Research Article

Immediately Preoperative use of Biological Therapy Does not Influence Liver Regeneration after Large Resection - Porcine Experimental Model with Monoclonal Antibody against Epidermal Growth Factor

V. LISKA, V. TRESKA, H. MIRKA, J. BENES, O. VYCITAL, J. BRUHA, P. PITULE, T. SKALICKY, A. SUTNAR, A. CHLUMSKA, J. RACEK, L. TREFIL, J. FINEK and L. HOLUBEC
In Vivo July 2012, 26 (4) 683-691;

Abstract

Background: The aim of this work was to study the influence of isolated biological therapy administered immediately before extended liver resection on liver function and regenerative capacity of future liver remnant (FLR) in a large-animal experiment. Materials and Methods: Nineteen piglets were included in this study (10 in the control group and 9 in the experimental group). A port-a-cath was introduced into the superior caval vein. On days 11 and 4 before liver resection, cetuximab was administered via this port at 400 mg/m2 of piglet body surface. Physiological solution was applied to the control group. Resection of the left lateral, left medial and right medial hepatic lobes was followingly performed (reduction of 50-60% of liver parenchyma). Blood samples were collected at different times before the operation and after liver resection. Serum levels of bilirubin, urea, creatinine, alkaline phosphatase, gamma glutamyltransferase, cholinesterase, aspartate aminotransferase, alanine aminotransferase, albumin, C-reactive protein and transforming growth factor-β1 were assessed. The ultrasonographic examinations at different time points were performed pre-operatively and after liver resection in order to assess the liver volume. The biopsies from the liver parenchyma were examined for proliferative activity, binocluated hepatocytes, size of hepatocytes, and the length of the lobuli. The comparison of distribution of the studied parameters between the groups was carried out using the Wilcoxon test. The Spearman rank correlation co-efficient was used because of the non-Gaussian distribution of the parameter values. The whole development of the studied parameters over time was compared between the groups using ANOVA. Results: There were no important complications of administration of biologic therapy during the operation or throughout the peri-operative period. There was no statistically significant difference in the regeneration of FLR nor were any differences in biochemical, immunoanalytical and histological parameters detected. Conclusion: The achieved results of comparable liver regeneration in both the experimental and control groups confirms the use of biological treatment with cetuximab in the pre-operative period for minimizing the recovery period.

Possibilities for liver surgery have been extended in recent years by new surgical techniques, and more highly developed procedures and skills. At present, surgery is the only curative option for the treatment of liver metastases from primary colorectal carcinoma. Today we are able to perform large radical resections of malignant liver lesions. Nevertheless, many patients with primary or secondary liver malignancies that undergo oncologic treatment before liver surgery are not directed to the radical surgical therapy that could extend their chance of complete remission for the malignancy. We fear the increased risk of acute liver failure after extended liver resection, where the liver parenchyma could be affected by previous chemotherapy and the liver functions could be reduced (1-3). Many patients are indicated for neoadjuvant oncologic treatment with the aim of down-staging and down-sizing the liver malignancy (4-7).

The use of standard combination of chemotherapy [oxaliplatin/5-fluorouracil (5-FU) or irinotecan/5-FU) has increased the resection rate up to 20-40% in selected patients (8). The addition of anti-EGFR monoclonal antibody, and anti VEGF mononclonal antibody therapy to doublet chemotherapy has demonstrated consistent improvements in the response rate in a number of randomized trials. However the intensification of treatment can lead to an increased rate of severe toxicity. Therefore careful selection of the patients that will undergo intensive chemotherapy and surgical intervention is very important (9, 10).

