cancer: A Retrospective Study

Hand-foot syndrome (HFS) is the most common adverse event associated with capecitabine, and its pathogenesis is known to be associated with inflammation. Proton pump inhibitors (PPIs) reportedly exert anti-inflammatory effects; however, the impact of PPIs on capecitabine-induced HFS needs to be clarified in the clinical setting. In the present study, we retrospectively investigated the efficacy and safety of PPIs in patients with breast cancer receiving capecitabine. We analyzed the effects of PPIs on the development of severe HFS (grade ≥2), progression-free survival (PFS), and overall survival (OS) in 195 patients who received capecitabine chemotherapy for breast cancer. In total, 50 patients (26%) were treated with PPIs, while 145 patients (74%) did not receive PPIs. The incidence of severe HFS was significantly lower in patients who received PPIs (18%) than in patients who did not receive PPIs (43%, p=0.001), and the discontinuation rate of capecitabine therapy due to HFS was also lower in patients receiving PPIs than in those who did not receive PPIs (p=0.003). Multivariate analysis revealed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of severe HFS (odds ratio (OR)=0.265, p=0.003). Meanwhile, no significant difference in median PFS and OS values was observed between patients treated with and without PPIs. Concomitant use of PPIs could ameliorate capecitabine-induced HFS in patients with breast cancer.

Clinical outcomes of concomitant use of proton pump inhibitors and regorafenib in patients with metastatic colorectal cancer: A multicenter study.

130 Background: Tyrosine kinase inhibitors (TKI) are the most common oral drugs in cancer patients. Similarly, proton pump inhibitors (PPI) are commonly used to relieve dyspeptic symptoms in patients with cancer. However, gastric pH levels may affect the absorption of TKI through the gastrointestinal system. However, all TKIs do not have the same chemical structure, and the absorption rate of each TKI depends on their solubility in different gastric pH levels. Limited data is available about the clinical outcomes of concomitant use of PPI and regorafenib in patients with metastatic colorectal cancer (mCRC). We present here the results of the multicenter study following the initial results of our single-center experience. Methods: Patients with mCRC treated with regorafenib were included in this multicenter and retrospective study. Patients prescribed PPI after initiation of regorafenib were assigned to the PPI user group, and the remaining patients were assigned to the PPI non-user group. To exclude immortal time bias, the log-rank test was performed between PPI non-user and all patients. The primary outcome was overall survival (OS), and secondary outcomes were time to treatment failure (TTF) and adverse events (AEs) profile. Results: Two hundred and seventy-two patients from eight cancer centers were included in this study. Most patients were male (59.9%), had liver metastasis (62.1%), and received regorafenib in the third line (52.2%). The median age at the initiation of regorafenib was 60 years (interquartile range (IQR): 51-66)). Eastern Cooperative Oncology Group performance score was 0 or 1 in approximately three out of four patients. The rate of patients with K-RAS mutation was 46.7%. There were 131 (48.2%) and 141 (51.8%) in the PPI user and non-user groups, respectively. The most prescribed PPI was pantoprazole (40.4%). At a median 34.2 months follow-up, the median OS was 6.9 months (95% Confidence Interval (CI): 5.3-8.5) and 7.7 months (95% CI:6.6-8.8) in the PPI non-user and all patients, respectively. No statistical significance was observed between the groups (p = 0.913). The median TTF was 3.3 months (95% CI: 2.6-3.9) and 3.4 months (95% CI:2.9-4.0) in the PPI non-user and all patients, respectively. No statistical significance was observed between the groups (p = 0.651). In the time-dependent covariate Cox regression model, there was no difference between PPI user and non-user groups in OS and TTF (adjusted Hazard Ratio (aHR):0.96, 95% CI:0.74-1.24, p = 0.735 for OS; aHR:0.88, 0.68-1.14, p = 0.354 for TTF). The rates of all AEs were also similar in the PPI user and non-user groups (p = 0.628). Conclusions: To our knowledge, this was the first study evaluating the effect of concomitant use of PPI and regorafenib in patients with mCRC, and no adverse survival and safety outcome was observed with the concomitant use of PPI and regorafenib in those patients.

