Individualized Medication Of Oral Phenytoin For The Prophylaxis Of Early Seizure After Craniocerebral Injury And Efficacy And Severe Adverse Reactions Of Cetuximab Combined With Chemotherapy In The Treatment Of Colorectal Cancer-a Meta-Analysis

Part one Individualized administration of oral phenytoin for the prophylaxis of early seizure after craniocerebral injuryObjectives The objectives of this study were to establish population pharmacokinetics (PPK) model of oral phenytoin to optimize the individualized medication, and to provide reference for the prophylaxis of early seizure after craniocerebral injury.Methods A total of 170 patients with craniocerebral injury were prospectively enrolled according to the inclusion criteria. Genotypes of CYP2C9 and CYP2C19 were detected by polymerase chain reaction (PCR) before operation. Serum concentrations of phenytoin collected on the 4th day and the 7th day were determined using fluorescence polarization immunoassay after the first day of oral phenytoin. Parameters of PPK were estimated by Nonlinear Mixed Effects Models (NONMEM) and internal validation was performed using bootstraps. The predictive performance of the final model was evaluated by normalized predictive distribution errors (NPDEs) and diagnostic goodness-of-fit plots. Individualized dose regimen of phenytoin in 40 new patients enrolled as external validation group were designed according to the final model.Results A total of 390 serum concentrations collected from 170 patients were detected in this study. The estimates of Vm, Km and the apparent volume of distribution (V) in the final model were 17.5mg/h,6.41mg/L and 54.8L/kg, respectively. The values of Vm in patients with extensive metabolizers, intermediate metabolizers and poor metabolizers were 28.18 X (1+TM X 0.203),24.33 X (1+TM X 0.203),17.5 X (1+TM X 0.203), respectively. The values of Km in patients with extensive metabolizers, intermediate metabolizers and poor metabolizers were 7.88mg/L,6.73mg/L and 6.41mg/L, respectively. Results of the internal validation by bootstraps showed stability and reliability of the final model. NPDEs with a normal distribution and scatterplot with symmetrical distribution showed good prediction. A total of 78 trough serum concentrations from 40 patients in the external validation group were determined at 7:30 on the 4th day and the 7th day. The percent of effective concentrations were 61.53% (24/39) and 94.87% (37/39), respectively, on the 4th day and the 7th day, which were respectively higher than 39.33% (59/150) and 52.10% (87/167) of 170 patients in modeling group (P<0.0001).Conclusions The PPK model of oral phenytoin established in this study showed good stability and reliability, which could provide reference for designing individualized dose regimen of phenytoin to prevent early seizure after craniocerebral injury.Part two Efficacy and severe adverse reactions of cetuximab combined with chemotherapy in the treatment of colorectal cancer—a meta-analysis Objectives The purpose of this meta-analysis was to assess the clinical efficacy and the risk of severe adverse reactions of cetuximab in combination with chemotherapy compared to chemotherapy alone in patients with advanced or metastatic colorectal cancer (CRC).Methods Relevant articles reporting randomized controlled trials (RCT) were identified by searching electronic databases including Medline, PubMed, Embase, Cochrane Library, CNKI, VIP and WANFANG Data. Eligible articles were included, data of which were extracted. Relative risk (RR), odds ratio (OR) or hazard ratio (HR) was used to analyze the clinical efficacy and the risk of severe adverse reactions. The inter-study heterogeneity was evaluated based on Q test. Fixed effect model was employed to calculate the pooled effects when homogeneity existed (P≥O.10,I2≤50%); otherwise, randomized effect model was used.Results Fourteen articles were included, of which 12 articles reported clinical efficacy and the risk of severe adverse reactions,2 articles of which only reported the risk of severe adverse reactions. In the intention-to-treat (ITT) population, patients in the experimental group had longer progression free survival (PFS) than patients in the controlled group [HR=0.87,95%CI(0.79,0.95), P=0.002], but the differences of overall survival (OS) [HR=0.92,95%CI(0.85,1.00), P=0.05] and disease control rate [OR=1.06, 95%CI (0.88,1.27), P=0.54] between two groups were not significant. Patients with wild type KRAS had longer PFS treating with cetuximab in combination with chemotherapy than patients treating with chemotherapy alone [HR=0.80,95%CI (0.66,0.98), P=0.03], but the difference of OS was not significant between two groups [HR=0.93,95%CI(0.79, 1.09), P=0.38]. The differences of OS [HR=1.04,95%CI(0.93,1.17), P=.48] and PFS [HR=1.14,95%CI (0.89,1.45), P=0.29] in patients with mutant KRAS were not significant between two groups. Nine severe adverse reactions, such as aceneform rash, stomatitis, hand-foot syndrome, hypersensitivity, anorexia, diarrhea, fatigue, nausea and vomiting, neutropenia were more common in experimental group than in controlled group, but severe pepripheral neuropathy had a lower incidence in experimental group than in controlled group [OR=0.67,95%CI (0.54,0.83),P<0.001] and the difference of severe anemia between experimental group and controlled group had no statistic significance [OR=1.11,95%CI(0.68,1.83), P=0.67].Conclusions In this meta-analysis, cetuximab in combination with chemotherapy could lengthen PFS in ITT population and patients with wild type KRAS but could not lengthen OS. Except severe anemia and pepripheral neuropathy, cetuximab in combination with chemotherapy was associated with an increased risk of other severe adverse reactions compared with chemotherapy alone in the treatment with advanced/metastatic CRC patients.