Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting

Bouchet, Stéphane; Poulette, S.; Titier, Karine; Moore, Nicholas; Lassalle, R.; Abouelfath, Abdelilah; Italiano, Antoîne; Chevreau, Christine; Bompas, Emmanuelle; Collard, Olivier; Duffaud, Florence; Rios, María; Cupissol, Didier; Adenis, Antoine; Ray‐Coquard, Isabelle; Bouché, Olivier; Cesne, Axel Le; Bui, Binh; Blay, Jean‐Yves; Molimard, Mathiéu

doi:10.1016/j.ejca.2015.12.029

Cited by 72 publications

(47 citation statements)

References 26 publications

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“…The relatively large inter- and interpatient variability in our study compared to other real-life cohorts [14, 18] could be explained by lack of compliance. Although oral cancer therapies offer patients the convenience of self-administration at home, evidence show that adherence to these therapies is far from optimal [28, 29].…”

Section: Discussionmentioning

confidence: 61%

“…A prospective PK study showed a significant decrease of approximately 30% in plasma IM concentration after 90 days of treatment [17], indicating that drug monitoring should preferentially be done after 3 months. This finding was recently supported by a study in real-life practice, where C min was analysed after more than 3 months of treatment, and concentrations above 760 ng/mL were associated with longer progression-free survival (PFS) [18]. …”

Section: Introductionmentioning

confidence: 83%

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Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour

et al. 2016

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BackgroundImatinib mesylate (IM) is the preferred treatment for the majority of patients with metastatic gastrointestinal stromal tumour (GIST). Low trough IM concentration (Cmin) values have been associated with poor clinical outcomes in GIST patients. However, there are few studies of repeated measurements of IM levels, and therapeutic drug monitoring is not yet a part of routine clinical practice. This study was conducted to reveal clinical scenarios where plasma concentration measurement of IM trough level (Cmin) is advantageous.MethodsPatients with advanced GIST receiving IM were included from January 2011 to April 2015. Heparin plasma was collected at each follow-up visit. Ninety-six samples from 24 patients were selected for IM concentration measurement. Associations between IM plasma concentration and clinical variables were analyzed by Students’ t test, univariate and multivariate linear regression analyses.ResultsThe mean IM Cmin plasma concentrations for patients taking <400, 400 and >400 mg daily were 782, 1132 and 1665 ng/mL, respectively (p = 0.010). High IM Cmin levels were correlated with age, low body surface area, low haemoglobin concentration, low creatinine clearance, absence of liver metastasis and no prior gastric resection in univariate analysis. In multivariate analysis age, gastric resection and liver metastasis were included in the final model. Eight patients had disease progression during the study, and mean IM levels were significantly lower at time of progression compared to the previous measurement for the same patients (770 and 1223 ng/mL, respectively; p = 0.020).ConclusionsOur results do not support repeated monitoring of IM levels on a routine basis in all patients. However, we have revealed clinical scenarios where drug measurement could be beneficial, such as for patients who have undergone gastric resection, suspicion of non-compliance, subjectively reported side effects, in elderly patients and at the time of disease progression.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 83%

Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour

et al. 2016

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“…Translational studies evaluated the relationship between imatinib blood levels and treatment response. It revealed that plasma levels below 760 ng/l after 3 months of treatment are associated with a worse prognosis [23]. Interestingly, in this cohort analyzed in France, there was also a strong correlation between the extent of gastric resection and imatinib blood levels.…”

Section: Principles Of Surgery and Different Rationales For Preoperatmentioning

confidence: 81%

Neoadjuvant Therapy to Downstage the Extent of Resection of Gastrointestinal Stromal Tumors

Jakob¹,

Hohenberger²

2018

Visc Med

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Introduction: Gastrointestinal stromal tumors (GIST) are rare malignant tumors in terms of incidence, and they are not linked to specific symptoms. Often, primary tumors, particularly of the stomach, rectum, or rectovaginal space, are quite large when detected, and multivisceral resection seems to be the treatment of choice as the mainstay of therapy is complete tumor removal. If a gain-of-function mutation in the KIT gene is present, drug therapy with receptor tyrosine kinase inhibitors (RTKIs) might significantly downstage primary GIST tumors. Methods: A review of the literature was performed to identify the current evidence for preoperative treatment of GIST regarding toxicity, efficacy, and oncological outcome, including mutational data from our own database. Results: Four phase II as well as several cohort studies showed acceptable toxicity and no increased perioperative morbidity of preoperative imatinib. Progressive disease during preoperative treatment was a rare event, and partial response was achieved in 40-80% of all patients. For methodological reasons, the trials cannot prove an oncological long-term superiority of preoperative treatment. Conclusion: Preoperative therapy with imatinib is safe and recommended for patients with locally advanced GIST. Neoadjuvant imatinib therapy may enable less invasive and organ-sparing surgery, avoid tumor rupture during extensive resectional procedures, and improve the quality of perioperative RTKI treatment.

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“…Retrospective data suggest that suboptimal plasma levels of imatinib are associated with a worse outcome, though a correlation with outcome has not been established prospectively [35]. A recent report confirmed that patients with imatinib trough levels of less than 760 ng/ml, taken after a minimum of 3 months’ treatment, which equates to steady state [36], had a worse outlook in terms of progression-free survival, which applied in the case of both gastric and small bowel GIST [37]. Aside from its potential use to tailor the imatinib dose, plasma level assessment may be useful in the case of: (i) patients receiving concomitant medications that put them at a risk of major interactions; (ii) unexpected observed toxicities; (iii) progression on 400 mg.…”

Section: Treatmentmentioning

confidence: 99%

UK clinical practice guidelines for the management of gastrointestinal stromal tumours (GIST)

et al. 2017

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BackgroundSoft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues. Gastrointestinal stromal tumour (GIST) is the commonest STS and arises within the wall of the gastrointestinal (GI) tract. While most GISTs occur in the stomach they do occur in all parts of the GI tract. As with other STS, it is important that GISTs are managed by expert teams, to ensure consistent and optimal treatment, as well as recruitment to clinical trials, and the ongoing accumulation of further knowledge of the disease. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field.MethodologyBritish Sarcoma Group guidelines for the management of GIST were initially developed by a panel of physicians experienced in the management of GIST. This current version has been updated and amended with reference to other European and US guidance. We have received input from representatives of all diagnostic and treatment disciplines as well as patient representatives. Levels of evidence and strength of recommendation gradings are those used by ESMO adapted from those published by the Infectious Disease Society of America.ConclusionsThe guidelines cover aetiology, genetics and underlying molecular mechanisms, diagnosis and initial investigations, staging and risk stratification, surgery, neoadjuvant and adjuvant therapy, the management of advanced disease and follow-up. The importance of mutational analysis in guiding treatment is highlighted, since this can indicate the most effective treatment and avoid administration of ineffective drugs, emphasising the need for management in specialist centres.

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Relationship between imatinib trough concentration and outcomes in the treatment of advanced gastrointestinal stromal tumours in a real-life setting

Cited by 72 publications

References 26 publications

Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour

Clinical implications of repeated drug monitoring of imatinib in patients with metastatic gastrointestinal stromal tumour

Neoadjuvant Therapy to Downstage the Extent of Resection of Gastrointestinal Stromal Tumors

UK clinical practice guidelines for the management of gastrointestinal stromal tumours (GIST)

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