Association of proton pump inhibitor use with survival outcomes in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background:Proton pump inhibitors (PPIs) have been shown to regulate the gut microbiome and affect the response to immune checkpoint inhibitors (ICIs). Contradictory results on survival have been observed in patients concomitantly treated with ICIs and PPIs. We performed a systematic review and meta-analysis to determine the association between PPI use and survival outcomes in ICI-treated cancer patients.Methods:EMBASE, MEDLINE/PubMed, Cochrane Library databases, and major oncology conference proceedings were searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI-treated and PPI-free groups of ICI-treated cancer patients were included. Data regarding study and patient characteristics, ICI and PPI treatments, and survival outcomes were extracted. Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using random effects models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among the studies.Results:A total of 33 studies were included, comprising 7383 ICI- and PPI-treated patients and 8574 ICI-treated and PPI-free patients. The pooled HR was 1.31 (95% CI, 1.19–1.44; p < 0.001) for OS and 1.30 (95% CI, 1.17–1.46; p < 0.001) for PFS, indicating a significant negative association between PPI use and survival in ICI-treated patients. Subgroup meta-analyses by factors including cancer type, ICI type, and time window of PPI use revealed that ICI and PPI use impacted survival in patients with non-small cell lung or urothelial cancer, patients treated with anti-PD-1/PD-L1 antibodies, and patients receiving PPI as baseline treatment or 60 days before ICI treatment initiation.Conclusions:PPI use in patients treated with ICIs was associated with shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled and appear to not impact survival if given temporarily after ICI initiation. These observations could provide the basis for clinical guidelines for concomitant PPI and ICI use.

Survival outcomes of patients with nonsmall cell lung cancer concomitantly receiving proton pump inhibitors and immune checkpoint inhibitors.

Recent evidence suggests that gut microbiota dysbiosis adversely affects the efficacy of immune checkpoint inhibitors (ICIs). Our objective was to investigate the association between concomitant use of proton pump inhibitors (PPIs) and ICIs, and poor prognosis in patients with nonsmall cell lung cancer (NSCLC). We conducted a cohort study using a completely enumerated lung cancer cohort from a nationwide healthcare database in South Korea. We identified 2963 patients treated with ICIs as second-line or later therapy for stage ≥IIIB NSCLC. PPI use was ascertained within 30-days before and on the date of ICI initiation, and nonuse was defined as no prescription of PPIs during this period. Using national vital statistics in South Korea, we assessed the risk of all-cause mortality associated with concomitant PPI use through a propensity score-matched Cox proportional hazard model. Among 1646 patients included after 1:1 propensity score-matching, concomitant PPI use was associated with a 28% increased risk of all-cause mortality, compared to nonuse (adjusted hazard ratio [HR] 1.28; 95% confidence intervals [CIs], 1.13-1.46). We observed an increased risk when we restricted the analysis to new users of PPI (adjusted HR=1.64; 95% CI=1.25-2.17). Subgroup analysis showed that PPI use was associated with high mortality risk among patients with viral hepatitis (adjusted HR=2.72; 95% CI=1.54-4.78; Pinteraction = .048). Our study indicates that PPI use is associated with poor prognosis in NSCLC patients treated with ICIs. Further prospective studies are required to determine the risk-benefit balance of concomitant use of PPIs and ICIs.

Influence of individual proton pump inhibitors on clinical outcomes in patients receiving clopidogrel following percutaneous coronary intervention.

Background:Data are conflicting on whether proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel. We investigated individual PPIs and adverse cardiovascular events in postpercutaneous coronary intervention (PCI) patients on dual antiplatelet therapy with clopidogrel.Methods:We searched Ovid-MEDLINE, EMBASE, and Cochrane from inception to March 2020 to identify studies that evaluated the efficacy and safety of clopidogrel added PPIs versus clopidogrel only in post-PCI patient. We extracted data from 28 studies for major adverse cardiovascular endpoints (MACE), myocardial infarction (MI), cardiovascular death, and gastrointestinal bleeding. Risk ratios (RR) and hazard ratios (HR) were pooled separately.Results:Data were extracted on 131,412 patients from the 28 studies included. Concomitant use of PPI with clopidogrel was associated with increased risk of MACE (RR 1.30; 95% confidence interval [CI] 1.15–1.48; P < .001) and MI (RR 1.43; 95% CI 1.25–1.64; P < .001). Random-effects meta-analyses with individual PPIs demonstrated an increased risk of MACE in those taking pantoprazole (RR 1.31; 95% CI 1.07–1.61, P = .01) or lansoprazole (RR 1.35; 95% CI 1.19–1.54, P < .0001) compared with patients not on PPIs. Likewise, in adjusted analyses, the pooled HR of adjusted events for MACEs showed that the increased risk of MACEs was similar for 4 classes of PPIs but not for rabeprazole (HR: 1.32; 95% CI 0.69–2.53, P = .40).Conclusion:The post-PCI patients on dual antiplatelet therapy with clopidogrel in the PPI group were associated with higher risk of MACE and MI. Although the results for rabeprazole were not robust, it was the only PPI that did not yield a significantly increased risk of MACE.

