Z Gastroenterol 2009; 47 - P390
DOI: 10.1055/s-0029-1241635

Multityrosinkinase inhibition by sorafenib increases necrosis size after radiofrequency ablation in rat liver but activates compensatory growth signaling

J Mertens 1, I Martin 2, P Frei 1, AH Mahnken 3, P Bruners 3, B Müllhaupt 1, A Geier 1, 2
  • 1University Hospital Zurich, Clinic for Gastroenterology & Hepatology, Zurich, Switzerland
  • 2University Hospital Aachen (RWTH), Department of Gastroenterology & Hepatology, Aachen, Germany
  • 3University Hospital Aachen (RWTH), Department of Radiology, Aachen, Germany

Aims: The most widely employed local ablative treatment for unresectable HCC is radiofrequency ablation (RFA). The multityrosinkinase inhibitor sorafenib has shown survival benefits in pts at advanced stages and is currently under investigation for adjuvant treatment after HCC resection/ablation in human trials. Of potential concern, sorafenib may reduce liver regeneration after tissue ablation. Furthermore, antiangiogenic therapy could increase the likelihood of tumour spread.

Aim: To evaluate effects of sorafenib treatment following RFA in rats on necrosis size and growth signaling pathways.

Methods: Male SD rats (n=5–9) were subjected to ultrasound guided RFA or sham liver puncture±sorafenib (5mg/kg b.w. by gavage daily starting at day -2) or saline alone. Livers were harvested 1, 3, and 7 days (d) after RFA. Whole blood and tissue samples from the necrosis periphery and unaffected liver were obtained. Gene expression of selected cytokines, growth factors/receptors and cyclins was quantified using TaqMan PCR. Proliferation was determined by PCNA immunofluorescence in kryopreserved tissue sections.

Results: Sorafenib treatment resulted in a larger necrosis volume at d3 (219±24 vs. 88±52mm3 in controls; P=0.03). At d7 necrosis volume almost equalized (76±37 vs. 47±58mm3; P=0.50). Increased ALT (2-fold) and LDH (5-fold) are in line with a more extensive liver damage at d3 in the sorafenib group. PCNA staining showed a decreased hepatocellular proliferation following sorafenib. VEGF mRNA was induced 4-fold during the early phase (d1) after sorafenib. For d3 and 7 a 6-fold induction of cyclin E was observed together with increased HGF (12-fold), EGF (7-fold) and EGFR (10-fold) mRNA. IL-6 was induced at d1 in both groups following RFA but persisted only in sorafenib until d3 (5-fold).

Conclusions: Our data demonstrate that multityrosinkinase inhibition by sorafenib augments the necrosis volume after RFA. However, a transient regenerative delay is compensated until d7 by induction of compensatory growth signals including HGF, EGF and VEGF, which also could promote metastatic tumor growth elsewhere in the liver. Based on these data from animal research further cautious investigation of adjuvant sorafenib treatment should be warranted in humans.