Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SMEffect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 200: 845-853

Department of Pathology and Immunology, Washington University in St. Louis, San Luis, Missouri, United States
Journal of the American College of Surgeons (Impact Factor: 4.45). 07/2005; 200(6):845-53. DOI: 10.1016/j.jamcollsurg.2005.01.024
Source: PubMed

ABSTRACT The objective was to evaluate the effect of preoperative administration of newer chemotherapeutic agents (irinotecan and oxaliplatin) on development of steatohepatitis, which could limit surgical options.
Thirty-seven patients were referred for resection of hepatic colorectal metastases. Thirteen patients received no neoadjuvant therapy (NO CHEMO group); 10 received neoadjuvant 5-fluorouracil only (5-FU group), and 14 received neoadjuvant irinotecan (n = 12), or oxaliplatin, or both (n = 4), in conjunction with 5-FU (IRI-OXALI group). Specimens were graded for the presence of nonalcoholic steatohepatitis (NASH) according to established criteria. Specimens were also evaluated by a nine-criteria liver injury score (LIS).
Mean biopsy scores were: NO CHEMO: NASH, 1.2, LIS, 5.2; 5-FU only: NASH, 1.1, LIS 5.7; and IRI-OXALI: NASH, 1.9, LIS, 9.4. Biopsy scores were significantly worse for IRI-OXALI compared with NO CHEMO or 5-FU only for NASH score, p = 0.003, and close to significantly worse for LIS score, p = 0.057. A multivariate analysis showed that both being in the IRI-OXALI group and body mass index were independent risk factors for developing this type of steatohepatitis.
Severe steatohepatitis can be associated with preoperative administration of irinotecan or oxaliplatin, especially in the obese. It can affect the ability to perform large liver resections. Consideration should be given to performing resections before commencing these agents and to obtaining preoperative biopsy in those who have received these agents.

