|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2065-2072 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.3074 Chemotherapy Regimen Predicts Steatohepatitis and an Increase in 90-Day Mortality After Surgery for Hepatic Colorectal Metastases
From the Departments of Surgical Oncology, Pathology, and Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pathology; Massachusetts General Hospital, Boston, MA; and Departments of Pathology and Surgical Oncology, Istituto per la Ricerca e la Cura del Cancro, Torino, Italy. Address reprint requests to Jean-Nicolas Vauthey, MD, Department of Surgical Oncology, Unit 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: jvauthey{at}mdanderson.org
PURPOSE: Chemotherapy before resection of hepatic colorectal metastases (CRM) may cause hepatic injury and affect postoperative outcome. PATIENTS AND METHODS: Four hundred six patients underwent hepatic resection of CRM between 1992 and 2005. Pathologic review of the nontumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal injury. The effect of chemotherapy and liver injury on perioperative outcome was analyzed. RESULTS: One hundred fifty-eight patients (38.9%) received no preoperative chemotherapy, whereas 248 patients (61.1%) did. The median duration of chemotherapy was 16 weeks (range, 2 to 70 weeks). Chemotherapy consisted of fluoropyrimidine-based regimens (fluorouracil [FU] alone, 15.5%; irinotecan plus FU, 23.1%; and oxaliplatin plus FU, 19.5%) and other therapy (3.0%). On pathologic analysis, 36 patients (8.9%) had steatosis, 34 (8.4%) had steatohepatitis, and 22 (5.4%) had sinusoidal dilation. Oxaliplatin was associated with sinusoidal dilation compared with no chemotherapy (18.9% v 1.9%, respectively; P < .001; odds ratio [OR] = 8.3; 95% CI, 2.9 to 23.6). In contrast, irinotecan was associated with steatohepatitis compared with no chemotherapy (20.2% v 4.4%, respectively; P < .001; OR = 5.4; 95% CI, 2.2 to 13.5). Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (14.7% v 1.6%, respectively; P = .001; OR = 10.5; 95% CI, 2.0 to 36.4). CONCLUSION: Steatohepatitis is associated with an increased 90-day mortality after hepatic surgery. In patients with hepatic CRM, the chemotherapy regimen should be carefully considered because the risk of hepatotoxicity is significant.
Surgical resection of hepatic metastases is the standard of care for resectable disease, with recent single and multicenter studies reporting up to a 58% 5-year survival rate.1-4 Even after successful hepatic resection, however, the majority of patients will develop recurrent disease, either in the liver alone or in combination with extrahepatic sites.5,6 Therefore, systemic chemotherapy (primarily fluoropyrimidine-based regimens) has been used as adjuvant therapy in combination with resection or as part of a multimodality approach of initially unresectable hepatic colorectal metastases (CRM).7-11 Although traditionally administered postoperatively, systemic chemotherapy has increasingly been used in the preoperative setting before liver resection7,8,12 because of several theoretical advantages. These include the potential to downsize tumor(s) preoperatively, to increase curative resection rates, and to convert some patients from having unresectable to resectable disease. Use of preoperative therapy in patients at high risk for recurrence may assist in identifying responders so that therapy can be tailored postoperatively based on preoperative response. In addition, patients with multiple tumors who progress on preoperative chemotherapy and who, therefore, may not benefit from resection can be spared nontherapeutic surgery.8,13 Although preoperative therapy has been shown to be effective and safe in other types of solid tumors, such as rectal and esophageal carcinoma,14,15 recent reports indicate a chemotherapy-associated increase in the incidence of steatosis,12 steatohepatitis,16 and sinusoidal injury.17 The impact of these changes on outcome after liver resection remains uncertain. In the current study, we analyzed the histopathologic changes associated with preoperative chemotherapy and report the postoperative outcome of patients who received chemotherapy before resection of hepatic CRM.
