levoleucovorin and Fatty-Liver

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 assess chemotherapy associated hepatotoxicity after 3 months' treatment and to correlate patterns of hepatotoxicity with perioperative morbidity.. Liver specimens of 50 patients with liver metastases from colorectal cancer receiving XELOX or FOLFOX4 for six cycles and 13 specimens of non-chemotherapy patients subjected to liver resection were analyzed. Different patterns of hepatotoxicity were evaluated according to widely accepted pathohistological scores. Furthermore, the histomorphological findings were correlated with perioperative morbidity.. Steatosis grades did not differ among the chemotherapy treated groups and non-chemotherapy patients. Chemotherapy showed an independent effect on fibrosis stage. Age and chemotherapy were independently associated with sinusoidal dilatation. Centrilobular vein fibrosis correlated with administration of chemotherapy. Higher fibrosis stages were associated with increased transfusion requirements.. XELOX and FOLFOX4 do not correlate with the development of steatosis or steatohepatitis. We do not detect a difference in liver injury between the XELOX and FOLFOX4 group. Although 5-fluorouracil based chemotherapy may cause profound changes in liver parenchyma, it can be safely applied. However, age and oxaliplatin predispose for the development of sinusoidal dilatation; therefore caution must be taken in old patients treated with oxaliplatin.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fatty Liver; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Morbidity; Organoplatinum Compounds; Oxaloacetates; Prognosis; Retrospective Studies; Risk Factors

Twenty-three patients with metastatic colorectal carcinoma were randomized as part of two multicenter Phase III trials to receive either 5-fluorouracil (5-FU)/interferon alpha-2A (INF-alpha) or 5-FU +/- leucovorin. The patients were evaluated regularly for response by CT of the abdomen when treatment began and then every six to eight weeks. incidentally, we found that four of 13 patients treated with 5-FU/INF-alpha and none of ten patients treated with 5-FU +/- leucovorin developed hepatic steatosis during treatment. The diagnoses were based on a decreased CT value of the liver parenchyma by the repeated CT, and histologically verified by liver biopsies. There was no relationship to cumulative 5-FU or INF-alpha dose. Based on posttreatment CT, the liver parenchyma changes were reversible after therapy was stopped. Recognition of this condition in patients receiving 5FU/INF-alpha is important to prevent a patient from being labeled as having progressive hepatic metastases.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Colonic Neoplasms; Fatty Liver; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Liver; Male; Middle Aged; Radiography; Rectal Neoplasms

Thirty previously untreated patients with metastatic colorectal carcinoma were randomized as part of two multicenter Phase III trials. Twenty-two patients were randomized to receive either 5-fluorouracil (5-FU)/interferon alfa-2A (IFN-alpha) or 5-FU/leucovorin (11 patients in each arm). Eight patients were randomized to receive 5-FU/IFN-alpha or 5-FU alone (4 patients in each arm).. Twenty-three patients (13 patients treated with 5-FU/IFN-alpha and 10 patients treated with 5-FU/leucovorin or 5-FU alone) were evaluated regularly for response by computed tomography (CT) scans of the abdomen when treatment began and then every 6-8 weeks.. Incidentally, four patients developed hepatic steatosis during treatment with IFN-alpha and 5-FU. The diagnosis was based on a decreased CT value of the liver parenchyma by repeated CT scans of the abdomen during treatment, and this diagnosis was verified histologically by liver biopsy. There was no relationship to cumulative IFN-alpha or 5-FU dose. Based on posttreatment CT scans, the liver parenchyma changes were reversible after therapy was stopped, and there were no significant clinical sequelae. No patients treated with 5-FU/leucovorin or 5-FU alone experienced a decreased CT value of the liver parenchyma.. Hepatic steatosis was been observed in approximately 30% of patients treated with IFN-alpha and 5-FU. The hepatic changes were fully reversible after the treatment was stopped. Recognition of this condition is important to prevent a patient from being labeled as having progressive hepatic metastases.