Oxaliplatin, irinotecan, cetuximab, and bevacuzimab are valuable drugs. The usage of these drugs can lead to a maximal response rate before the liver surgery; on the other hand, the prolonged exposure to these drugs may results in hepatotoxicity and the potential for further complications (11). The protracted use of cytotoxic drugs can therefore lead to progressive liver damage and surgical intervention is often not possible afterwards (12). The usage of oxaliplatin in neoadjuvant regimens of chemotherapy can lead to morphological lesions involving hepatic microvasculature. Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non-tumoral liver are the most often adverse side-effect of to the use of oxaliplatin (13). The hepatotoxicity of a combination of 5-FU and levamisole in an adjuvant or palliative setting is mild and only rarely symptomatic (14). Irinotecan regimens are associated with a higher frequency of steatosis and steatohepatitis. Such damage can affect post-operative mortality of patients (15).

The impact of anti-angiogenesis agents on liver regeneration and wound healing is not yet fully understood. The potential side-effect of bevacizumab is delayed wound healing and possible delayed hepatic regeneration. But no specific data are available to guide the optimal timing before the elective surgery. The optimal time for termination of the treatment before elective surgery is at least 4-6 weeks. A similar delay is also seen in the timing of the continuation of bevacizumab treatment after liver surgery (16).

A crucial end point of neoadjuvant treatment is the achievment of a high R0 resection rate (17). The efficacy of cetuximab in patients with unresectable hepatic metastases and wild-type KRAS was confirmed in the multicentric randomised CELIM study.

The study enrolled a total of 111 patients with unresectable hepatic metastases. Unresectability criteria in this study were as follows: five and more metastatic lesions; technical unresectability; infiltration of the hepatic vessels; infiltration of both hepatic arteries or infiltration of both branches of the portal vein. In these patients, a combination therapy with (FOLFIRI) or (FOLFOX 6) was evaluated. A significant reduction of 79% in the size and spread of metastases, observed in patients with wild-type KRAS gene, enabled resection of metastases in 43% of patients (radical R0 resection was achievable in 34% of patients) (18, 21). Chemotherapy-associated hepatotoxicity has often been described using many classical oncologic regimens (19, 20). The question remains whether the chemotherapy can be administered immediately before liver surgery, or if a recovery period is required between the end of the neoadjuvant chemotherapy and proper surgical procedure. A particular question is also the use of biological treatment that interferes with the key growth factors that are involved in liver parenchyma regeneration and so play key roles in the restoration of future liver remnant volume and also liver function after extended liver resection. The most frequently used type of biological treatment in relation to neoadjuvant chemotherapy of secondary liver malignancies is cetuximab (2, 22-23). Cetuximab inhibits the effects of EGF via EGFR. The role of EGF in the promotion of hepatocyte proliferation has also been demonstrated (24-26).

The aim of the present animal experiment was to study the influence of cetuximab administered immediately before extended liver resection. The results could be used in human liver surgery to increase the number of patients who can undergo radical extended liver resection for malignancy because the recovery period between the chemotherapy and liver resection could be shortened.

Materials and Methods

The performed experimental surgical and anaesthesiological procedures and the use of piglets were certified by the Commission for Work with Experimental Animals at the Pilsen Medical Faculty of the Charles University, Prague, and were under the control of the Ministry of Education of the Czech Republic. All the performed procedures were prepared and performed under the law of the Czech Republic, which is compatible with legislation of the European Union.

Choise of biological therapy. The most frequently used type of biological treatment in neoadjuvant chemotherapy for secondary liver malignancies is cetuximab (Erbitux; Merck KGaA, Germany) that inhibits the effect of EGF via EGFR (2, 22, 23). Cetuximab recognizes the structural epitope in the extracellular region of EGFR. Based on the known cetuximab binding site in human EGFR, we have compared sequences of human and porcine EGFR using BLAST software. From 14 amino acids important for proper binding of cetuximab to human EGFR, 10 are identical, 2 similar and 2 different, which can reduce the affinity of antibody to porcine EGFR, but the binding is still possible (37, 38). We have concluded that the correspondency of domains is sufficient for inactivation of this receptor and the use of cetuximab for this porcine experimental model is efficient.

