On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable. AIM: To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC. METHODS: In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively. RESULTS: A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose. CONCLUSION: Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.

The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure: implications for drug development.

BACKGROUND: Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin-bilirubin (ALBI) grade is a validated index of liver function in patients with HCC. AIM: To test the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment. METHODS: From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer C stage (62%), 75% of whom were of Child class A at initiation. Clinical variables at sorafenib discontinuation were analysed for their impact on post-sorafenib overall survival using uni- and multivariable analyses. RESULTS: Median post-sorafenib overall survival of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening Child class to C in 40 (10%). Median post-sorafenib overall survival in patients eligible for second-line therapies (n = 294) was 17.5, 7.5 and 1.9 months according respectively to ALBI grade 1, 2 and 3 (P < 0.001). CONCLUSIONS: The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow improved patient selection for second-line therapies in advanced HCC.

Toxocara encephalitis presenting with autonomous nervous system involvement.

Human toxocariasis has been reported to cause a broad spectrum of neurological syndromes, including encephalitis, meningitis and meningo-radiculitis. Nevertheless, cerebral infection by Toxocara may go undiagnosed due to its rarity, elusive symptoms and lack of availability of appropriate testing. We report the case of a 54-year-old man who presented with abdominal pain and paralytic ileus approximately 3 weeks after having eaten raw snails (a folk remedy for peptic ulcer). Three weeks later, marked eosinophilia ensued, associated with mental clouding, nystagmus, diplopia, peripheral limbs ataxia, urinary retention, slackened deep tendon reflexes, arthralgias and myalgias. Cerebrospinal fluid (CSF) examination demonstrated an eosinophilic meningitis, and Toxocara canis cerebral infection was diagnosed by positive serology and by the detection of T. canis DNA in the CSF. The patient made a full recovery following treatment with albendazole and corticosteroids. Physicians should be aware of this rare presentation of toxocariasis, whose diagnosis is, today, facilitated by molecular biology techniques. A history of ingestion of raw snails may alert the clinician to consider the possibility of such an uncommon condition.