A retrospective review of patients who underwent hepatic surgery for CRM with curative intent at The University of Texas M.D. Anderson Cancer Center (Houston, TX) and the Department of Surgical Oncology, Istituto per la Ricerca e la Cura del Cancro Candiolo (Torino, Italy) between June 1992 and June 2005 was undertaken. Hepatic resections were defined according to the Brisbane terminology.18,19 Patients were divided into the following five groups based on their preoperative chemotherapy regimen: (1) no preoperative chemotherapy; (2) fluoropyrimidine-based chemotherapy with fluorouracil (FU) and leucovorin alone; (3) fluoropyrimidine-based chemotherapy with FU plus irinotecan; (4) fluoropyrimidine-based chemotherapy with FU plus oxaliplatin; and (5) other therapy. Patients who received chemotherapy for their primary tumor within 1 year of liver resection and patients who received regional therapy were excluded. Patients who underwent preoperative portal vein embolization were also excluded because of the histopathologic changes affecting the nontumorous hepatic parenchyma.20 Standard demographic data were collected on all patients including type and duration of preoperative chemotherapy; details of the resection; estimated blood loss (EBL), which was calculated as previously described21; characteristics of the resected tumor; and 90-day morbidity and mortality.
Four attending pathologists (T.-T.W., M.R., G.Y.L., and M.M.-K.) with hepatobiliary expertise and who were blinded to the clinical data evaluated the resected specimens. Pathologic findings of the hepatic parenchyma remote from the resected tumor were scored as follows: (1) degree of steatosis was graded as none, mild (< 30%), moderate (
Summary statistics were obtained using the  2 and Fisher's exact tests for comparing categoric variables; the Kruskal-Wallis test was used to compare continuous variables among the treatment groups. The odds ratios (ORs) and the 95% CIs were estimated, and a P < .05 was considered to be statistically significant.
Table 1 lists the clinicopathologic features of the 406 patients in the study. There were 250 men and 156 women; the median patient age was 59 years (range, 18 to 86 years). Most patients had a primary colon carcinoma (n = 310; 76.3%) with node-positive disease (n = 245; 60.3%). The median number of lesions was two (range, one to 12 lesions), and the median size of the largest lesion was 3.5 cm (range, 1.1 to 9.4 cm).
The majority of patients received preoperative chemotherapy (n = 248; 61.1%) before surgical treatment of the hepatic metastases (Table 2). Most of these patients (n = 204 of 248; 82.3%) were resectable at presentation, and chemotherapy was administered as neoadjuvant therapy. In 44 patients (17.7%), the hepatic CRM were initially unresectable, and preoperative chemotherapy resulted in tumor downsizing, thereby allowing subsequent resection. Chemotherapy consisted of fluoropyrimidine-based regimens (FU alone, 15.5%; FU plus irinotecan, 23.1%; and FU plus oxaliplatin, 19.5%) and other therapy (3.0%; capecitabine, 1.7%; floxuridine, 0.5%; and tegafur with uracil 0.8%; Table 2). In the latter part of the study, bevacizumab was combined with oxaliplatin (n = 18) or with irinotecan (n = 1); no patient received cetuximab. Of the 248 patients who received preoperative chemotherapy, the median duration of treatment was 16 weeks (range, 2 to 70 weeks).
At the time of operation, the extent of hepatic resection was less than a hemihepatectomy in 131 patients (32.3%), a hemihepatectomy in 203 patients (50.0%), and an extended hepatectomy in 72 patients (17.7%). Resection was combined with radiofrequency ablation in 126 patients (31.0%). The median operative time was similar for patients who had received preoperative chemotherapy (173 minutes; range, 61 to 564 minutes) compared with patients who had not received chemotherapy treatment (176 minutes; range, 60 to 577 minutes; P = .43). The median EBL was comparable between patients with a history of preoperative chemotherapy (250 mL; range, 0 to 3,400 mL) and patients with no history of chemotherapy (300 mL; range, 0 to 15,000 mL). Patient characteristics and operative details were stratified according to chemotherapy regimens (Table 3). In general, tumor characteristics and surgery details were similar among all chemotherapy groups. Patients who received FU alone tended to have less major hepatectomies (P = .06) and had smaller tumors that were more likely to be solitary (both P < .05). Patients treated with FU alone also had a longer duration of chemotherapy treatment (P = .001). The EBL was significantly lower in patients receiving oxaliplatin, which likely reflects recent changes in operative technique.21
The perioperative complication rate was 20.9%. Nineteen patients (4.7%) suffered from hepatic complications including liver failure (n = 5), hepatic insufficiency (n = 4), bile leaks/biloma (n = 4/3), hepatic cut surface bleeding (n = 1), and portal vein thrombosis (n = 2). Nonhepatic complications occurred in 66 patients (16.2%); there were 23 pulmonary complications (5.7%; pleural effusion, n = 5; pneumonia, n = 10; atelectasis, n = 2; pneumothorax, n = 2; respiratory failure, n = 2; and pulmonary emboli, n = 2), eight cardiovascular complications (2.0%; myocardial infarction, n = 1; tachycardia/arrhythmias, n = 5; stroke, n = 1; and congestive heart failure, n = 1), one renal insufficiency (0.2%), one multiorgan failure (0.2%), four infected (1.0%) and six sterile fluid collections (1.5%), two postoperative bleedings (0.5%), seven patients with postoperative ileus (1.7%), three other infectious complications (0.7%), and 11 miscellaneous complications (2.7%). Perioperative complication rates were similar between the different chemotherapy groups (P = .27). The median length of stay was 7 days (range, 3 to 38 days) and did not differ between the preoperative chemotherapy (7 days) and no preoperative chemotherapy groups (7 days; P = .92).
