Systemic treatment of advanced biliary cancers: present and future

Deux essais randomisés de phase III récents ont démontré que les combinaisons gemcitabine – platine (schémas GEMOX et GEMCIS) étaient supérieures en termes de survie globale aux meilleurs soins de support et à la gemcitabine seule, respectivement, faisant de ces deux schémas les options thérapeutiques de choix en première ligne de traitement des patients atteints de cancers biliaires avancés. Si aucune donnée ne permet de définir actuellement de standard au-delà de la première ligne, un schéma à base de fluoropyrimidine peut être proposé sur la foi d’une revue systématique de plus de 100 essais de chimiothérapie. L’inhibition ciblée d’altérations moléculaires oncogéniques tumorales d’intérêt, comme l’activation de la voie EGFR ou de MEK, seule ou en association à la chimiothérapie, a permis d’obtenir des premiers résultats encourageants.Two randomized phase III trials have recently demonstrated that gemcitabine – platinum combinations (GEMOX and GEMCIS regimens) were superior in terms of overall survival over best supportive care and gemcitabine alone, respectively, making these two regimens treatment options of choice in first-line treatment of patients with advanced biliary cancers. Although no data are currently available beyond first-line therapy, fluoropyrimidinebased regimens can be proposed on the basis of a systematic review of over 100 trials of chemotherapy. The targeted inhibition of tumor oncogenic molecular alterations of interest such as EGFR pathway or MEK activation, alone or in combination with chemotherapy, has yielded encouraging results

Thiopurine Metabolism in the Era of Combotherapy

International audience6-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few studies investigated the interaction between thiopurine metabolism and anti-tumor necrosis factor therapy among patients with IBD on combotherapy. Two studies demonstrated that infliximab therapy increases 6-thioguanine nucleotides level, while such effect could not be observed with adalimumab. Three studies showed that a Delta mean corpuscular volume >7 and high 6-thioguanine nucleotides levels are associated with favorable outcomes, i.e., greater mucosal healing rates, and have a positive impact on the pharmacokinetics of infliximab. These results suggest a synergistic effect between thiopurine metabolism and anti-tumor necrosis factor therapy, especially with infliximab. We propose here some algorithms for clinical practice integrating thiopurine metabolism in patients with IBD on combotherapy. Further randomized controlled trials are needed to further investigate the relationships between thiopurine metabolism and anti-tumor necrosis factor therapy and to establish the clinical utility of measuring thiopurines' metabolites in these patients in clinical practice. Whether measuring thiopurine metabolism can be used to guide decision-making in patients with IBD on combotherapy when considering drug de-escalation or discontinuation will require further investigation

Golimumab pharmacokinetics in ulcerative colitis: a literature review

Golimumab (GLM) is the latest anti-tumor necrosis factor (TNF) that gained its marketing license. Thanks to the PURSUIT induction and maintenance trials, it was approved for the treatment of ulcerative colitis (UC) in 2013. The other anti-TNF drugs available are infliximab and adalimumab. These two drugs have validated algorithms concerning prescription and therapeutic drug monitoring (TDM) but little is known about GLM. The available data on GLM’s exposure–response relationship in UC are from the PURSUIT trials and are recently published. The data reveal all the factors that may impact the pharmacokinetic (PK) parameters: dosage, body weight (BW), concomitant drugs, the presence of anti-drug antibodies (ADAbs), sex and age. In addition, the GLM trough level at steady-state appears to be correlated with the patient’s improvement which may make it a precious indicator to predict the clinical response. There is, however, no consensus on a possible therapeutic level or cutoff associated with clinical response, remission, or any other outcome measure such as endoscopic healing in UC. This lack of a threshold value, and its validation with different assay techniques, makes it difficult to use GLM TDM in clinical practice. As with other anti-TNF agents, GLM is associated with development of ADAbs, of which the prevalence and effects are still insufficiently described. The objective of this review is to describe current data and understanding of the PK of GLM including serum concentrations of GLM and ADAbs in UC patients. Better understanding of these parameters could lead to improved patient care with GLM

Pharmacokinetics of Infliximab and Reduction of Treatment for Inflammatory Bowel Diseases

International audienceLocal or national policy, patients' preferences, safety and/or economic concerns, or reimbursement issues may dictate stopping drug in inflammatory bowel diseases (IBD) patients. Sustained deep remission is an important predictor of a better outcome after anti-tumor necrosis (TNF) factor therapy discontinuation, including infliximab (IFX) in IBD patients, but this is not sufficient to prevent future relapse in these patients. In IBD patients under combotherapy, trough level of infliximab (TRI) could be helpful to choose stopping one of the two drugs. In patients on IFX monotherapy, TRI could help to decide reduction of drug dosing, particularly in IBD patients with supratherapeutic trough levels. Incidental findings of undetectable TRI in patients with deep remission may identify a subset of patients who may be considered for IFX cessation. Controlled trials further assessing this issue are eagerly awaited. Pending these trials, clear international recommendations for discontinuing anti-TNF therapy are needed