Concomitant Proton Pump Inhibitors and Outcome of Patients Treated with Nivolumab Alone or Plus Ipilimumab for Advanced Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) represent the standard of care as first- or second-line treatment in patients with renal cell carcinoma (RCC). Proton pump inhibitors (PPIs) are among the most prescribed drugs worldwide and are known to affect gut microbiota, which is gaining interest in its association with outcomes for patients on ICIs. The aim of this study was to evaluate the impact of PPIs on outcomes in RCC patients receiving immunotherapy. We retrospectively collected data from patients with metastatic RCC who received the combination of ipilimumab and nivolumab for first-line treatment (Cohort 1) or single-agent nivolumab for second-line or third-line treatment (Cohort 2) from five international centers with expertise in the treatment of RCC. Data about clinicopathological characteristics, PPI use, and outcome on ICIs were collected. Endpoints of the study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two hundred and eighteen patients (71% male, median age 61years) were included in the analysis, 62 in Cohort 1 (including 25 patients receiving PPIs) and 156 in Cohort 2 (including 88 patients receiving PPIs), and were followed up for a median of 42months. In Cohort 1, no difference was observed in ORR (48% vs 57%; p=0.203), PFS (12.2 vs 8.5months; p=0.928), or OS (not reached [NR] vs 27.3months; p=0.84). In Cohort 2, no difference was observed in ORR (32% vs 28%; p=0.538), PFS (6.7 vs 9.0months; p=0.799), or OS (16.0 vs 26.0months; p=0.324). In patients with RCC, concomitant PPI use did not seem to affect survival outcomes on ICIs, either as combination therapy or monotherapy.

Proton pump inhibitors and colorectal cancer: A systematic review.

BACKGROUNDThe use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk. AIMTo summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies. METHODSThis systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design. RESULTSData from basic research indicates that PPI do not stimulate CRC development via the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen.CONCLUSIONAn unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.

Characteristics of Patients with Nonvariceal Upper Gastrointestinal Bleeding - Are We Underestimating Gastroprotection during NSAIDs Therapy?

The aim of our study was to determine the etiological factors, treatment and outcome of patients with non-variceal bleeding from upper gastrointestinal tract. This study enrolled 200 patients admitted to Sarajevo University Clinical Center with signs and symptoms of upper gastrointestinal bleeding, from January 2019 to July 2020. All patients had undergone gastroscopy, confirming the cause of gastrointestinal bleeding. Clinical and laboratory data were collected retrospectively, including previous non-steroid antiinflammatory drugs (NSAIDs) and anticoagulant therapy, comorbidities, risk factors, as well as endoscopic findings, laboratory findings, treatment and clinical follow-up. The majority of patients were men (59%) with an average age of 53±6 years. Duodenal and gastric ulcers were the most common cause, followed by other etiologies. In our study, previous NSAIDs therapy had been registered in 29.5% of patients, anticoagulants in 8%, and proton pump inhibitors (PPI) in 2.9% of patients. Endoscopic intervention was required in 34% of patients. The need for transfusion occurred in 44.5% of cases. Rebleeding during hospitalization was observed in 7.5% of patients, mortality in 1.5% and surgery in 3% of patients. The patients admitted to our hospital with symptoms of acute nonvariceal upper gastrointestinal bleeding were elderly, predominantly males, with significant comorbidities and a higher incidence of NSAID use. Gastroprotection is underutilized during NSAID treatment in patients with other coexisting risk factors, with a low rate of concomitant use of PPI during NSAIDs therapy. Endoscopic therapy, together with PPI, significantly reduces rebleeding rates, mortality and the number of emergency surgical interventions.