On final pathologic analysis of the resected specimen, hepatic injury was present in 92 patients (22.7%). Steatosis more than 30% was identified in 36 patients (8.9%), grade 2 to 3 sinusoidal dilation was found in 22 patients (5.4%), and steatohepatitis Kleiner score
Chemotherapy and body mass index (BMI) were further analyzed using the BMI cut point of 25 kg/m2. Irinotecan was associated with steatohepatitis irrespective of BMI (BMI < 25 kg/m2: no chemotherapy, 0% v irinotecan, 12.1%; BMI  25 kg/m2: no chemotherapy, 7.1% v irinotecan, 24.6%; both P < .01; Table 5).
Eleven patients died within 90 days of surgery, for a perioperative mortality rate of 2.7%. The median EBL for patients who died within 90 days was 550 mL compared with 275 mL for patients who did not die (P = .041). There were six deaths (6.5%) in 92 patients with hepatic injury (three from liver failure, of which two were associated with bile leak; one from acute respiratory distress syndrome; one from cerebrovascular accident; and one from unknown cause) compared with five deaths (1.6%) in 314 patients without hepatic injury (two from liver failure, of which one was associated with bile leak; one from myocardial infarction; one from coagulopathy; and one from bile leak and sepsis; P = .01). Of the patients with hepatic injury, no deaths occurred in the 22 patients with sinusoidal injury. Rather, the six patients with hepatic injury who died had either steatosis more than 30% (n = 1) or steatohepatitis (Kleiner score 4; n = 5). Patients with steatohepatitis had an increased 90-day mortality rate compared with patients who did not have steatohepatitis (14.7% v 1.6%, respectively; P = .001; OR = 10.5; 95% CI, 2.0 to 36.4). Patients with steatohepatitis (n = 34) also had a higher risk of death specifically from postoperative liver failure (5.8%) versus all other patients (0.8%; P = .01; OR = 7.7; 95% CI, 1.24 to 47.7). All five patients with steatohepatitis who died postoperatively underwent resection (hemihepatectomy, n = 4; wedge resection, n = 1) combined with radiofrequency ablation of one lesion (median diameter, 1.5 cm) in the remnant liver. However, resection combined with ablation was not associated with increased mortality in patients without steatohepatitis (resection plus radiofrequency ablation, 1.8% v resection alone, 1.5%; P = .8).
To our knowledge, the current study is the first to systematically analyze the association between chemotherapy, histopathologic changes of the liver, and postoperative outcome in a large cohort of patients who underwent liver resection for hepatic CRM. We report that preoperative chemotherapy may be associated with pathologic changes of the liver parenchyma, which may translate into adverse clinical outcomes after hepatic surgery. Specifically, oxaliplatin was associated with an increase in sinusoidal injury but no increase in perioperative morbidity or mortality. Preoperative treatment with irinotecan was associated with an increased risk of steatohepatitis. In turn, steatohepatitis was associated with an increased overall postoperative mortality and, specifically, death from postoperative liver failure. Although previous studies16,23 had suggested an increased likelihood of adverse events in patients treated preoperatively with chemotherapy, the current study is the first not only to quantify this risk, but also to identify chemotherapy-specific toxicity associated with an increase in postoperative mortality. We defined postoperative mortality as any death occurring within 90 days of the operative procedure. The reason for using 90-day mortality was to account for the broad spectrum of complications and deaths that can occur late in the postoperative course of patients having undergone a liver resection. Although postoperative technical complications are reflected in the early postoperative morbidity and mortality and have been minimized even after extended liver resection,24 it has become evident that outcome after hospital discharge or 30 days underestimates morbidity and mortality after hepatic resection. A recent study reporting on resection of hepatocellular carcinoma in patients with chronic liver disease revealed postoperative mortality that occurred beyond the hospital stay and the traditional 30-day postoperative period.25 As such, 90-day mortality may better define the subset of patients who die from progressive liver failure related to impaired hepatic regeneration. In the present study, three of the five deaths in the subset of patients with steatohepatitis occurred after discharge and more than 30 days after hepatic resection. In some patients, the development of liver failure may be associated with an adverse physiologic event such as a bile leak, abscess, or septic event. Typically, these patients succumb to a late postoperative death from progressive intrahepatic cholestasis often with minimal other associated signs of liver failure.26,27 The effect of chemotherapy on perioperative outcome has been controversial. New chemotherapy regimens for CRM, such as FU plus irinotecan or oxaliplatin,28-30 have response rates up to 56%,30 but there have been reported cases of severe histopathologic changes in the resected liver of patients treated with these regimens.16,17 Rubbia-Brandt et al17 reported an increased rate of sinusoidal dilation in patients who had received chemotherapy, most of whom (78%) had received preoperative oxaliplatin. In 21 (48%) of these 44 patients, perisinusoidal and occlusive fibrosis were noted, whereas diffuse nodular regenerative hyperplasia was present in seven patients.17 In the current study, oxaliplatin was also shown to be significantly associated with an increased risk of sinusoidal dilation.