Surgical procedure. Nineteen piglets were included in this study (10 in the control group and 9 in the experimental group). No piglet was excluded because of untimely death or any type of surgical complication. The piglets were premedicated intramuscularly with 1.0 mg atropine, 200 mg ketamine (approximately 5-10 mg/kg) and 160 mg azaperon (2-8 mg/kg). Anesthesia was administered continually through a peripheral or central venous catheter in the following total average doses: propofol (1% mixture, 5-10 mg/kg/h) and fentanyl (1-2 μg/kg/h). Muscle relaxation was ensured by bolus administration of 0.1-0.2 mg/kg pancuronium at the beginning of surgery. The piglets were intubated and mechanically ventilated during the surgical procedure and received infusion and volume substitution when needed [Plasmalyte (Baxter Healthcare Ltd., UK) and Gelofusine (B.Braun Melsungen AG, Germany) respectively]. Aminopenicilline and clavulic acid (1.2 g) was used as antibiotic prophylaxis throughout the procedure. Monitoring of electrocardiogram, oxygen saturation and central venous pressure was implemented. The surgical procedure was performed under aseptic and antiseptic conditions.

Firstly a port-a-cath was introduced into the superior caval vein. On days 11 and 4 before liver resection, cetuximab at 400 mg/m2 of piglet body surface was administered (23). Physiological solution was applied to the control group.

Liver resection followed. Firstly, a central laparotomy was performed. The resection of the left lateral, left medial and right medial hepatic lobes was performed (reduction of 50-60% of liver parenchyma). The laparotomy was closed in anatomical layers.

The animals were extubated and monitored each day for the next 14 days, with particular emphasis on the clinical examination (attention to wound healing, infection of the port-a-cath and function of the gastrointestinal system) to diagnose possible surgical complications. Postoperative analgesia was provided by intramuscular application of small dosis of Azaperon (10 mg).

Biochemistry. Blood samples were collected from the central vein catheter: on the 14th, 11th and 4th preoperative days; immediately before the operation, immediately after liver resection; 2 hours after liver resection; and on the 1st, 3rd, 7th, 10th and 14th post-operative days. Biochemical serum parameters were assessed with focus on liver functions to detect the influence of the applied monoclonal antibody on the animal and to recognise possible differences between experimental and the control groups. Serum levels of bilirubin, urea, creatinine, alkaline phosphatase (ALP), gammaglutamyltransferase (GGT), cholinesterase (CHE), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin were assessed by an Olympus 2700 biochemical analyzer. Serum levels of C-reactive protein (CRP) and transforming growth factor- β1(TGF-β1) were also assessed to provide information about the termination of liver proliferation.

Ultrasonography. Ultrasonographic examinations were performed on the 14th and 4th preoperative days; immediately before the operation; immediately after liver resection; on the 3rd, 7th, 10th and 14th postoperative days (ultrasound apparatus, Medison Sonoace 9900; convex probe with a frequency of 3.5 MHz). The diameters of the hypertrophic lobes were measured in B-mode in all three basic planes (axial, sagittal and coronal). The volume of the lobes was assessed by using the standard ultrasonographic formula that is also used in human medicine: axial × sagittal × coronal 2. The volumes are presented as a percentage of baseline values (immediately postoperative liver lobe volumes) to provide better information about the changes in volumes that were achieved.

Termination of experiment. The piglets were sacrificed on the 14th post-operative day under deep general anesthesia with a concentrated solution of potassium chloride administered into the central venous catheter. The piglets were dissected and measurement of the hypertrophic liver lobes was performed. These data were compared with the proportions estimated by ultrasonography. Bioptic samples from the atrophic and hypertrophic liver lobes were collected and stored in 10% formaldehyde (methanal) and also frozen below −70°C.

Figure 1.
Figure 1.