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    • "The histopathological examination in terms of chemotherapyinduced liver toxicities represents a controversial issue in patients treated with an intensive chemotherapy regimen in association with a biologic agent. Every single cytotoxic agent is related to a specific liver toxicity (Rubbia-Brandt et al, 2004; Fernandez et al, 2005; Aloia et al, 2006; Vauthey et al, 2006) and the use of bevacizumab has raised the issue of perioperative complications because of its mechanism of action, mainly the risk of bleeding, wound healing and liver regeneration (Gruenberger et al, 2008). "
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    ABSTRACT: Background: The FOLFOXIRI regimen produces a high rate of radiological and histopathological responses. Bevacizumab added to chemotherapy showed an improvement in pathological response and necrosis of colorectal liver metastases (CLMs). FOLFOXIRI plus bevacizumab produced promising early clinical results and is under investigation in several randomised trials, although no data are currently available on its effects on response of CLMs and on liver toxicities. Methods: Starting from 499 patients enrolled in first-line phase II/III trials, we selected on the basis of tissue sample availability 18 patients treated with FOLFOXIRI/XELOXIRI and 24 patients treated with FOLFOXIRI plus bevacizumab who underwent secondary resection of CLMs. The 28 untreated patients who underwent primary resection of CLMs were included as control group. Responses of CLMs and chemotherapy-induced toxicities were assessed. Results: Among the patients, 63% of those treated with FOLFOXIRI plus bevacizumab, as compared with 28% of those treated with only FOLFOXIRI/XELOXIRI, showed a histopathological response (P=0.033). In the two groups, 52% and 12.5%, respectively, showed necrosis ⩾50% (P=0.017). The incidence of liver toxicities was not significantly increased in patients treated with FOLFOXIRI plus bevacizumab. Conclusion: The addition of bevacizumab to FOLFOXIRI produces high rates of pathologic responses and necrosis of CLM without increasing liver toxicity.
    British Journal of Cancer 05/2013; 108(12). DOI:10.1038/bjc.2013.245 · 4.82 Impact Factor
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    • "Oxaliplatin is usually responsible [7] [11] [35]. Other lesions such as steatosis [7] [11] [13] [34] [35] have been less clearly demonstrated, while in 3 studies [7] [9] [35] steatohepatitis was associated with the use of irinotecan. The impact of all of these lesions on postoperative morbidity and mortality remains controversial [7] [13] [34] [35]. "
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    ABSTRACT: Background and Aims. Chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. We describe these lesions and assess risk factors and impacts on postresection morbidity and mortality in naive patients to chemotherapy before the era of bevacizumab. Methods. Noncancerous liver tissue lesions were analysed according to tumour, chemotherapy, surgery, and patient characteristics. Results. Fifty patients aged 62 ± 9.3 years were included between 2003 and 2007. Thirty-three (66%) received chemotherapy, with Folfox (58%), Folfiri (21%), LV5FU2 (12%), or Xelox (9%) regimens. Hepatotoxicity consisted of 18 (36%) cases of severe sinusoidal dilatation (SD), 13 (26%) portal fibrosis, 7 (14%) perisinusoidal fibrosis (PSF), 6 (12%) nodular regenerative hyperplasia (NRH), 2 (4%) steatosis >30%, zero steatohepatitis, and 16 (32%) surgical hepatitis. PSF was more frequent after chemotherapy (21% versus 0%, P = 0.04), especially LV5FU2 (P = 0.02). SD was associated with oxaliplatin (54.5% versus 23.5%, P = 0.05) and low body mass index (P = 0.003). NRH was associated with oxaliplatin (P = 0.03) and extensive resection (P = 0.04). No impact on mortality and morbidity was observed, apart postoperative elevation of bilirubin levels in case of PSF (P = 0.03), longer hospitalization in case of surgical hepatitis (P = 0.03), and greater blood loss in case of portal fibrosis (P = 0.03). Conclusions. Chemotherapy of colorectal liver metastases induces sinusoidal dilatation related to oxaliplatin and perisinusoidal fibrosis related to 5FU, without any impact on postoperative mortality.
    03/2013; 2013:314868. DOI:10.1155/2013/314868
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    • "Chemotherapyinduced liver pathology increases both morbidity and mortality [2] [3] after liver surgery. It may augment the consequences of ischemia/reperfusion (I/R) injuries during liver surgery, since either steatotic livers or livers with vascular pathology from etiologies other than chemotherapy have been reported to be more sensitive to I/R injuries [4] [5] [6] [7]. "
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    ABSTRACT: Liver pathology induced by chemotherapy (steatosis or vascular injury) is known to increase the liver's sensitivity to ischemia/ reperfusion (I/R) injury, thereby increasing morbidity and mortality after liver resection. Our aim was to assess whether ischemic preconditioning (IP) reduces I/R injury to livers with chemotherapy-induced pathology. We analyzed a series of livers from patients treated with chemotherapy for colorectal cancer who underwent IP (n=30) or not (n=31) before hepatectomy. All but one of the livers exhibited chemotherapy-induced steatosis and/ or peliosis before the I/R insult. Necrosis was less frequent (p=0.038) in livers with IP than in the others. IP had no influence on apoptosis as assessed by terminal transferase uridyl nick-end labeling (TUNEL) assay or caspase-3, -8 and -9 expression. IP induced a twofold increase in B-cell leukemia/ lymphoma 2 (Bcl-2; p<0.05), which was localized to hepatocytes of centrolobular and peliotic areas and colocalized with the autophagy protein beclin-1 in livers with IP, suggesting their coordinated role in autophagy. Increased expression of the phosphorylated Bcl-2 was observed in preconditioned livers and was associated with a decreased immunoprecipitation of beclin-1 and the increased expression of light chain 3 type II (LC3-II). The increased number of autophagic vacuoles seen by electron microscopy confirmed an association of autophagy in chemotherapy-injured livers following IP. However, the differences in protein expression were not reflected in postresection liver-injury tests or measure of patient morbidity. IP is associated with a reduction in necrosis of hepatocytes already damaged by chemotherapy and an activation of autophagy. Bcl-2 and beclin-1 could be major targets in the regulation of cell death during I/R injury.
    Journal of Hepatology 08/2009; 51(5):881-9. DOI:10.1016/j.jhep.2009.06.028 · 10.40 Impact Factor
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