Anti-angiogéniques et rein

Transcription

1 Anti-angiogéniques et rein JM Rebibou Séminaire DES, Strasbourg 9 octobre 2015 VEGF VEGF 5 isoformes VEGFR 1 et 2, VEGFR1 activité tyrosine kinase réduite mais une forme soluble (SFLT1) ayant probablement un rôle dans la prééclampsie La délétion homozygote du gène de VEGFA est létale, la délétion hétérozygote fans le podocyte entraine une protéinurie. La surexpression du gène est accompagnée d une «collapsing glomérulopathy» L inactivation du gène de VEGFA à l'âge adulte induit une protéinurie et une MAT Advani A, Curr Opin Nephrol Hypertens

2 Antiangiogéniques 2

3 VEGFI : Caractéristiques de l HTA Quasiment 100% des patients augmentent leur PA Dés le début du traitement Réversible a l arrêt du traitement Effet dose dépendant Augmente chez les patients traités avec une association L incidence est sous-estimée dans les études randomisées du fait de la sélection des patients inclus dans ce type d étude Elle est plus élevée dans les études «real life» L HTA est un effet secondaire dit «on target» lié directement à l activité du médicament L HTA pourrait être un signe d efficacité du traitement 3

4 HTA et VEGFI : MAPA Maitland ML, Clin Cancer Res, 2009 Risk of Hypertension in Cancer Patients Treated with Aflibercept: A Systematic Review and Meta-Analysis Wei-Xiang Qi, Clin Drug Invest 2014 Background Aflibercept is currently approved as second-line treatment for patients with metastatic colorectal cancer, and its application in other types of tumors is undergoing clinical evaluation. Hypertension is one of its major adverse effects with a substantial variation in the reported incidences and has not been systematically investigated. Methods We searched PubMed, EMBASE, and Cochrane Library databases from January 2000 to August 2013 and abstracts presented at annual meetings from 2004 to 2013 to identify relevant studies. Eligible studies were phase II and III prospective clinical trials of aflibercept in patients with any type of cancer describing events of hypertension. Summary incidence rates, odds ratios (OR), and 95 % confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. Results A total of 15 trials with 4,451 patients were included for the meta-analysis. The summary incidences of allgrade and high-grade hypertension were 42.4 % (95 % CI ) and 17.4 % (95 % CI ), respectively. The use of aflibercept in cancer patients was associated with a significantly increased risk of all-grade (OR 4.47, 95 % CI , p < 0.001) and high-grade (OR 4.97, 95 % CI , p < 0.001) hypertension. The risk of developing hypertension with aflibercept was significantly higher than that of bevacizumab (all-grade: OR 1.93, 95 % CI , p < 0.001; high-grade: OR 2.06, 95 % CI , p < 0.001). Conclusions The use of aflibercept is associated with a significantly increased risk of developing all-grade and highgrade hypertension compared with control. Close monitoring and adequate managements are highly recommended to decrease cardiovascular complication. 4

5 Physiopathologie de l HTA Small HY, Can J Cardiol, 2014 Deux raisons de traiter 5

6 Meta-Analysis of Randomized Controlled Trials for the Incidence and Risk of Treatment- Related Mortality in Patients With Cancer Treated With Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors Fabio A.B. Schutz, Youjin Je, Christopher J. Richards, and Toni K. Choueiri Purpose Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become the cornerstone in the treatment of several malignancies. These drugs have also been associated with an increase in the risk of potentially life-threatening adverse events, such as arterial thrombotic events, bleeding, congestive heart failure, and others. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in patients with cancer treated with VEGFR TKIs. Methods MEDLINE and PubMed databases were searched for articles published from January 1966 to February Eligible studies were limited to trials of US Food and Drug Administration approved VEGFR TKIs (pazopanib, sunitinib, and sorafenib) that reported on patients with cancer with any primary tumor type, randomized design, and adequate safety profile. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results In all, 4,679 patients from 10 randomized controlled trials (RCTs) were included, with 2,856 from sorafenib, 1,388 from sunitinib, and 435 from pazopanib trials. The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P.023) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between different VEGFR TKIs or tumor types. No evidence of publication bias was observed. Conclusion In a meta-analysis of RCTs, the use of VEGFR TKIs was associated with an increased risk of FAEs compared with control patients. J Clin Oncol 30: by American Society of Clinical Oncology 15% des effets indésirables mortels sont des IDM Posterior reversible encephalopathy syndrome 6

