The multikinase inhibitorsorafenibwas recentlyapproved inEurope forthetreatment of advanced hepatic carcinoma (AHC). We reporta case of hepaticencephalopathy inducedby sorafenib,with positive rechallenge. Case Report. A 63-year-old patientwasdiagnosed with AHCassociated with Child-Pugh Class A alcohol-relatedcirrhosis (prothrombin 61%; bilirubin 13 mg/dL,albumin 2.9 g/dL,no ascitesor encephalopathy).There was no portalthrombosis and the patienthad not used alcohol since 2006. Chronic medical therapy consisted of propranolol 40 mg/day(for esophagealvarices),paroxetine20 mg/day,zopiclone7.5 mg/day, andoxybutynin 5 mg/day. In November 2008,sorafenib 400 mg twicedaily(approved dosing) was introduced.since chemoembolization had not succeeded.There were no complicationsfor 20 days after sorafenib initiation,except blood pressurevalues of 160/90mm Hg. The patientwas admittedto the hospital on day 21 due to confusion and asterixis. Results of an electroencephalogram revealed no lesionand computedtomography scan of the brainshoweddiffusesubcortical atrophy appropriate for age.There was no hemorrhage, infection, or renalinsufficiency. Drug-inducedhepatic encephalopathy was suspected and sorafenibwas discontinued. Within 24 hours,all neurologic symptoms resolved. The patient was discharged5 days later and sorafenib 200 mg twicedaily was reintroduced. Eightdays later,the patientpresented with a new episode of confusionand asterixis,as severe as the first one despite the dose reduction. Sorafenib was stopped,the symptoms resolved within 24 hours, and the patient no longerpresented hepatic encephalopathy. Discussion.The most commonadverseeffectsof sorafenibare liver dysfunction,diarrhea, and hand-footskin reaction.To our knowledge, this is thefirstpublished reportof hepatic encephalopathy induced by sorafenib. Use of the Naranjo probability scale indicates the role of sorafenib in hepaticencephalopathyto be probable.' The delay between sorafenib initiation and onset of neurotoxicity for both consecutive episodes is suggestive.The rapid improvementof symptomsafter sorafenib withdrawal and the positive rechallengestrengthenthe role of this drug in this case. Finally,comprehensive medicalexams and tests ruledout common causesof hepatic encephalopathy. This adverse effectis not clearlyidentified. Hepatic encephalopathy is not reported in the safetydata from pivotal studies in patients with AHC treated with sorafenib.There is only one case mentioned in a Phase I clinical trial evaluating the doxorubicin/sorafenib combination in patients with AHC. 1 However,preliminary results from a French study (unpublished results) reported 2 casesof hepatic encephalopathy in 2 patients with relapsed hepatocellular carcinoma associated with Child-Pugh Class A cirrhosis. 3 In addition, we found 5 cases of hepatic encephalopathy associated with sorafenib reported by medical professionals to an independent drug database," None of these cases is well described, but 3 patients required hospitalizationand 2 patients died. Lastly, a recentstudysuggestst...
Objective: To identify easily available predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer. Methods: Retrospective analysis of patients treated with cetuximab (400 mg/m2 in week 1, 250 mg/m2 in subsequent weeks) plus irinotecan (180 mg/m2 every 2 weeks). We assessed demographic data, prior response to chemotherapy, number of metastatic sites, disease and metastatic disease durations, irinotecan-free interval and tumoral immunohistochemical epidermal growth factor receptor status. Results: We analyzed 311 patients. Objective response rate under cetuximab-irinotecan was 26%. In univariate analysis, prior response to irinotecan, presence of only 1 metastatic site, disease duration, metastatic disease duration and irinotecan-free interval equal or above median (24, 18 and 1.8 months, respectively) were predictive of response to cetuximab-irinotecan. Multivariate analysis confirmed independent predictive value of prior response to irinotecan, number of metastatic sites and disease duration. Conclusion: Prior response to irinotecan, number of metastatic sites and disease duration may contribute to better select patients suitable for cetuximab-irinotecan therapy.
The CRYSTAL study demonstrated an advantage in terms of objective response and progression-free survival for the FOLFIRI-cetuximab combination compared with first-line FOLFIRI for patients with metastatic colorectal cancer. The results of an ancillary biological study with screening for a KRAS gene mutation in 540 patients were reported at the 2008 American Society of Clinical Oncology congress. The analysis confirmed the value of adding cetuximab only in the absence of KRAS mutation. These results led to recommend restriction of the use of cetuximab in Europe to patients with a tumour bearing wild-type KRAS. How should this apparent simplification be integrated into clinical practice? The FOLFIRI-cetuximab combination is certainly a useful supplementary first-line option although its place in relation to other high-dose regimens (high-dose FOLFIRI, FOLFOXIRI or FOLFOX-7), conventional chemotherapy plus bevacizumab, or even a fluoropyrimidine alone in the case of unresectable metastases, has yet to be specified. For subsequent lines, no study has prospectively assessed the value of the chemotherapy--anti-epidermal growth factor receptor combination as a function of KRAS status. Should the absence of objective response constantly observed in retrospective analyses in patients with a tumour presenting a KRAS mutation definitively exclude these patients while stable disease (and potentially a slight gain in survival) may be obtained?
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