Bevacizumab Allows Preservation of Liver Function and its Regenerative Capacity after Major Hepatectomy

Author(s): Amparo Valverde, Rubén Ciria, Javier Caballero-Villarraso*, Patricia Aguilar-Melero, Gustavo Ferrín, Isidora Ranchal, Clara Linares, Carmen Herencia, Sandra González-Rubio, Manuel de la Mata, Álvaro Naranjo, Javier Briceño.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 11 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Parallel to the safety of liver resections, new chemotherapy drugs have emerged for the control of liver metastases. However, there is unclear evidence about the combination of intensive BVZ-therapy and extended resections. The main aim was to analyse the impact of Bevacizumab (BVZ) in terms of liver safety and tolerability in two experimental models: a basal-toxicity situation and after major hepatectomy.

Methods: Eighty male-Wistar rats were grouped as toxicity analysis (sham-operated rats-OS-) and regeneration after- surgery analysis (hepatectomy rats-H-). Eight further subgroups were created according to sacrifice (6- hours-6h- or 24-hours-24h-) and dose (μg) of BVZ (none, 100, 200, 400). Several measurements were performed, including biochemical serum samples, histopathological analysis, cytokines (IL-6, TNF-α, TGF-β), oxidative-stress (GSH/GSSG, ATP), lipid-peroxidation (TBARS) and epidermal and vascular endothelium growth-factors (EGF and VEGF).

Results: In the toxicity analysis, safe results with BVZ were observed, with no significant differences among the groups. A trend towards a lower oxidative status was observed in the OS 6 h-100, -200 and -400 versus the OS 6 h-none group. Similar results were observed in the hepatectomy model, with stable oxidative-stress-index and IL-6, TNF- α, and TGF- β levels. Despite higher lipid peroxidation status, overall regeneration was preserved. As expected, VEGF was almost undetectable in BVZ-treated groups after resection, but not in the non-resection group.

Conclusion: It was concluded that liver status was not impaired by BVZ even at the high-dose. Similarly, liver regeneration after extended hepatectomy in BVZ-treated animals was well-preserved. Extended liver resections may be encouraged in BVZ-treated patients due to its excellent tolerability and good liver regeneration status.

Keywords: Neoadjuvant chemotherapy, angiogenesis inhibitor, monoclonal antibody, regeneration, liver toxicity, hepatotoxicity, hepatectomy.

