CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib ...(GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles.
This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment.
122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%).
By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021).
CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients.
German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.
•Patients with R1 resection of pancreatic ductal adenocarcinoma (PDAC) relapsed in more than 90%.•Gemcitabine + sorafenib is not effective in the postoperative treatment of PDAC.•Adjuvant gemcitabine exceeding 6 months may be beneficial in R1-resected PDAC not suitable for mFOLFIRINOX.
Background
Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate‐activated glutaminase (GLS ) gene was ...associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency (CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis.
Methods
We recruited 158 patients (66% men; mean age 59 years, range 23–86) with liver cirrhosis. Mean model for end‐stage liver disease score was 13.8 (range 5–35); 48% of patients presented with Child–Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short–long forms (depending on the length of the macrosatellite alleles).
Results
In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26–57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short–long form (48%) and was consistent with Hardy–Weinberg equilibrium. CFF values differed significantly between groups (P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46–7.13, P = 0.004).
Conclusion
CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition.
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