Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases

Pool, Anne E. M. van der; Marsman, H.A.; Verheij, Joanne; Kate, Fibo J. ten; Eggermont, Alexander M.M.; IJzermans, Jan N.M.; Verhoef, Cornelis

doi:10.1002/jso.23142

Cited by 33 publications

(28 citation statements)

References 31 publications

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“…VEGF-A, which usually acts as a vasodilator, may paradoxically act as a vasoconstrictor under conditions of endothelial failure (22). Moreover, bevacizumab, an antibody against VEGF-A, was found to protect against SOS in patients administered oxaliplatin-based chemotherapy for CRLM (23)(24)(25). In summary, treatment of CRLM patients with oxaliplatin-based NAC induces thrombocytopenia, along with platelet aggregation in zone III.…”

Section: Discussionmentioning

confidence: 96%

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

Tajima

Ohta

Miyashita

et al. 2015

Molecular and Clinical Oncology

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Abstract.Oxaliplatin-based chemotherapy plays a central role in the treatment of patients with colorectal liver metastasis (CRLM). This treatment, however, has been associated with hepatic sinusoidal obstruction syndrome (SOS), a clinically important adverse effect characterized by a bluish hue of the liver, splenomegaly and thrombocytopenia, resulting in liver dysfunction. The significant association between the sinusoidal endothelium and platelets has suggested that oxaliplatin-based chemotherapy affects platelets in the liver. This study compared platelet counts in patients who did and did not receive oxaliplatin-based neoadjuvant chemotherapy (NAC). The peripheral blood platelet count was significantly lower in the NAC group (n=17) compared to that in the non-NAC, or control group (n=15) (P<0.05). The spleen index was also higher in the NAC group, although the difference was not significant. However, the spleens of the patients in the NAC group were significantly enlarged following treatment (P<0.01). Immunostaining for the platelet surface marker CD42b (glycoprotein Ib), revealed more platelets in the liver in the NAC compared to the control group, particularly in the centrilobular zone III, adjacent to the hepatic central vein and in contact with hepatocytes (P<0.01). The platelets present in the spaces of Disse, referred to as extravasated platelet aggregation (EPA), secrete a number of growth factors, including transforming growth factor-β, vascular endothelial growth factor-A, plasminogen activator inhibitor-1 and thromboxane A2. In conclusion, EPA may play an important role in the development of hepatic SOS. Moreover, antiplatelet drugs may prevent the onset of SOS and hepatic injury in patients treated with oxaliplatin-based chemotherapy for CRLM.

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Section: Discussionmentioning

confidence: 96%

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

Tajima

Ohta

Miyashita

et al. 2015

Molecular and Clinical Oncology

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“…In resected livers with colorectal metastases, VEGF‐C and VEGF‐D are up‐regulated when SD is present. Bevacizumab appears to protect patients receiving oxaliplatin from developing SD …”

Section: Experimental and Epidemiological Data On Pathogenesismentioning

confidence: 99%

The significance of nonobstructive sinusoidal dilatation of the liver: Impaired portal perfusion or inflammatory reaction syndrome

et al. 2015

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Sinusoidal dilatation found in the absence of an impaired sinusoidal blood outflow has been so far of unclear significance. Sinusoidal dilatation may actually be a nonspecific feature of impaired portal venous blood inflow, whatever the cause, or a feature of severe systemic inflammatory reaction syndrome, whatever the cause. Sinusoidal dilatation is mainly located in the centrilobular area even in the absence of an outflow block. A predominantly periportal location is specifically found in oral contraceptive users, associated with an inflammatory condition. There is strong evidence for the association of sinusoidal dilatation and oxaliplatin-based chemotherapy but not for estroprogestative steroids or thiopurine derivatives. Exposure to anabolic androgen steroids appears to cause sinusoidal changes different from a mere sinusoidal dilatation. Conclusion: There is evidence of activation of the interleukin-6 and vascular endothelial growth factor pathways in sinusoidal dilatation, but the mechanisms linking the activation of these pathways with the microvascular changes must be identified. (HEPATOLOGY 2015;62:956-963) S inusoidal dilatation (SD) in the absence of postsinusoidal outflow block is characterized by enlarged hepatic sinusoids as a predominant histopathological feature.

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“…Bevacizumab lowered the incidence of sinusoidal dilatation in patients receiving oxaliplatin and become reduced to less than a third that of severe (grade 2-3) sinusoidal dilatation (8 versus 28%) [48]. However, the overall complication rate was not significantly different between those who received oxaliplatin-based neoadjuvant chemotherapy with or without bevacizumab [49]. …”

Section: Prevention and Treatmentmentioning

confidence: 99%

Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy

Maor

Malnick

2013

International Journal of Hepatology

112

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Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies.

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Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases

Cited by 33 publications

References 31 publications

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

Oxaliplatin-based chemotherapy induces extravasated platelet aggregation in the liver

The significance of nonobstructive sinusoidal dilatation of the liver: Impaired portal perfusion or inflammatory reaction syndrome

Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy

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