Prognostic impact of proton pump inhibitors for immunotherapy in advanced urothelial carcinoma.

ObjectiveTo evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma.Patients and methodsWe retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune‐related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression‐free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting‐adjusted Cox regression analysis.ResultsOf the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non‐PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting‐adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non‐PPI users, whereas Abs use was not associated with poorer outcomes.ConclusionThe concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.

Impact of Proton Pump Inhibitor Use on the Effectiveness of Immune Checkpoint Inhibitors in Advanced Cancer Patients.

The gut microbiome plays a critical role in modulating the therapeutic effect of immune checkpoint inhibitors (ICIs). Proton pump inhibitors (PPIs) are commonly used in cancer patients and may affect the gut microbiome by altering gut pH. To evaluate if concurrent use of PPI is associated with overall survival (OS) and progression-free survival (PFS) in patients with stage IV non-small-cell lung cancer (NSCLC), melanoma, renal cell carcinoma, transitional cell carcinoma, or head and neck squamous cell carcinoma. This was a single-center retrospective cohort study of advanced cancer adult patients who received nivolumab or pembrolizumab between September 1, 2014, and August 31, 2019. Concomitant PPI exposure was defined as PPI use 0 to 30 days before or after initiation of ICIs. Treatment outcome was OS and PFS. A total of 233 patients were included in our study. Concomitant PPI use was not significantly associated with OS (hazard ratio [HR] = 1.22; 95% CI = 0.80-1.86) or PFS (HR = 1.05; 95% CI = 0.76-1.45) in patients with ICI use. The effect estimates were robust after adjusting for covariates in multivariate analysis and in patients with NSCLC. Concomitant PPI use was not associated with the effectiveness of nivolumab or pembrolizumab. Certain predictors of survival outcomes related to PPI use in patients receiving immunotherapy, such as the time window and indication of PPI exposure and autoimmune disorders, should be explored in the future to better carve out the impact of PPI on the effectiveness of ICI use.

Concomitant Use of Proton Pump Inhibitors With Capecitabine Based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: Is it Safe?

Capecitabine (Cape) is routinely used for the neoadjuvant chemoradiation treatment (NACRT) of locally advanced rectal cancers (LARCs). Previous reports have suggested that the concomitant use of proton pump inhibitors (PPIs) may affect the efficacy of Cape, although the true effect of PPIs when used with Cape as a radiosensitizer for neoadjuvant radiation is unclear. The aim of our study was to evaluate the impact of concurrent PPI use along with fluorouracil (FU) and Cape based NACRT in terms of pathologic and oncological outcomes, in patients with LARC. LARC patients treated at our center with NACRT from 2010 to 2016 were identified. Postoperative pathology and follow-up outcomes were examined for any differences with relation to the use of PPIs concurrently with FU and Cape based NACRT and adjuvant chemotherapy regimens. Three hundred four and 204 patients received treatment with FU and Cape based NACRT. No difference in pathologic complete response rate was noted between the 2 arms with the concurrent use of PPIs (25.8% and 25%, respectively, P=0.633); or with and without the use of PPIs in the Cape-NACRT arm specifically (20% and 20.7%, P=0.945). At a median follow-up of 5 years, no statistical difference in local or distant control was noted in the Cape-NACRT patients, with and without concomitant PPI use (P=0.411 and 0.264, respectively).Multivariate analysis showed no association of PPI use and NACRT with Cape, in terms of local control (hazard ratio=0.001, P=0.988) or overall survival (hazard ratio=1.179, confidence interval=0.249-5.579, P=0.835). Our study revealed that there was no adverse pathologic or oncological outcome with the concurrent use of PPIs along with Cape-NACRT in the treatment of LARC. We report that it may be safe to use PPIs if essential, in this clinical setting, although it would be wise to exercise caution.