[1]
Bismuth, H. Surgical anatomy and anatomical surgery of the liver. World J. Surg., 1982, 6(1), 3-9.
[2]
Khan, A.Z.; Morris-Stiff, G.; Makuuchi, M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J. Hepatobiliary Pancreat. Surg., 2009, 16(2), 137-144.
[3]
Morris-Stiff, G.; Tan, Y.M.; Vauthey, J.N. Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases. Eur. J. Surg. Oncol., 2008, 34(6), 609-614.
[4]
Wong, R.; Cunningham, D.; Barbachano, Y.; Saffery, C.; Valle, J.; Hickish, T.; Mudan, S.; Brown, G.; Khan, A.; Wotherspoon, A.; Strimpakos, A.S.; Thomas, J.; Compton, S.; Chua, Y.J.; Chau, I. A multicentre study of capecitabine, oxaliplatin plus Bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann. Oncol., 2011, 22(9), 2042-2048.
[5]
Tomida, C.; Yamagishi, N.; Nagano, H.; Uchida, T.; Ohno, A.; Hirasaka, K.; Nikawa, T.; Teshima-Kondo, S. VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. Int. J. Oncol., 2018, 52(4), 1350-1362.
[6]
Xu, R.; Xu, C.; Liu, C.; Cui, C.; Zhu, J. Efficacy and safety of bevacizumab-based combination therapy for treatment of patients with metastatic colorectal cancer. OncoTargets Ther., 2018, 11, 8605-8621.
[7]
García-Alfonso, P.; Cavanagh Podesta, M.; Muñoz Martín, A.; Blanco Codeisido, M.; Calvo, A.; Peligros, I.; Corcuera, A.; Belén Rúperez Blanco, A.; Custodio-Cabello, S.; López Trabada, D.; Martín, M.; Ramón, D.E.E. Chemotherapy plus bevacizumab as neoadjuvant or conversion treatment in patients with colorectal liver metastases. Anticancer Res., 2018, 38(5), 3069-3077.
[8]
Li, D.B.; Ye, F.; Wu, X.R.; Wu, L.P.; Chen, J.X.; Li, B.; Zhou, Y.M. Preoperative administration of bevacizumab is safe for patients with colorectal liver metastases. World J. Gastroenterol., 2013, 19(5), 761-768.
[9]
Taniguchi, E.; Sakisaka, S.; Matsuo, K.; Tanikawa, K.; Sata, M. Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats. J. Histochem. Cytochem., 2001, 49(1), 121-130.
[10]
Van Buren, G.; Yang, A.D.; Dallas, N.A.; Gray, M.J.; Lim, S.J.; Xia, L.; Fan, F.; Somcio, R.; Wu, Y.; Hicklin, D.J.; Ellis, L.M. Effect of molecular therapeutics on liver regeneration in a murine model. J. Clin. Oncol., 2008, 26(11), 1836-1842.
[11]
Zorzi, D.; Chun, Y.S.; Madoff, D.C.; Abdalla, E.K.; Vauthey, J.N. Chemotherapy with Bevacizumab does not affect liver regeneration after portal vein embolization in the treatment of colorectal liver metastases. Ann. Surg. Oncol., 2008, 15(10), 2765-2772.
[12]
Millet, G.; Truant, S.; Leteurtre, E.; Hebbar, M.; Zerbib, P.; Huet, G.; Boleslawski, E.; Pruvot, F.R. Volumetric analysis of remnant liver regeneration after major hepatectomy in Bevacizumab-treated patients: a case-matched study in 82 patients. Ann. Surg., 2012, 256(5), 755-761.
[13]
Aussilhou, B.; Dokmak, S.; Faivre, S.; Paradis, V.; Vilgrain, V.; Belghiti, J. Preoperative liver hypertrophy induced by portal flow occlusion before major hepatic resection for colorectal metastases can be impaired by Bevacizumab. Ann. Surg. Oncol., 2009, 16(6), 1553-1559.
[14]
Duwe, G.; Knitter, S.; Pesthy, S.; Beierle, A.S.; Bahra, M.; Schmelzle, M.; Schmuck, R.B.; Lohneis, P.; Raschzok, N.; Öllinger, R.; Sinn, M.; Struecker, B.; Sauer, I.M.; Pratschke, J.; Andreou, A. Hepatotoxicity following systemic therapy for colorectal liver metastases and the impact of chemotherapy-associated liver injury on outcomes after curative liver resection. Eur. J. Surg. Oncol., 2017, 43(9), 1668-1681.
[15]
Margonis, G.A.; Buettner, S.; Andreatos, N.; Sasaki, K.; Pour, M.Z.; Deshwar, A.; Wang, J.; Ghasebeh, M.A.; Damaskos, C.; Rezaee, N.; Pawlik, T.M.; Wolfgang, C.L.; Kamel, I.R.; Weiss, M.J. Preoperative bevacizumab and volumetric recovery after resection of colorectal liver metastases. J. Surg. Oncol., 2017, 116(8), 1150-1158.
[16]
Umehara, M.; Umehara, Y.; Takahashi, K.; Murata, A.; Nishikawa, S.; Tokura, T.; Matsuzaka, M.; Tanaka, R.; Morita, T. Preoperative chemotherapy with bevacizumab extends disease-free survival after resection of liver metastases from colorectal cancer. Anticancer Res., 2016, 36(4), 1949-1954.
[17]
Bergeat, D.; Rayar, M.; Mouchel, Y.; Merdrignac, A.; Meunier, B.; Lièvre, A.; Boudjema, K.; Sulpice, L. Preoperative bevacizumab and surgery for colorectal liver metastases: A propensity score analysis. Langenbecks Arch. Surg., 2017, 402(1), 57-67.
[18]
Lim, C.; Doussot, A.; Osseis, M.; Esposito, F.; Salloum, C.; Calderaro, J.; Tournigand, C.; Azoulay, D. Bevacizumab improves survival in patients with synchronous colorectal liver metastases provided the primary tumor is resected first. Clin. Transl. Oncol., 2018, 20(10), 1274-1279.
[19]
Karanlik, H.; Kurt, A.; Kunduz, E.; Serin, K.; Saglam, S.; Soydinc, H.O.; Yasasever, V.; Olgac, V.; Asoglu, O. Effects of intraperitoneal bevacizumab administration on colonic anastomosis and early postoperative adhesion formation. Surg. Innov., 2013, 20(6), 559-565.