Comparison of hypertrophic liver lobe growth relative to these point 4 between experimental and control groups. Time points: 4, after liver resection; 5-8, 3rd, 7th, 10th and 14th postoperative days, respectively.

Histology. Biopsies from the liver parenchyma were examined after staining with hematoxylin-eosine and periodic acid-Schiff (PAS) staining after digestion of preparations with diastase. The proliferative activity was examined using the Ki 67 antibody (MIB1, 1:1000; DakoCytomation, Denmark). The primary antibodies were visualised using a streptavidin- biotin-peroxidase complex (DakoCytomation). The number of binucleated hepatocytes was measured in 20 microscopic fields with the aid of an eyepiece micrometer (Olympus). The size of the hepatocytes and the length of the lobuli were examined twice using the eyepiece micrometer.

Statistical analysis. Statistical analysis was performed with the CRAN 2.4.0 and the STATISTICA (98 Edition) software. The assessed parameters (biochemistry, ultrasonography, histology) were analyzed by the following statistical tests: the comparison of distribution of the studied parameters over the groups was counted using a Wilcoxon distribution-free test. The Spearman rank correlation co-efficient was used because of the non-Gaussian distribution of parameter values. The development of the studied parameters over time was compared between the groups using ANOVA.

Results

The volumes of hypertrophic liver lobes measured by ultrasonography and physical examination were comparable on the 14th postoperative day. The differences in absolute volume of remnant hypertrophic lobes (right lateral and caudate lobes) between experimental and control groups were not statistically significant (Figure 1).

Figure 2.
Figure 2.
Figure 2.

Comparison of serum levels of studied biochemical parameters between experimental and control groups. Time points: 1-3, 14th, 11th and 4th days before surgery; 4, immediately before the operation; 5,immediately after liver resection; 6, 2 hours after liver resection; 7-11, 1st, 3rd, 7th, 10th, 14th postoperative days, respectively.

Figure 3.
Figure 3.

Comparison of the length of lobuli (cm) in hypertrophic lobes between experimental and control groups.

Figure 4.
Figure 4.

Comparison of the frequency of binucleated hepatocytes in hypertrophic lobes between experimental and control groups. The number of binucleated hepatocytes were counted in 20 microscopic fields.

The serum levels of all the studied biochemical parameters at the different time points are presented in Figure 2. All the studied serum biochemical parameters were comparable in both experimental groups and the differences were not statistically significant between the experimental and the control group at each time point (Figure 2). No adverse reaction to cetuximab application was observed.

The histological examination was performed on biopsies that were conducted at the end of the experiment after the animals had been sacrificed, when the proliferative phase of liver regeneration had in fact finished. The differences in the length of lobuli between studied groups were not statistically significant (Figure 3). Statistical analysis also showed no significant increase in the number of binucleated hepatocytes in the hypertrophic liver lobes in the experimental group (Figure 4). The size of hepatocytes was also not a statistically significant parameter for differences between the experimental group and the control group (Figure 5). Proliferative activity in both experimental and control groups was greatly reduced.

Figure 5.
Figure 5.

Comparison of the size of hepatocytes (cm) in hypertrophic lobes between experimental and control groups.