Proton Pump Inhibitor and Clopidogrel Use After Percutaneous Coronary Intervention and Risk of Major Cardiovascular Events

PurposeDue to shared hepatic metabolism, concomitant medication with a proton pump inhibitor (PPI) and clopidogrel might reduce the effectiveness of clopidogrel in the prevention of cardiovascular events after percutaneous coronary intervention (PCI). We aimed to examine the risk of major cardiovascular events after PCI comparing patients who used clopidogrel together with PPI with those who used clopidogrel alone.MethodsThis Swedish nationwide cohort study included patients who received clopidogrel after primary PCI in 2005–2019. Patients were followed for up to 12 months after PCI. Data were retrieved from the Swedish Prescribed Drug Registry, Patient Registry, Cancer Registry, and Cause of Death Registry. Multivariable Cox regression provided hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular events comparing PPI users (exposed) with non-users of PPI (non-exposed). The HRs were adjusted for sex, age, comorbidity, calendar period, obesity, diabetes, anti-diabetic medication, tobacco-related diseases, hypertension, and congestive heart failure.ResultsThe cohort included 99,836 patients who received clopidogrel after primary PCI. Among these, 35,772 (35.8%) received concomitant PPI. Compared to non-users, PPI users had increased adjusted HRs of all study outcomes, i.e., the main outcome myocardial infarction (HR = 1.23, 95% CI 1.15–1.32) and the secondary outcomes coronary heart disease (HR = 1.28, 95% CI 1.24–1.33), stroke (HR = 1.21, 95% CI 1.05–1.40), and death due to coronary heart disease (HR = 1.52, 95% CI 1.37–1.69). The results were similar in analyses including both primary and secondary PCIs.ConclusionsIn patients who receive clopidogrel after PCI, concomitant use of PPI seems to increase the risk of major cardiovascular events.

Evaluation of the Effect of Proton Pump Inhibitors on the Efficacy of Dacomitinib and Gefitinib in Patients with Advanced Non-Small Cell Lung Cancer and EGFR-Activating Mutations.

IntroductionDacomitinib and gefitinib are irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) indicated for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Pharmacokinetic (PK) studies in healthy volunteers suggested that acid-reducing drugs such as proton pump inhibitors (PPI) decreased dacomitinib and gefitinib exposure by limiting the pH-dependent absorption. This analysis retrospectively evaluates the effect of concomitant PPI use on dacomitinib exposure and on progression-free survival (PFS) and overall survival (OS) in patients treated with dacomitinib 45 mg QD or gefitinib 250 mg QD in a 1:1 randomized phase 3 study (ARCHER 1050).MethodsThe analysis grouped all patients (n = 452) treated in each arm of the study as non-PPI users, PPI users, or extensive PPI users. PFS and OS data were presented by Kaplan–Meier plots and analyzed using Cox proportional hazards models. Dacomitinib exposure was compared using a linear mixed-effects model.ResultsResults showed that dacomitinib PFS and OS did not differ significantly when comparing PPI users (N = 59) to non-PPI users (N = 152), while extensive PPI users (N = 24) had shorter PFS [hazard ratio (HR): 1.94, p = 0.011] and OS (HR: 1.77, p = 0.027) when compared to non-PPI users. For patients treated with gefitinib, PFS did not differ significantly when comparing PPI users (N = 51) and extensive PPI users (N = 19) to non-PPI users (N = 159); however, both PPI users (HR: 1.65, p = 0.007) and extensive PPI users (HR: 1.70, p = 0.050) had shorter OS when compared to non-PPI users. Further analysis by adjusting potential confounders indicated no statistically significant differences in PFS or OS between any PPI user vs. non-PPI user groups in the dacomitinib and gefitinib arms. PPI use did not appear to affect dacomitinib exposure.ConclusionIn conclusion, PPI use in patients with NSCLC likely has minimal impact on dacomitinib or gefitinib efficacy despite decreased absorption of these drugs observed in PK studies.Trial RegistrationClinicalTrials.gov identifier, NCT01774721

Association of proton pump inhibitors with survival in Veterans with non-small cell lung cancer receiving immunotherapy.

