Hepatic regeneration in a rat model is impaired by chemotherapy agents used in metastatic colorectal cancer

Abstract

Purpose

Administering Oxaliplatin prior to resection of colorectal liver metastases often induces a Sinusoidal Obstruction Syndrome (SOS), which can affect postoperative patient outcome. Bevacizumab (Anti-VEGF-A) can decrease the severity of SOS and the associated risk of postoperative liver failure. We investigated the impact of both Oxaliplatin (Oxali) and Bevacizumab on liver regeneration in a rat model.

Material and methods

Male Wistar rats underwent a 70% partial hepatectomy (PH) 3 days after a 2 ml intraperitoneal injection of either saline (controls, n = 17), or Oxaliplatin 10, 20 or 50 mg/kg, 5-Fluorouracil 100 mg/kg (5-FU) and Bevacizumab 5 or 10 mg/kg in various combinations (total 98 rats, 11 groups, n = 5–18/group). Liver regeneration was assessed by remnant liver weight recovery and cell proliferation by immunodetection of BrDU incorporation (days 1, 2, 3, 7). Hepatic mRNA expression levels of VEGF-A and of its 2 receptors (Flt-1 and KDR) were quantified by PCR technique.

Results

Liver regeneration was impaired for 3 days post PH by Oxali 20 alone and Oxali 10 + 5-FU, without any rescue effect by neither Bevacizumab 5 nor 10 mg/kg. Unlike in humans, there were no sinusoidal changes. VEGF-A mRNA expression and receptor 2 (KDR) expressions decreased 24 h post PH in a similar fashion in controls, Oxali 20 and Oxali 10 + 5-FU groups. All groups had recovered over 60% of their liver weight by day 7.

Conclusion

Oxaliplatin causes early hepatocyte proliferation impairment post PH, unaffected by Bevacizumab and unexplained by changes in VEGF-A signalling in a Wistar rat model.

Introduction

Patients suffering from colorectal adenocarcinoma have or will develop liver metastases in 60% of the cases.¹ Liver resection remains the standard treatment for patients with resectable colorectal liver metastases (CLRM) and is the only single-modality therapy associated with cure. A five-year-survival rate after liver resection of CLRM as high as 58% has been reported.2, 3, 4 Only a minority (15–30%) of patients suffering from CLRM have metastases that are resectable at the time of diagnosis.5, 6 For others, a chemotherapy neoadjuvant treatment for tumour downstaging or downsizing is necessary prior to resection.⁷ A response rate of 54–56% is obtained after treatment with 5-fluorouracil (5-FU) combined either to Oxaliplatin, a platinum derivative, or to Irinotecan, a topoisomerase I inhibitor.8, 9, 10 However, these chemotherapeutic agents may induce toxic side-effects on the non-tumoral liver parenchyma, potentially leading to liver dysfunction or defective hepatic regeneration post resection. Oxaliplatin is known to cause sinusoidal damage in the form of a Sinusoidal Obstruction Syndrome (SOS),¹¹ whilst Irinotecan can induce steatohepatitis, associated with 15% perioperative mortality following liver resection, mainly linked to liver failure.¹² In Oxaliplatin-induced SOS, hepatic sinusoids are dilated associated to extravasation into centrolobular hepatic zones, leading to portal hypertension in the most severe form, called Nodular Regenerative Hyperplasia (NRH).13, 14 Several authors have indeed reported an increased morbidity with liver failure after major hepatectomy, an increased need for transfusion and a longer hospital stay after liver resection in patients treated pre-operatively with Oxaliplatin.15, 16, 17 However, recent newly developed molecular targeted therapies such as Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and Cetuximab, an anti-epidermal growth factor receptor (EGFR) appear promising. These drugs, usually administered in combination with cytotoxic agents, are reported to induce a cytostatic response rate reaching 70%.¹⁸ In addition to its antitumoral effects, Bevacizumab has been shown to decrease both the severity of SOS19, 20, 21 and the associated risk of postoperative liver failure.²² Experimental studies have to date, however, yielded conflicting results regarding the impact of anti-VEGF therapies on liver regeneration.23, 24 In this study we investigated whether Oxaliplatin alone or combined to 5-FU had a direct impact on liver regeneration in a Wistar rat model, and whether Bevacizumab modified this effect.