levoleucovorin and Hepatic-Veno-Occlusive-Disease

Neoadjuvant chemotherapy is increasingly being used to enlarge the cohort of patients who can be offered hepatic resection for malignancy. However, the impact of these agents on the liver parenchyma itself, and their effects on clinical outcomes following hepatic resection remain unclear. This review identifies patterns of regimen-specific chemotherapy-induced hepatic injury and assesses their impact on outcomes following hepatic resection for colorectal liver metastases (CLM).. An electronic search was performed using the MEDLINE (US Library of Congress) database from 1966 to May 2007 to identify relevant articles related to chemotherapy-induced hepatic injury and subsequent outcome following hepatic resection.. The use of the combination of 5-flourouracil and leucovorin is linked to the development of hepatic steatosis, and translates into increased postoperative infection rates. A form of non-alcoholic steatohepatitis (NASH) related to chemotherapy and otherwise known as chemotherapy-associated steatohepatitis (CASH) is closely linked to irinotecan-based therapy and is associated with inferior outcomes following hepatic surgery mainly due to hepatic insufficiency and poor regeneration. Data on sinusoidal obstruction syndrome (SOS) following treatment with oxaliplatin are less convincing, but there appears to be an increased risk for intra-operative bleeding and decreased hepatic reserve associated with the presence of SOS. Intra-arterial floxuridine therapy damages the extrahepatic biliary tree in addition to causing parenchymal liver damage, and has been shown to be associated with increased morbidity after hepatic resection.. Agent-specific patterns of damage are now being recognized with increasing use of neoadjuvant chemotherapy prior to surgery. The potential benefits and risks of these should be considered on an individual patient basis prior to hepatic resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Fatty Liver; Floxuridine; Fluorouracil; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Irinotecan; Leucovorin; Liver; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Risk Factors

The aim of this study was to investigate the effects of preoperative chemotherapy on the healthy, metastasis-free part of the liver in colorectal cancer patients with liver metastasis, and the relationship between chemotherapy and postoperative complications.. Our study included 90 cases of colorectal cancer liver metastasis resected after preoperative chemotherapy. The patients were divided into three groups according to the received chemotherapy regimen: 20 cases received mFOLFOX6, 54 cases a combination of mFOLFOX6 with bevacizumab, and 16 cases a combination of mFOLFOX6 and cetuximab or panitumumab.. The mean numbers of sinusoidal injuries for each chemotherapy type were compared. The group treated with the combination of mFOLFOX6 and bevacizumab showed a lower extent of sinusoidal injury relative to other groups; this intergroup difference became increasingly remarkable as the number of chemotherapy cycles increased. Complications of various extents were found in all three groups, but no significant differences were observed between the three groups.. In cases where preoperative chemotherapy was extended over a long period, combined use of bevacizumab was thought to be effective because of stabilization of disturbed liver hemodynamics resulting from sinusoidal injury suppression effects, allowing effective distribution of anti-cancer agents to tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Postoperative Complications; Preoperative Period

The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM).. One hundred patients with CRLM having undergone at least one liver segment resection were prospectively included, and chemotherapy data recorded. Specimens were reviewed by a single pathologist and CALI were described. Prevalence of CALI was compared to our previous experience published in 2013. NRH diagnosis was performed on reticulin special stain, by contrast to our previous study. Postoperative outcome was analysed.. Bevacizumab was more frequently administrated in patients of the present study: 53/100 (53%) compared to 20/151 (13%), p < 0.0001. Overall, in the present series, SOS was only observed in 28/100 (28%) patients compared to 116/151 (77%) in 2013 (p < 0.001). When looking specifically to patients receiving Bevacizumab with Folfox, we observed a reduced SOS prevalence compared to Folfox alone (p = 0.008). A higher prevalence of NRH was found in the present study, related to increased detection accuracy, but in patients receiving Bevacizumab in association with Folfox, this prevalence was also reduced compared to Folfox alone (p = 0.03). Both SOS and NRH were associated with severe complications (p = 0.008 and p = 0.005, respectively) and postoperative liver insufficiency (p < 0.001 and p < 0.01, respectively).. The routine use of Bevacizumab in association with Folfox significantly reduced CALI prevalence, in turn linked to severe postoperative complications.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Belgium; Bevacizumab; Biological Products; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Postoperative Complications; Prevalence