[20]
von Baumgarten, L.; Brucker, D.; Tirniceru, A.; Kienast, Y.; Grau, S.; Burgold, S.; Herms, J.; Winkler, F. Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumour cells. Clin. Cancer Res., 2011, 17(19), 6192-6205.
[21]
Ignjatovic, D.; Aasland, K.; Pettersen, M.; Sund, S.; Chen, Y.; Spasojevic, M.; Nesgaard, J.M. Intra-abdominal administration of Bevacizumab diminishes intra-peritoneal adhesions. Am. J. Surg., 2010, 200(2), 270-275.
[22]
Higgins, G.M.; Anderson, R.M. Experimental pathology of the liver: restoration of the liver of a white rat following surgical removal. Arch. Pathol., 1931, 12, 186-206.
[23]
Kwon, A.H.; Uetsuji, S.; Yamamura, M.; Hioki, K.; Yamamoto, M. Effect of administration of fibronectin or aprotinin on liver regeneration after experimental hepatectomy. Ann. Surg., 1990, 211(3), 295-300.
[24]
Adinolfi, L.E.; Gambardella, M.; Andreana, A.; Tripodi, M.F.; Utili, R.; Ruggiero, G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology, 2001, 33(6), 1358-1364.
[25]
Assy, N.; Minuk, G.Y. Liver regeneration: methods for monitoring and their applications. J. Hepatol., 1997, 26(4), 945-952.
[26]
Jones, D.P.; Carlson, J.L.; Mody, V.C.; Cai, J.; Lynn, M.J.; Sternberg, P. Redox state of glutathione in human plasma. Free Radic. Biol. Med., 2000, 28(4), 625-635.
[27]
Tietze, F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues. Anal. Biochem., 1969, 27(3), 502-522.
[28]
Griffith, O.W. Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal. Biochem., 1980, 106(1), 207-212.
[29]
Lepage, G.; Munoz, G.; Champagne, J.; Roy, C.C. Preparative steps necessary for the accurate measurement of malondialdehyde by high-performance liquid chromatography. Anal. Biochem., 1991, 197(2), 277-283.
[30]
Vauthey, J.N.; Pawlik, T.M.; Ribero, D.; Wu, T.T.; Zorzi, D.; Hoff, P.M.; Xiong, H.Q.; Eng, C.; Lauwers, G.Y.; Mino-Kenudson, M.; Risio, M.; Muratore, A.; Capussotti, L.; Curley, S.A.; Abdalla, E.K. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J. Clin. Oncol., 2006, 24(13), 2065-2072.
[31]
Kishi, Y.; Zorzi, D.; Contreras, C.M.; Maru, D.M.; Kopetz, S.; Ribero, D.; Motta, M.; Ravarino, N.; Risio, M.; Curley, S.A.; Abdalla, E.K.; Capussotti, L.; Vauthey, J.N. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann. Surg. Oncol., 2010, 17(11), 2870-2876.
[32]
Wicherts, D.A.; de Haas, R.J.; Sebagh, M.; Saenz Corrales, E.; Gorden, D.L.; Lévi, F.; Paule, B.; Azoulay, D.; Castaing, D.; Adam, R. Impact of Bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br. J. Surg., 2011, 98(3), 399-407.
[33]
Mahfud, M.; Breitenstein, S.; El-Badry, A.M.; Puhan, M.; Rickenbacher, A.; Samaras, P.; Pessaux, P.; Lopez-Ben, S.; Jaeck, D.; Figueras, J.; Alain-Clavien, P. Impact of preoperative Bevacizumab on complications after resection of colorectal liver metastases: Case-matched control study. World J. Surg., 2010, 34(1), 92-100.
[34]
D.E, Pasquale. M.D.; de Ville de Goyet, J.; Monti, L.; Grimaldi, C.; Crocoli, A.; Castellano, A. Bevacizumab combined with chemotherapy in children affected by hepatocellular carcinoma: A single-center experience. Anticancer Res., 2017, 37(3), 1489-1493.
[35]
Rickenbacher, A.; DeOliveira, M.L.; Tian, Y.; Jang, J.H.; Riener, M.O.; Graf, R.; Moritz, W.; Clavien, P.A. Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy. Liver Int., 2011, 31(3), 313-321.
[36]
Iguchi, A.; Kobayashi, R.; Yoshida, M.; Kobayashi, K.; Matsuo, K.; Kitajima, I.; Maruyama, I. Vascular Endothelial Growth Factor (VEGF) is one of the cytokines causative and predictive of hepatic Veno-Occlusive Disease (VOD) in stem cell transplantation. Bone Marrow Transplant., 2001, 27(11), 1173-1180.
[37]
Ribero, D.; Wang, H.; Donadon, M.; Zorzi, D.; Thomas, M.B.; Eng, C.; Chang, D.Z.; Curley, S.A.; Abdalla, E.K.; Ellis, L.M.; Vauthey, J.N. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatinbased chemotherapy for colorectal liver metastases. Cancer, 2007, 110(12), 2761-2767.
[38]
Starlinger, P.; Alidzanovic, L.; Schauer, D.; Maier, T.; Nemeth, C.; Perisanidis, B.; Tamandl, D.; Gruenberger, B.; Gruenberger, T.; Brostjan, C. Neoadjuvant Bevacizumab persistently inactivates VEGF at the time of surgery despite preoperative cessation. Br. J. Cancer, 2012, 107(6), 961-966.
[39]
Keizer, R.J.; Huitema, A.D.; Schellens, J.H.; Beijnen, J.H. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet., 2010, 49(8), 493-507.
[40]
Verheul, H.M.; Lolkema, M.P.; Qian, D.Z.; Hilkes, Y.H.; Liapi, E.; Akkerman, J.W.; Pili, R.; Voest, E.E. Platelets take up the monoclonal antibody Bevacizumab. Clin. Cancer Res., 2007, 13(18), 5341-5347.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 11
Year: 2019
Page: [1388 - 1398]
Pages: 11
DOI: 10.2174/1871520619666190417162409
Price: $58

Article Metrics

PDF: 21
HTML: 2

Special-new-year-discount