Prior research has shown that camptothecin derivatives, such as irinotecan, are directly toxic to primary hepatocytes in vitro.31 Fernandez et al16 suggested an association between preoperative chemotherapy for hepatic CRM and steatohepatitis. In their study, 10 of the 14 patients who developed steatohepatitis had received preoperative irinotecan-containing fluoropyrimidine chemotherapy. Our data confirmed this presumed association of irinotecan with steatohepatitis in patients receiving preoperative chemotherapy for CRM. Traditionally, steatohepatitis has been associated with certain patient factors such as hyperglycemia and obesity.32,33 In our study, irinotecan was associated with an increased risk of steatohepatitis irrespective of BMI, but the effect was more pronounced in patients with a higher BMI (BMI < 25 kg/m2, 12.1% v BMI Whether chemotherapy-induced histopathologic changes of the liver result in adverse postoperative outcomes has not previously been adequately addressed. Behrns et al34 reported a nonsignificant increase in the likelihood of complications and liver failure in seven patients with moderate to severe steatosis among 135 patients who underwent liver resection for CRM in the era predating irinotecan and oxaliplatin. Belghiti et al35 similarly reported an increased morbidity in 37 patients with steatosis compared with patients without underlying liver disease. Kooby et al23 reported an increase in surgical complications and an association between marked steatosis, chemotherapy, and BMI. However, all of these studies analyzed steatosis only, whereas steatohepatitis and the effect of preoperative chemotherapy regimens were not specifically examined. In the current study, preoperative chemotherapy with oxaliplatin, although associated with sinusoidal injury, was not associated with increased morbidity or mortality rates. In fact, of the patients with hepatic injury, no deaths occurred in the 22 patients with sinusoidal injury despite similar rates of major hepatectomy between groups (77.2% in patients with sinusoidal dilation, 61.7% in patients with steatohepatitis, and 58.3% in patients with steatosis > 30%; P = .45). This finding is consistent with a preliminary report from a randomized study showing no increase in mortality in 174 patients who received continuous infusion FU and leucovorin plus oxaliplatin (FOLFOX4) chemotherapy before hepatic resection.9 Similarly, Adam et al7 reported no increase in the morbidity or mortality of patients treated preoperatively with chronomodulated systemic chemotherapy with FU, leucovorin, and oxaliplatin for a median of 20 weeks before the patients underwent hepatic resection. Although a recent study reported an association between duration of preoperative chemotherapy and perioperative morbidity,36 our study indicated no increase in the rate of hepatic injury over time. However, the effect of prolonged chemotherapy deserves further investigation because the current study included mostly patients presenting with resectable disease (82.3%) and the median durations of treatment with oxaliplatin and irinotecan were only 12 and 16 weeks, respectively. Perhaps the most important finding of the current study was the association of irinotecan with steatohepatitis and subsequent postoperative mortality after hepatic surgery. Although steatohepatitis is generally a benign condition, the presence of steatohepatitis has been associated with an increased risk of liver disease and liver failure in some patients.37-39 Steatohepatitis of the liver may cause defective cell proliferation through alterations of the nuclear factor-kappa B pathway, which is crucial for the priming phase of liver regeneration.40-43 Fernandez et al16 reported an index case of a patient with steatohepatitis who died from liver failure, possibly as a result of chemotherapy-associated hepatic injury. Our data confirm the presumptive association between steatohepatitis and increased risk for mortality after hepatic surgery. In conclusion, preoperative chemotherapy can induce regimen-specific histopathologic hepatic changes. In the case of oxaliplatin, the chemotherapy-associated liver injury was not associated with an increased risk of perioperative morbidity