e18729 Background: Proton pump inhibitors (PPI) can disrupt the gut microbiome and thereby modulate response to immunotherapy in cancer patients. In a recently published post-hoc analysis of 757 non-small cell lung cancer (NSCLC) patients receiving atezolizumab pooled from two prospective trials, overall survival (OS) and progression-free survival were significantly lower among the 234 patients receiving PPI. We investigated the impact of PPI in a larger cohort of NSCLC patients treated with ICI within the Veterans Health Administration. Methods: We conducted a nested cohort study of Veterans who were diagnosed with NSCLC between 2010 &amp; 2018 and treated with ICI (immune checkpoint inhibitors). Exposure was defined as receipt of a PPI prescription within 90 days of an ICI infusion. Chi-square tests were used to compare characteristics of exposed versus unexposed Veterans. OS was measured from start of ICI. Cox proportional hazard multivariate (MV) regression was used to calculate hazard ratios (HR) corresponding to variables associated with OS. Results: We identified 3,634 Veterans receiving ICI with non-exclusive exposures to nivolumab (59.3%), pembrolizumab (35.1%), durvalumab (6.9%), and atezolizumab (3.3%). Their median age was 69, and a plurality had male gender (97.0%), white race (73.0%), comorbidity count ≥1 (60.4%), adenocarcinoma (47.8%), and stage IV disease at diagnosis (40.9%). In this nested cohort, 2,159 (59.4%) were exposed to PPI, predominantly omeprazole (1,264 or 85.6% of PPI group). Patients receiving PPI were more likely to be ≤71 years of age, to be white, to reside in rural areas, to have a higher comorbidity burden, to have adenocarcinoma histology, and to receive chemotherapy (all p≤0.04). On MV analysis, PPI use was not significantly associated with detriment in OS (HR 0.96 [0.89-1.04], p= 0.35). In the matched cohort analysis, median survival did not significantly differ between the 1,389 patients taking PPI and the 1,389 without PPI (median 10 versus 10 months, HR 0.98 [0.90-1.06], p= 0.59). Conclusions: In the largest analysis to date of concurrent PPI use in patients with NSCLC receiving ICI, there were no survival differences associated with concomitant PPI use. These results suggest that PPIs do not compromise ICI efficacy.

Proton pump inhibitors and antibiotics impact on toxicities and clinical outcomes in cancer patients treated with immunotherapy.

2652 Background: Gut microbiome dysbiosis impairs systemic immune responses and recent evidence suggests its critical role in patients (pts) treated with immune checkpoint inhibitors (ICI). Proton pump inhibitors (PPI) and antibiotics (ATB) may alter the microbiome and their impact on clinical outcomes and toxicities requires further investigation. Methods: This retrospective cohort included consecutive metastatic cancer pts treated with ICI with palliative intent. We reviewed pts' records, concomitant medication and toxicities graded by CTCAE 4.0. Pts with PPI or ATB exposure were analyzed according to previous use (pPPI and pATB, ≤60 days to ICI) and concomitant use (cPPI and cATB). We estimated median overall survival (mOS) and progression free survival (PFS) by Kaplan–Meier and used a Cox proportional-hazards model to adjust for differences in baseline characteristics. Toxicities and ATB/PPI interaction was calculated using Pearson Chi-square method. Results: We enrolled 216 pts with a median age of 59 years, mostly ECOG-PS 0 (34%) or 1 (58%). ICI employed were mostly anti-PD-1 (60.2%), anti-CTLA-4 (16.2%) and anti-PD-L1 (12.5%). Most frequent primary tumor sites were lung n = 39 (18.1%), gastrointestinal n = 34 (15.7%) and melanoma n = 33 (15.2%). Half of the pts (108) received ATB and 114 (52.8%) PPI. Compared to control, pPPI group n = 57 (26.4%) had shorter mOS (11.6m vs 19.7m, p &lt; 0.001) and PFS (2.8m vs 8.5m, p &lt; 0.001), but no statistically significant difference in toxicities grade ≥3 and/or leading to ICI discontinuation (36% vs 29.1%; p = 0.29). cPPI n = 100 (46.3%) depicted a negative impact on mOS (12.1m vs 17.0m; p = 0.01), PFS (4.3m vs 7.1m; p = 0.04) and augmented toxicities (42% vs 19%; p &lt; 0.001). pATB n = 34 (15.7%) had shorter OS (6.9m vs 19.3m, p &lt; 0.001) and PFS (3.2 vs 7.2m, p = 0.005) and higher incidence of toxicities (45.9% vs 28.1%; p = 0.04 ). cATB use n = 92 (42.6%) did not impact OS (12.1m vs 15.6m; p = 0.32) or PFS (5.5m vs 5.9m; p = 0.82), but had a higher incidence of toxicities: 37% vs. 24.2% (p = 0.05). Multivariate analyses confirmed that pATB therapy and pPPI respectively remained as independent prognostic variables associated with OS (HR 2.39; 95% CI, 1.60-3.59; P &lt;.001 and HR 1.73; 95% CI 1.23-2.44; P = 0.002) and PFS (HR 1.72; 95% CI, 1.14-2.61; P = 0.01 and HR 2.36; 95% CI 1.67 - 3.34; P &lt; 0.001) adjusted by performance status, age and line of treatment. Conclusions: These data suggest that concomitant use of PPI and ATB is associated with increased toxicities in ICI treated pts. pPPI and pATB can negatively impact OS and PFS and merit clinician’s attention.