Discussion

This experimental study presents the possibility of the application of extrinsic monoclonal antibody against EGF immediately before surgery. The regenerative capacity of liver parenchyma was not reduced by cetuximab administration. We demonstrated that liver functions were also not affected. The use of large animals, especially piglets, in this experimental surgical study is appropriate in relation to human medicine and clinical surgery because of the similar physiology of piglets and humans. The results of the present study show that the recovery period could be shortened for patients indicated for liver resection who undergo oncologic treatment. The effect of a monoclonal antibody against EGFR is lost rather quickly and the recovery period differs between patients that undergo classical chemotherapy and those patients that were treated by biological therapy (39). The concentration (recommended dose) and timing of the application of the monoclonal antibody selected for our study did not reduce liver parenchyma regeneration in comparison to the one in the control group. The secondary effects that could be hypothesized after application of the monoclonal antibody against the key pleiotropic growth factor (changes in immune reactions and homeostasis) were also not observed, neither during application nor throughout the postoperative period. In previous experiments, we have demonstrated that administration of cytokines of the first phase of liver regeneration, interleukin-6 and tumor necrosis factor–α, increase regeneration of future liver remnant (27, 39). These cytokines have pleiotropic functions, which could be altered or changed by application of these cytokines from an extrinsic source (28). It was our aim in this experiment to select a monoclonal antibody against the growth factor that plays a role during the first phase of liver regeneration. By blocking of its receptor, we wanted to inhibit the proliferation of hepatocytes. Nevertheless, the regenerative capacity of the liver parenchyma was not negatively influenced by cetuximab administrations. No statistically significant differences were observed between serum levels of the studied biochemical parameters at particular points in time. This also demonstrates that there was no unsuitable effect of the applied monoclonal antibody on liver function. These results support our choise of a monoclonal antibody against EGFR for future clinical studies in human liver surgery.

The broad distribution of the of binucleated hepatocytes in the hypertrophic parenchyma of individual animals from both groups could be explained by incomplete liver regeneration at the end of experiment. Because there were practically no mitotic figures, or the number was the same as in the normal liver parenchyma without any surgical procedures or toxic insult, it was possible to hypothesize that the first phase of liver regeneration was finished and the next phase of regeneration was proceeding, namely the remodelling phase and the phase when the liver microstructure is restored (29).

The next objective for future studies would be the detection of changes on the extracellular matrix during the process of liver regeneration. The size of hepatocytes and the length of lobuli were not statistically different between study and control groups. The same size of hepatocytes and length of lobuli in the bioptical samples from the hypertrophic parenchyma could be also explained in the same way as for the binucleated hepatocytes. This hypothesis is supported by the restitution of all liver functions monitored by biochemical parameters and completion of the proliferative phase of liver regeneration at the moment of sacrificing of the experimental animals.

The most important point for discussion among all clinicians is the problematic recovery period which is necessary for restoration of liver functions after administration of classical chemotherapeutics (30). On the other hand, we have observed that a proportion of our patients experience progression of malignancy during this period. This could also bring more experimental oriented experience into the discussion of whether the administration of biological therapy, for example bevacizumab, is associated with increased risk of postoperative complications (31-36). We conclude that immediate pre-operative administration of cetuximab in the experimental model used here did not increase this risk. The results of this experiment could be useful to support the administration of biological therapy until surgery in order to reduce the risk of the preoperative progression of malignancy.

The present study describes a new usage of a monoclonal antibody against EGFR in large-animal experimental model of extended liver resection, which simulates the situation in human medicine. The achieved results of comparable liver regeneration in both experimental and control groups confirms the use of biological treatment with cetuximab in the preoperative period with minimal recovery period. The experimental results could lead to a clinical study in patients with neoadjuvant treatment with biological therapy.

Acknowledgements

This study was supported by research project MSM 0021620819 (Replacement of and support to some vital organs) and grant IGA MZ CR 9731 and IGA MZ CR 12025 and specific students research grant of Charles University SVV-2011- 262 806. This study also had the approval of the local Ethical Committee.

  • Received November 17, 2011.
  • Revision received January 29, 2012.
  • Accepted February 2, 2012.

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Immediately Preoperative use of Biological Therapy Does not Influence Liver Regeneration after Large Resection - Porcine Experimental Model with Monoclonal Antibody against Epidermal Growth Factor
V. LISKA, V. TRESKA, H. MIRKA, J. BENES, O. VYCITAL, J. BRUHA, P. PITULE, T. SKALICKY, A. SUTNAR, A. CHLUMSKA, J. RACEK, L. TREFIL, J. FINEK, L. HOLUBEC
In Vivo Jul 2012, 26 (4) 683-691;
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