7 VEGFI : traitement HTA Small HY, Can J Cardiol, 2014 Halimi JM, Nephrol Thera,

8 26/11/2015 VEGF I et Protéinurie Dose dépendante 23 à 60% des patients selon les études Grade 3 plus rares entre 3 et 8% suivant la tumeur et la dose La progression vers un syndrome néphrotique est rare Eremina V, New Engl J Med,

9 Eremina V, New Engl J Med, 2008 Profil clinique et biologique Izzedine H, Ann Oncol,

10 Profil clinique et biologique Izzedine H, Ann Oncol, 2011 Vigneau C, Nephrol Dial Transplant :

11 Vigneau C, Nephrol Dial Transplant : 2014 Kidney Diseases Associated With Anti-Vascular Endothelial Growth Factor (VEGF): An 8-year Observational Study at a Single Center. Izzedine, Hassan; Medicine TABLE 1 Clinical Characteristics of Anti-VEGF-Associated Kidney Diseases 2 11

12 26/11/2015 Kidney Diseases Associated With Anti-Vascular Endothelial Growth Factor (VEGF): An 8-year Observational Study at a Single Center. Izzedine, Hassan; Medicine FIGURE 1. Collapsing glomerulopathy (CG) and thrombotic microangiopathy (TMA) lesions in renal biopsies from patients with anti-vegf agents. CG: there is a collapse of the capillary tuft (A) with overlying swollen and hyperplastic epithelial cells (B) (HES, original magnification x 200) often having a pseudocrescent-like appearance (C) (Masson trichrome, x 200). TMA: luminal thrombosis within the glomerular capillary (D) (Masson trichrome, x 200). The capillary basement membranes were thickened with double-contoured appearance of the capillary wall, best appreciated with methenamine silver stain (E) (x 200) associated with mesangiolysis (F) (Masson trichrome, x 200). 3 Comment traiter? Izzedine H, Ann Oncol,

13 Cas numéro 1 Homme 72 ans Métastases de Cancer Rein CC Traité par un Aangio depuis 3 mois Bonne réponse tumorale Protéinurie 1g/J Créat stable 82micromoles/l HTA contrôlée ARA2 Amlodipine Le cancérologue vous appelle 1. Vous convoquez le patient pour une PBR 2. Vous contre-indiquez définitivement le patient pour tous les Aangio 3. Vous demandez un bilan de MAT pour donner votre avis 4. Vous discutez une diminution de dose 5. Vous préconisez une surveillance rapprochée de la créat et de la protéinurie 6. Vous lui demandez d appeler la Pitié Cas numéro 2 Homme de 68 ans Rechute tumeur du cardia Bonne réponse à un traitement Aangio instauré depuis 4 mois (inhibiteur de TK) Le cancérologue vous explique que d autres types de traitement peuvent être proposés sans certitude sur la réponse Bilan de MAT négatif Protéinurie 3,5g/j Créat stable 90mg 1. Vous arrêtez immédiatement le traitement 2. Vous expliquez au cancérologue que seul le traitement du cancer importe 3. Vous n arrêtez le traitement que si la biopsie révèle une MAT 4. Vous maintenez le traitement si la biopsie montre des signe de collapsing glomerulopathy 13

14 Cas numéro 3 Mr G 76 tumeur digestive Avastin première ligne HTA contrôlée avec 100mg de losartan Créat 220 micromoles Proteinurie 1,5g/j Vous ne discutez avec le résultat de la biopsie et maintenez le traitement Vous arrêtez le traitement avec une CI définitive Vous arrêtez en attendant le résultat de la biopsie 14

15 Merci de votre attention 15

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