or mortality. In contrast, steatohepatitis was associated with irinotecan and with an increased perioperative risk of death, especially in patients undergoing a major resection combined with radiofrequency ablation. Some have recommended liver biopsy to evaluate for steatosis or steatohepatitis16; however, given the problems associated with sampling error as well as intra- and interobserver variation in the evaluation of steatosis,44 we do not advocate this approach. Rather, laparoscopy before laparotomy in patients with preoperative imaging studies that suggest steatosis should be considered to directly evaluate the liver.45 The extent of resection and type of chemotherapy regimen should be carefully considered and individualized, including a consideration for BMI and related comorbid factors. In patients who require major hepatic surgery and have proven hepatic injury, preoperative portal vein embolization may be considered based on prior experience with major hepatectomy in cirrhosis,46,47 although the specific indications for this approach remain to be defined.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825, 2004[CrossRef][Medline] 2. Choti MA, Sitzmann JV, Tiburi MF, et al: Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766, 2002[CrossRef][Medline] 3. Fernandez FG, Drebin JA, Linehan DC, et al: Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 240:438-447, 2004[CrossRef][Medline] 4. Pawlik TM, Scoggins CR, Zorzi D, et al: Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 241:715-724, 2005[CrossRef][Medline] 5. Kemeny NE, Kemeny MM, Lawrence TS: Liver metastases, in Abeloff MD, Armitage JO, Lichter AS, et al (eds): Clinical Oncology. New York, NY, Churchill Livingstone, 2000, pp 886-921 6. Vauthey JN, Marsh Rde W, Cendan JC, et al: Arterial therapy of hepatic colorectal metastases. Br J Surg 83:447-455, 1996[Medline] 7. Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004[Medline] 8. Adam R, Pascal G, Castaing D, et al: Tumor progression while on chemotherapy: A contraindication to liver resection for multiple colorectal metastases? Ann Surg 240:1052-1061, 2004[CrossRef][Medline] 9. Nordlinger B, Sorbye M, Debois M, et al: Feasibility and risks of pre-operative chemotherapy (CT) with Folfox 4 and surgery for resectable colorectal cancer liver metastases (LM): Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 23:253s, 2005 (suppl, abstr 3528) 10. Abdalla EK, Barnett CC, Doherty D, et al: Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg 137:675-680, 2002 11. Jaeck D, Oussoultzoglou E, Rosso E, et al: A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg 240:1037-1049, 2004[CrossRef][Medline] 12. Parikh AA, Gentner B, Wu TT, et al: Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 7:1082-1088, 2003[CrossRef][Medline] 13. Allen PJ, Kemeny N, Jarnagin W, et al: Importance of response to neoadjuvant chemotherapy in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest Surg 7:109-117, 2003[CrossRef][Medline] 14. Vauthey JN, Marsh RW, Zlotecki RA, et al: Recent advances in the treatment and outcome of locally advanced rectal cancer. Ann Surg 229:745-752, 1999[CrossRef][Medline] 15. Swisher SG, Hofstetter W, Wu TT, et al: Proposed revision of the esophageal cancer staging system to accommodate pathologic response (pP) following preoperative chemoradiation (CRT). Ann Surg 241:810-817, 2005[CrossRef][Medline] 16. Fernandez FG, Ritter J, Goodwin JW, et al: Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 200:845-853, 2005[CrossRef][Medline] 17. Rubbia-Brandt L, Audard V, Sartoretti P, et al: Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004 18. Zorzi D, Mullen JT, Abdalla EK, et al: Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases. J Gastrointest Surg 10:86-94, 2006[CrossRef][Medline] 19. Strasberg SM: For the International Hepato-Pancreato-Biliary Association Terminology Committee Survey: The Brisbane 2000 Terminology of Liver Anatomy and Resections. HPB 2:333-339, 2000 20. Vauthey JN, Chaoui A, Do KA, et al: Standardized measurement of the future liver remnant prior to extended liver resection: Methodology and clinical associations. Surgery 127:512-519, 2000[CrossRef][Medline] 21. Aloia TA, Zorzi D, Abdalla EK, et al: Two-surgeon