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

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. 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. 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. 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.

The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma.

Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC. This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method. We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups. In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC. Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.

Ethnic variance on long term clinical outcomes of concomitant use of proton pump inhibitors and clopidogrel in patients with stent implantation: A PRISMA-complaint systematic review with meta-analysis.

Background:Pharmacokinetic and pharmacodynamic study showed a lower clopidogrel response when coprescribed with proton pump inhibitors (PPIs). Despite this, PPIs is necessary for patients treated with long term dual antiplatelet therapy (DAPT). Ethnic variance also played a different effect on clopidogrel response. Our study evaluated the effect of concomitant use of DAPT and PPIs and assessed whether ethnic variance exert different effect on clinical outcomes.Methods:We carefully searched EMBASE, PubMed/Medline databases, and the Cochrane library in April 2019. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE) and individual endpoints reported. We also focused on bleeding events. Studies were excluded if the follow-up were <12 months and patients were not treated with clopidogrel after stent implantation.Results:A total of 18 studies were included in the systematic review (involving 79,670 patients). No randomized controlled trials (RCTs) were included. PPIs comedication were associated with increased MACCE (odds ratio [OR] = 1.38; 95% confidence interval [CI] = 1.28–1.49) while not associated with decreased bleeding risks, such as gastrointestinal bleeding (OR = 1.05; 95% CI = 0.53–2.11). PPIs comedication were associated with increased risk for all endpoints among Caucasian population while not with increased risk for MACE (OR = 1.20; 95% CI = 0.99–1.39), all-cause death (OR = 1.24; 95% CI = 0.74–2.06), cardiac-death (OR = 1.29; 95% CI = 0.64–2.57) among Asian population.Conclusion:PPIs comedication were associated with adverse clinical outcomes, and ethnic variance may exert different effect on clinical outcomes. Subgroup analysis indicated that concomitant use of PPI might be suitable for Asian patients after stent implantation.

Proton Pump Inhibitors and Oncologic Treatment Efficacy: A Practical Review of the Literature for Oncologists.

Proton pump inhibitors (PPIs) are the most commonly used anti-acid drugs worldwide, including among cancer patients. However, drug-drug interactions between PPIs and other agents may lead to decreased drug absorption with possible reduced therapeutic benefit, or even increased toxicity. Unfortunately, only scarce data exist regarding the safety of concomitant PPI use with anti-cancer agents. We aim at reviewing current evidence on this possible interaction by dividing anti-cancer agents by class. Until further data is available, we encourage healthcare providers to limit unnecessary PPI overuse.

Concomitant Use of Levothyroxine and Proton Pump Inhibitors in Patients with Primary Hypothyroidism: a Systematic Review.

The aim of this study was to assess the effect of concomitant use of levothyroxine (LT4) and proton pump inhibitors (PPIs) on thyroid-stimulating hormone (TSH) levels in patients with primary hypothyroidism. A systematic review of interventional and observational studies that compared the TSH levels before and after concomitant use of LT4 and PPI was performed. Articles published in English up to September 1, 2019, were included. PubMed, EMBASE, and Cochrane Library databases. Gray literature was also searched in repositories, websites OpenGrey and Google Scholar, and abstracts of major international congresses. Study quality was assessed with the Newcastle-Ottawa quality assessment scale for observational studies and the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool was used. Five thousand twelve discrete articles were identified. Following assessment and application of eligibility criteria, seven studies were included. There was a considerable heterogeneity among the included studies in design, sample size, inclusion and exclusion criteria, treatment regimen, and baseline demographics. Each of the included studies showed an increase in TSH levels following LT4 and PPI consumption, and in the majority of these, the increase was statistically significant. The concomitant use of LT4 and PPI showed a significant increase in TSH concentration. However, given the small number of studies, further research is needed to clarify the interfering role of PPI on LT4 intestinal absorption. CRD42020047084.