Topics: Adenocarcinoma; Colonic Neoplasms; Fatty Liver; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Recombinant Proteins; Rectal Neoplasms; Tomography, X-Ray Computed

The combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is more toxic than gemcitabine, but it is a safe regimen with manageable toxicities.. We report a case with steatohepatitis mimicking liver metastasis as toxicity that was not seen in study patient population.. The adverse events of drugs are important predictive factor for treatment management, as important as efficacy. Especially the new lesion and metastasis is the most important factor for changing treatment. The clinicians must be careful about adverse events of regimens.. FOLFIRINOX regimen is the most important combination in pancreas cancer adjuvant setting. This case shows us the different presentation of usual adverse event.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fatty Liver; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

Chemotherapy-induced liver injury after potent chemotherapy is a considerable problem in patients undergoing liver resection. The aim of this study was to assess the relationship between the fractal dimension (FD) of Tc-99m diethylenetriaminepentaacetic acid (DTPA) galactosyl human serum albumin (GSA) and pathologic change of liver parenchyma in liver cancer patients who have undergone chemotherapy.. We examined 34 patients (10 female and 24 male; mean age, 68.5 years) who underwent hepatectomy. Hepatic injury was defined as steatosis more than 30 %, grade 2-3 sinusoidal dilation, and/or steatohepatitis Kleiner score ≥4. Fractal analysis was applied to all images of Tc-99m DTPA GSA using a plug-in tool on ImageJ software (NIH, Bethesda, MD). A differential box-counting method was applied, and FD was calculated as a heterogeneity parameter. Correlations between FD and clinicopathological variables were examined.. FD values of patients with steatosis and steatohepatitis were significantly higher than those without (P > .001 and P > .001, respectively). There was no difference between the FD values of patients with and without sinusoidal dilatation (P = .357). Multivariate logistic regression showed FD as the only significant predictor for steatosis (P = .005; OR 36.5; 95 % CI 3.0-446.3) and steatohepatitis (P = .012; OR, 29.1; 95 % CI 2.1-400.1).. FD of Tc-99m DTPA GSA was the significant predictor for fatty liver disease in patients who underwent chemotherapy. This new modality is able to differentiate steatohepatitis from steatosis; therefore, it may be useful for predicting chemotherapy-induced pathologic liver injury.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Fluorouracil; Fractals; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Predictive Value of Tests; Radionuclide Imaging; Radiopharmaceuticals; Risk Factors; ROC Curve; Technetium Tc 99m Aggregated Albumin; Technetium Tc 99m Pentetate

Hepatotoxic side effects of neoadjuvant chemotherapy for colorectal liver metastases increase perioperative morbidity and mortality. Glycine protects liver from injury in various animal models. Thus, this study was designed to assess its effect on liver after chemotherapy. Sprague-Dawley rats (200-220 g) were fed a synthetic diet containing 5% glycine for 5 days. Subsequently, chemotherapy (FOLFIRI: irinotecan, folinic acid and fluorouracil, or FOLFOX: oxaliplatin, folinic acid and fluorouracil) was administered at standard doses. Transaminases, histology, immunohistochemistry and in vivo microscopy were used to index liver injury, to monitor intrahepatic microperfusion and activation of Kupffer cells. Glycine significantly decreased transaminases after chemotherapy to 25-50% of control values (p < 0.05). Microvesicular steatosis was significantly reduced from 18.5 ± 3.4 and 57.1 ± 8.6% in controls to 9.5 ± 1.8 and 37.7 ± 4.4% after FOLFIRI and FOLFOX, respectively. Furthermore, phagocytosis of latex beads was reduced by about 50%, while leukocyte adherence in central and midzonal subacinar zones decreased to 60-80% after glycine (p < 0.05). Glycine significantly reduced expression of inducible nitric oxide synthase after chemotherapy, while hepatic microcirculation was increased (p < 0.05). This study shows for the first time that glycine reduces chemotherapy-induced liver injury. The underlying mechanisms most likely include Kupffer cells and an improved intrahepatic microperfusion.

Topics: Animals; Antineoplastic Agents; Camptothecin; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Dietary Supplements; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Female; Fluorouracil; Glycine; Immunohistochemistry; Irinotecan; Kupffer Cells; Leucovorin; Liver; Microcirculation; Neoadjuvant Therapy; Nitric Oxide Synthase Type II; Organoplatinum Compounds; Oxaliplatin; Phagocytosis; Rats; Rats, Sprague-Dawley; Transaminases