technique for hepatic parenchymal transection of the noncirrhotic liver using saline-linked cautery and ultrasonic dissection. Ann Surg 242:172-177, 2005[CrossRef][Medline] 22. Kleiner DE, Brunt EM, Van Natta M, et al: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313-1321, 2005[CrossRef][Medline] 23. Kooby DA, Fong Y, Suriawinata A, et al: Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 7:1034-1044, 2003[CrossRef][Medline] 24. Vauthey JN, Pawlik TM, Abdalla EK, et al: Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 239:722-732, 2004[CrossRef][Medline] 25. Regimbeau JM, Abdalla EK, Vauthey JN, et al: Risk factors for early death due to recurrence after liver resection for hepatocellular carcinoma: Results of a multicenter study. J Surg Oncol 85:36-41, 2004[CrossRef][Medline] 26. Pawlik TM, Vauthey JN: Factors affecting morbidity and mortality of liver surgery, in Cameron JL (ed): Current Surgical Therapy. Philadelphia, PA, Elsevier Mosby, 2004, pp 348-352 27. Takeda K, Togo S, Kunihiro O, et al: Clinicohistological features of liver failure after excessive hepatectomy. Hepatogastroenterology 49:354-358, 2002[Medline] 28. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 29. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 30. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 31. Fulco RA, Costa C, Germano MP, et al: Hepatotoxicity of camptothecin derivatives in a primary culture system of rat hepatocytes. J Chemother 12:345-351, 2000[Medline] 32. Hamaguchi M, Kojima T, Takeda N, et al: The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 143:722-728, 2005 33. Musso G, Gambino R, Durazzo M, et al: Adipokines in NASH: Postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 42:1175-1183, 2005[CrossRef][Medline] 34. Behrns KE, Tsiotos GG, DeSouza NF, et al: Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg 2:292-298, 1998[CrossRef][Medline] 35. Belghiti J, Hiramatsu K, Benoist S, et al: Seven hundred forty-seven hepatectomies in the 1990s: An update to evaluate the actual risk of liver resection. J Am Coll Surg 191:38-46, 2000[CrossRef][Medline] 36. Karoui M, Penna C, Amin-Hashem M, et al: Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1-7, 2006[CrossRef][Medline] 37. Charlton M, Kasparova P, Weston S, et al: Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl 7:608-614, 2001[CrossRef][Medline] 38. Marchesini G, Forlani G, Bugianesi E: Is liver disease a threat to patients with metabolic disorders? Ann Med 37:333-346, 2005[Medline] 39. Dixon JB, Bhathal PS, O'Brien PE: Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91-100, 2001[CrossRef][Medline] 40. DeAngelis RA, Markiewski MM, Taub R, et al: A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha. Hepatology 42:1148-1157, 2005[CrossRef] 41. Todo S, Demetris AJ, Makowka L, et al: Primary nonfunction of hepatic allografts with preexisting fatty infiltration. Transplantation 47:903-905, 1989[Medline] 42. Cressman DE, Greenbaum LE, Haber BA, et al: Rapid activation of post-hepatectomy factor/nuclear factor kappa B in hepatocytes, a primary response in the regenerating liver. J Biol Chem 269:30429-30435, 1994 43. Yang SQ, Lin HZ, Mandal AK, et al: Disrupted signaling and inhibited regeneration in obese mice with fatty livers: Implications for nonalcoholic fatty liver disease pathophysiology. Hepatology 34:694-706, 2001[CrossRef] 44. Fiorini RN, Kirtz J, Periyasamy B, et al: Development of an unbiased method for the estimation of liver steatosis. Clin Transplant 18:700-706, 2004[CrossRef][Medline] 45. Iwasaki M, Takada Y, Hayashi M, et al: Noninvasive evaluation of graft steatosis in living donor liver transplantation. Transplantation 78:1501-1505, 2004[CrossRef][Medline] 46. Kubota K, Makuuchi M, Kusaka K, et al: Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology 26:1176-1181, 1997[Medline] 47. Madoff DC, Abdalla EK, Vauthey JN: Portal vein embolization in preparation for major hepatic resection: Evolution of a new standard of care. J Vasc Interv Radiol 16:779-790, 2005[Medline] Submitted December 10, 2005; accepted February 17, 2006.
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
5%; 1 = 5% to 33%; 2 
(steatohepatitis present, n = 34 v steatohepatitis absent, n = 371)
