Impact of Concomitant Administration of Gastric Acid–Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials

Mir, Olivier; Touati, Nathan; Lia, Michela; Litière, Saskia; Cesne, Axel Le; Sleijfer, Stefan; Blay, Jean Yves; Leahy, Michael; Young, Rowan D.; Mathijssen, Ron H.J.; Erp, Nielka P. van; Gelderblom, Hans; Graaf, Winette Ta van der; Gronchi, Alessandro

doi:10.1158/1078-0432.ccr-18-2748

Cited by 70 publications

(60 citation statements)

References 22 publications

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“…Other studies defined a threshold for duration of clinically meaningful overlap between ASMs and TKIs ranging from 20−80% . In this study, we did not set a predefined threshold for percent overlap and instead included any duration of concomitant ASM use.…”

Section: Discussionmentioning

confidence: 99%

“…In patients with STS in particular, Mir et al 11 reported in abstract form that of 333 European patients with STS retrospectively analyzed from the European Organization for Research and Treatment of Cancer (EORTC) 62043/62072 trials, 117 patients received concomitant ASMs with PAZ, and median PFS was shorter in the concomitant acid suppressive group vs. the no ASM group (2.8 months vs. 4.6 months; P = 0.008). Our study supports these findings, but is also the first to describe the real-world use of PAZ with concomitant ASM and counseling as to appropriate timing in a non-European cohort.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies defined a threshold for duration of clinically meaningful overlap between ASMs and TKIs ranging from 20−80%. 9,11 In this study, we did not set a predefined threshold for percent overlap and instead included any duration of concomitant ASM use. The mean percent overlap in the combination ASM and PAZ group was high overall, with 88% overlap in the PPI-containing group and 85% in the H2RA group.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Acid‐Suppressive Strategies on Pazopanib Efficacy in Patients With Soft‐Tissue Sarcoma

Pisano

Hoffman

Legasto

et al. 2019

Clinical Translational Sci

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Pazopanib (PAZ), a tyrosine kinase inhibitor used in the treatment of soft tissue sarcoma (STS), should not be administered with acid‐suppressive medications (ASMs) due to decreased drug solubility. Common practice for patients requiring ASM with PAZ is to separate administration by 12 hours; however, there is little real‐world evidence describing clinical outcomes using this strategy. The aim of this study was to determine whether concomitant ASM impacted efficacy and adverse event rates in patients with STS receiving PAZ. Medical records were retrospectively reviewed for patients with STS who received PAZ from June 2011 to July 2017. Patients were stratified into two groups, PAZ with or without ASM (PAZ + ASM or PAZ only). The primary objective was to determine whether progression‐free survival (PFS) differed between groups. Secondary objectives were to determine overall survival (OS) and occurrence of grade 3/4 toxicities. Ninety‐one patients were included in the study, 42 patients in the PAZ + ASM group and 49 in the PAZ only group. Median PFS was significantly shorter in the PAZ + ASM group than the PAZ only group (5.3 vs. 6.7 months). The PAZ + ASM group also had a 74% higher relative risk of progression or death than the PAZ only group, but there was no difference in OS. Regarding adverse events, the PAZ + ASM group trended toward lower levels of grade 3/4 hypertension (19% vs. 37%). These results suggest that ASM should be avoided in patients with STS receiving PAZ. Larger studies are needed to further elucidate the impact of ASM use with PAZ in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of Acid‐Suppressive Strategies on Pazopanib Efficacy in Patients With Soft‐Tissue Sarcoma

Pisano

Hoffman

Legasto

et al. 2019

Clinical Translational Sci

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“…Two studies reported shorter PFS and overall survival (OS) in patients treated with pazopanib receiving concomitant pH‐elevating medication, though in one of these studies the effect on treatment outcome was not statistically significant . Unfortunately, no pazopanib plasma concentrations were measured.…”

Section: Methodsmentioning

confidence: 99%

“…Two studies reported shorter PFS and overall survival (OS) in patients treated with pazopanib receiving concomitant pH-elevating medication, though in one of these studies the effect on treatment outcome was not statistically significant. 148,149 Unfortunately, no pazopanib plasma concentrations were measured. However, considering the essential role of gastric pH in the absorption of pazopanib and the previously established decrease in pazopanib AUC when combined with a proton pump inhibitor, it is likely that the shortened survival is caused by underexposure to pazopanib.…”

Section: Gastric Phmentioning

confidence: 99%

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

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Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.

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Prevalence of Proton Pump Inhibitor Use Among Patients With Cancer

Raoul

Guérin‐Charbonnel

Edeline³

et al. 2021

JAMA Netw Open

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The cancer armamentarium is evolving with evidence of the efficacy of oral treatments. Their mode of administration is simple and convenient, but absorption is influenced by diet and gastric pH.Moreover, the efficacy of checkpoint inhibitors (CPIs) depends on the gut microbiome. Proton pump inhibitors (PPIs), which are among the most widely prescribed drugs, decrease the bioavailability of oral cancer treatments, lowering their efficacy, 1-4 and induce major microbial alterations in the gut. 4 We conducted a study to evaluate the prevalence of PPI prescribing, to identify the factors associated with PPI prescription, and to focus on patients receiving tyrosine kinase inhibitors (TKIs), CPIs, and capecitabine. MethodsThis cross-sectional study was conducted in 4 French Comprehensive Cancer Centers from June 15 to 19 and from June 22 to 26, 2020. It was approved by the ethics committee of Angers University, which waived the need for informed consent in accordance with university policy. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.Volunteer physicians collected data from patients with cancer seen in consultation or in the Same Day Unit. An information sheet (explaining the goals of the study, that patients could refuse to participate, and that all data would be anonymized) was given to patients; those who accepted were included. The physicians then completed a form (with scrolling menu) based on the patient's medical records and answers to a few questions.Parameters were compared using Welch t test, χ 2 test, or Fisher exact test as appropriate.Significant parameters were entered into a multivariable logistic regression with a stepwise procedure. All P values were 2-sided with P < .05 considered significant. Statistical analyses were performed with R statistical software version 4.0.2 (R Project for Statistical Computing). ResultsIn total, 872 complete and verified (data manager) forms corresponding to 566 women ( 64.9%) and 306 men (35.1%) (median [range] age, 63 [20-91] years) (Table 1) were recorded. Among these, 229 patients (26.3%) were taking PPIs on the day of inclusion. Most patients who used PPIs did so on a regular basis (163 patients [71.1%]), at normal dosage (154 patients [67.2%]), for epigastric pain (114 patients [50.0%]), retrosternal pain (32 patients [14.0%]), proven esophageal or gastric ulcer (18 patients [8.0%]), or gastroprotection (34 patients [15.0%]).

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Impact of Concomitant Administration of Gastric Acid–Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials

Cited by 70 publications

References 22 publications

Effect of Acid‐Suppressive Strategies on Pazopanib Efficacy in Patients With Soft‐Tissue Sarcoma

Effect of Acid‐Suppressive Strategies on Pazopanib Efficacy in Patients With Soft‐Tissue Sarcoma

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Prevalence of Proton Pump Inhibitor Use Among Patients With Cancer

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