Systemic chemotherapy is being used increasingly in patients with colorectal cancer. The effects of prior systemic adjuvant or palliative chemotherapy on morbidity following hepatic resection for metastases are not well defined.. To assess the peri-operative impact of systemic chemotherapy on liver resection for colorectal cancer hepatic metastases.. Ninety-six resections for colorectal cancer hepatic metastases performed from July 2001 to July 2003 (93% > or =2 segments) were reviewed. Pre-operative demographics, peri-operative features, and post-operative outcomes were collected prospectively. Type of chemotherapy and the temporal relationship of chemotherapy to the liver resection were analyzed.. Fifty-three of 96 patients (55%) received a mean of 5.7 cycles (6.1 months) of systemic chemotherapy prior to hepatic resection, with a median interval of 12 months from end of chemotherapy to liver resection (range 1-75 months). Thirty-five received 5-fluorouracil/leucovorin (5-FU/LV) alone, nine had irinotecan (CPT-11) in addition to 5-FU/LV, and nine were not specified. Pre-operative age, sex, co-morbidities, ASA score, biochemical and liver enzyme profiles, tumor number, and extent and technique of hepatic resection were the same in the chemotherapy and non-chemotherapy cohorts. Mean tumor size was smaller (4.5 cm vs. 5.8 cm) and synchronous metastases were half as common (25% vs. 49%) in the chemotherapy group. Liver resection operative time was equivalent (270 min) in the two groups. Higher estimated blood loss (EBL) (1,000 ml vs. 850 ml), but fewer transfusions (23% vs. 15%) were associated with the chemotherapy group. Although not statistically significant, post-operative liver enzyme peaks were higher in the chemotherapy group (AST = 402 U/L vs. 302 U/L, P = 0.09 and ALT = 433 U/L vs. 312 U/L, P = 0.1). Peak changes in INR and serum bilirubin did not differ. Complications and length of stay (LOS) did not differ between the groups. The only post-operative death was in the non-chemotherapy group. Interestingly, hepatic steatosis was present in 28% of the non-chemotherapy cases and 57% of the chemotherapy resection specimens (P = 0.005) and was marked (>30%) in 7% and 10%, respectively. Further analysis of the chemotherapy group based on the interval between completion of chemotherapy and the hepatic resection (<6 months, 7-12 months, 1-2 years, and >2 years) revealed a trend towards worse outcomes in most categories for those in the >2 years cohort. When comparing the 5-FU/LV alone, to the CPT-11 group there were no significant differences except higher intra-operative blood loss in the group receiving 5-FU/LV alone (1,295 ml vs. 756 ml, P = 0.01).. Despite variations in biochemical function and hepatic steatosis, short-term clinical outcomes are not affected by the administration of chemotherapy prior to hepatic resection. Furthermore, there is no detrimental effect of close timing of chemotherapy prior to resection, and there are no appreciable differences between irinotecan containing regimes and more traditional 5-FU-only based therapies, although the subset sample sizes were small in this study.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Cohort Studies; Colorectal Neoplasms; Drug Administration Schedule; Fatty Liver; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Preoperative Care; Retrospective Studies; Treatment Outcome

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22-26) and 24 (23-25) kg/m(2), respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fatty Liver; Female; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies

In order to discuss the role of preoperative chemotherapy for colorectal liver metastases, which is used frequently before hepatic resection, even in patients with resectable disease at presentation, we herein report the development of two complications, partial portal vein thrombosis and hepatic steatosis with lobular inflammation, during the course of preoperative chemotherapy with FOLFIRI plus bevacizumab for colorectal liver metastases, which recognition led to timely discontinuation of chemotherapy as well as a change in the surgical strategy to resect the tumors and the damaged liver through advanced techniques. We conclude that duration of treatment and drug doses and combinations may impact the development of chemotherapy-induced liver injury. Surgeons and medical oncologists must work together to devise safe, rational, and oncologically appropriate treatments for patients with multiple colorectal liver metastases, and to improve the understanding of the pathogenesis of chemotherapy-induced liver injury.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Fatty Liver; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Portal Vein; Venous Thrombosis

The frequency and severity of fatty infiltration of the liver in patients receiving 5-fluorouracil (5-FU) and folinic acid has not been documented systematically. Its development can result in difficulty assessing disease progression, and treatment may be altered inappropriately. Twenty-seven patients with colon cancer and liver metastases receiving 5-FU and folinic acid were studied with computerized tomography (CT) before treatment and after six or 12 cycles of chemotherapy. Forty-seven per cent of patients developed hepatic steatosis during treatment. There was no correlation between development of hepatic steatosis and the dose of chemotherapy or the liver function tests. Hepatic steatosis occurs commonly in patients receiving 5-FU and folinic acid and can be severe. Its development can make hepatic metastases difficult to assess and if its benign nature is not appreciated treatment may be inappropriately altered.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Fatty Liver; Female; Fluorouracil; Humans; Leucovorin; Liver; Male; Middle Aged; Tomography, X-Ray Computed