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Aims: The exposure‐response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time‐dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure‐response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Methods: Bevacizumab pharmacokinetics was described using target‐mediated drug disposition modelling. Relationships between target kinetics, progression‐free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic‐driven and response‐driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Results: Estimated target‐mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4 nM), steady‐state dissociation constant (KSS = 10 nM) and antibody‐target complexes elimination constant (kint = 0.52 day−1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. Conclusion: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in‐depth description of this relationship. [ABSTRACT FROM AUTHOR]

Résumé: Le risque de neutropénie sévère chimio-induite varie selon le schéma de chimiothérapie prescrit et des facteurs clinico-biologiques. Par exemple, dans la prise en charge du cancer colorectal traité par chimiothérapie, les risques de neutropénie sévère de grade 3/4 (< 1 000 polynucléaires neutrophiles/mm3) et fébrile varient respectivement de 2 à 50 % et moins de 1 à 10 % en fonction du schéma prescrit. Pour la majorité des schémas de chimiothérapie prescrits en cancérologie digestive, la prévention et la gestion de cette toxicité hématologique reposent surtout sur le recours à des reports de cures généralement associés à des diminutions de doses de chimiothérapies au détriment de la dose-intensité des schémas prescrits. Pour les schémas associés à des risques plus élevés de neutropénie sévère tels que les schémas DCF, VP16-sel de platine et FOLFIRINOX, la prescription de G-CSF en prophylaxie primaire ou secondaire est à discuter voire à recommander systématiquement. La recherche d'un déficit en DPD avant la prescription de 5-FU contribue à prévenir le risque de toxicité sévère hématologique lié au 5-FU. La gestion du risque de neutropénie imputable à la prescription d'une chimiothérapie nécessite une bonne connaissance des profils de tolérance des chimiothérapies prescrites et des facteurs de risque liés au patient. The risk of severe chemotherapy-induced neutropenia varies according to the chemotherapy regimen and clinico-biological factors. For instance, concerning the chemotherapy-based treatment of colorectal cancer, the risks of severe neutropenia that is grade 3 to 4 (<1.000 neutrophils/mm3) and febrile neutropenia range from 2% to 50 % and <1% to 10 %, respectively. For the majority of chemotherapy regimens prescribed in gastrointestinal oncology, the prevention and management of severe chemotherapy-induced neutropenia is mainly based on delaying cycles generally associated with decreasing drug dosage to the detriment of the regimen's intensity-dose ratio. For regimens associated with a higher risk of severe neutropenia such as DCF, VP16-platinum and FOLFIRINOX regimens, the prescription of G-CSF in primary or secondary prophylaxis should be discussed or recommended systematically. The search for a DPD deficiency before the prescription of 5-FU helps to prevent the risk of severe haematological toxicity related to 5-FU. The management of the risk of neutropenia attributable to the prescription of chemotherapy requires a good knowledge of the tolerance profiles of the prescribed chemotherapies and risk factors related to the patient. [ABSTRACT FROM AUTHOR]

Pharmacokinetics is the study of the time course of drug concentration in the body. Several monoclonal antibodies are now in clinical use for digestive cancer therapy and several are emerging, especially immune checkpoint inhibitors. Pharmacokinetics of these drugs shows a large interindividual variability which can be explained by different factors. In some cases, tumor burden may influence pharmacokinetics: when tumor burden increases, exposure of monoclonal antibody decreases. There is also a relationship between drug exposure and clinical efficacy. This can be used to identify appropriate dose regimen at the individual level. [ABSTRACT FROM AUTHOR]

Background: Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line.Methods: Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model.Results: Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin ⩾30 μmol l-1 (P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS.Conclusions: Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC. [ABSTRACT FROM AUTHOR]

Copyright of Hépato-Gastro & Oncologie Digestive is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Hépato-Gastro & Oncologie Digestive is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background and Aims: Bevacizumab-based chemotherapy is a recommended first-line treatment for metastatic colorectal cancer (mCRC). Robust biomarkers with clinical practice applicability have not been identified for patients with this treatment. We aimed to evaluate the prognostic yield of serum mid-infrared spectroscopy (MIRS) on patients receiving first-line bevacizumab-based chemotherapy for mCRC., Methods: We conducted an ancillary analysis from a multicentre prospective study (NCT00489697). All baseline serums were screened by attenuated total reflection method. Principal component analysis and unsupervised k-mean partitioning methods were performed blinded to all patients' data. Endpoints were progression-free survival (PFS) and overall survival (OS)., Results: From the 108 included patients, MIRS discriminated two prognostic groups. First group patients had significantly lower body mass index (p = 0.026) and albumin levels (p < 0.001), and higher levels of angiogenic markers, lactate dehydrogenase and carcinoembryonic antigen (p < 0.001). In univariate analysis, their OS and PFS were shorter with respective medians: 17.6 vs 27.9 months (p = 0.02) and 8.7 vs 11.3 months (p = 0.03). In multivariate analysis, PFS was significantly shorter (HR = 1.74, p = 0.025) with a similar trend for OS (HR = 1.69, p = 0.061)., Conclusion: By metabolomic fingerprinting, MIRS proves to be a promising prognostic tool for patients receiving first-line bevacizumab-based chemotherapy for mCRC., Competing Interests: Declaration of competing interest Authors have declared no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence their work regarding this study., (Copyright © 2024. Published by Elsevier Ltd.)