Oxaliplatin can cause hepatic sinusoidal obstruction syndrome (SOS). SOS can cause chemotherapy-related adverse effects or morbidity after liver resection. Conventionally, SOS is diagnosed using liver biopsy. Recently, it was reported that increased splenic volume (SV) can be used to detect SOS. In this study, we evaluated the changes in SV during adjuvant chemotherapy.. We enrolled 103 consecutive patients with stage III and high-risk stage II colorectal cancer treated with mFOLFOX6 (n = 37) or oral fluorouracil and leucovorin (n = 66) after curative surgery. SV was measured three times; pre-operatively, after chemotherapy, and 1 year after chemotherapy.. SV was higher after mFOLFOX6 (median 135.89 mL) than pre-operatively (105.75 mL) (P < 0.001); SV at 1-year after finishing mFOLFOX6 (114.16 mL) returned to the same level as before surgery (P = 0.0015). SV increased in 28 patients (75.7%) treated with mFOLFOX6 (95%CI, 61.8-89.5), but had not recovered in 12 of these cases (42.9%) 1 year after finishing treatment (95%CI, 17.3-47.5). In contrast, oral fluorouracil and leucovorin did not change SV.. SV increased after adjuvant mFOLFOX6, and had not recovered in almost half of cases 1-year after finishing chemotherapy. This increase may indicate continuous SOS, which can adversely affect treatment after recurrence.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies

Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI).. The expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores.. Abnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02).. The CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.

Topics: Actins; Adult; Aged; Aged, 80 and over; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Glutamate-Ammonia Ligase; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients.. Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells.. Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, -42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly.. Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; DNA; Female; Fluorouracil; Genotyping Techniques; Glutathione S-Transferase pi; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Leukocytes, Mononuclear; Liver Neoplasms; Male; Matrix Metalloproteinase 9; Middle Aged; Nitric Oxide Synthase Type III; Organoplatinum Compounds; Platelet Count; Polymorphism, Single Nucleotide; Retrospective Studies; Sequence Analysis, DNA; Splenomegaly; Thrombocytopenia; Tomography, X-Ray Computed; Treatment Outcome; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds

Topics: Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Neoplasms; Organoplatinum Compounds

The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS.. Seventy-nine patients who received OX-based chemotherapy with (OX + Bmab group: n = 48) or without Bmab (OX group: n = 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy.. A significant increase in the splenic volume was observed in the OX group, but not in the OX + Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX + Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX + Bmab group (50.0% vs. 16.0%, p = 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p = 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS.. This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organ Size; Organoplatinum Compounds; Oxaliplatin; Radiography; Retrospective Studies; Spleen; Treatment Outcome

Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies.. C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine.. FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS.. We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Cycle; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cytokines; Disease Models, Animal; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Inflammation Mediators; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Oxidative Stress; Serpin E2; Thrombosis

Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury.. We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI.. In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury.. It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Collagen Type I; Colorectal Neoplasms; Fluorouracil; Hepatic Veno-Occlusive Disease; Inflammation; Leucovorin; Liver; Liver Neoplasms; Matrix Metalloproteinase 2; Megakaryocytes; Mice; Mice, Inbred C57BL; Organoplatinum Compounds; Plasminogen Activator Inhibitor 1; Spleen; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Chemotherapy-induced liver injury is a considerable problem in patients undergoing surgery for colorectal liver metastases, since an increase in postoperative morbidity and mortality has been observed. We investigated whether liver damage had further implications on long-term outcome in these patients.. Liver specimens from 196 patients resected for colorectal liver metastases were evaluated for chemotherapy-associated hepatic damage in the nontumorous liver. Injury patterns were correlated with recurrence free (RFS) and overall survival (OS). Factors leading to sinusoidal injury were identified.. Patients who developed grade 2 or 3 sinusoidal dilatation had a significantly shorter RFS (hazard ratio [HR] 2.05; 95% confidence interval [95% CI] 1.23-3.39, P = .005) and OS (HR 2.90; 95% CI 1.61-6.19, P < .001), compared to patients without this alteration. Those patients also had significantly more intrahepatic recurrences (66.7% vs 30.5%, P = .003). Other patterns of chemotherapy-associated liver damage (nonalcoholic steatohepatitis, fibrosis) were not associated with impaired survival. Factors indicating sinusoidal injury were oxaliplatin-based chemotherapy, tumor size >5 cm, and elevated alkaline phosphatase or gamma glutamyltransferase.. Sinusoidal obstruction syndrome due to oxaliplatin-based chemotherapy may not only compromise perioperative outcome, but can lead to early recurrence and decreased survival in the long term. Strategies to prevent this condition are clearly needed.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Survival Rate; Time Factors; Treatment Outcome

In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited.. Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST).. Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone.. This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Chi-Square Distribution; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaloacetates; Regression Analysis; Retrospective Studies; Statistics, Nonparametric; Treatment Outcome

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds