Data for this Review were identified by searches of PubMed and references from relevant articles, using the terms “chemotherapy”, “hepatotoxicity”, “liver toxicity”, “liver injury”, “liver regeneration”, “colorectal liver metastases”, “oxaliplatin”, “5-fluorouracil”, “fluoropyrimidine”, “irinotecan”, “bevacizumab”, “cetuximab”, “steatohepatitis”, “sinusoidal injury”, and “sinusoidal obstruction syndrome.” Only papers published in English between January, 1990, and November, 2008, were
ReviewManagement of chemotherapy-associated hepatotoxicity in colorectal liver metastases
Introduction
For patients with stage IV colorectal cancer confined to the liver, tumours were once resectable in less than 10%.1 For patients with resectable disease, 5-year survival was about 25%, with high recurrence rates. Advances in systemic therapy have led to improved responses, so that patients with initially unresectable metastases can undergo resection with more than 30% 5-year survival (figure 1).2 In patients with resectable metastases, perioperative chemotherapy has led to improvements in progression-free survival.3 The increased use of preoperative chemotherapy for colorectal liver metastases has led to a growing awareness of potential hepatotoxicity caused by such treatment. Clinical data have shown associations between specific chemotherapeutic drugs and histological changes in the liver. A key molecular event that might underlie chemotherapy-induced hepatotoxicity is the production of reactive oxygen species (ROS), resulting in oxidative stress in hepatocytes (figure 2). Management of treatment-related hepatic injury is an important issue, because more patients than ever before are receiving chemotherapy for colorectal liver metastases—including prolonged, multiple-line therapies that might increase the risk of avoidable postoperative complications and liver insufficiency. Management of chemotherapy-associated hepatotoxicity involves limiting the duration of chemotherapy, heightened awareness of patients at risk for hepatic steatosis, and perioperative strategies—eg, liver volumetry and portal vein embolisation in patients with known, or suspected, hepatic injury.
Section snippets
Rationale for systemic therapy in colorectal liver metastases
Preoperative systemic therapy can reduce the size of metastases as well as improve selection of patients for surgery. In a study by Adam and colleagues,4 patients with multiple colorectal liver metastases whose tumours progressed on preoperative chemotherapy had a 5-year survival rate of only 8%, compared with 37% in those whose tumours responded to chemotherapy. A study by Blazer and colleagues5 supported these results: response to preoperative systemic therapy was an independent predictor of
Patterns of liver injury and associations with chemotherapy
Clinical data have shown associations between specific chemotherapy and histological changes in the liver. However, these associations are observational with many potentially confounding factors. The causative molecular events linking fluorouracil, irinotecan, or oxaliplatin with hepatic injury are not clearly defined, but they can be inferred from studies of other diseases that cause similar histological changes. Because patients are usually treated with a combination of systemic drugs,
Steatosis
The effect of mild to moderate steatosis without associated inflammation on postoperative outcome is likely small (table28, 29, 30, 31, 32, 33, 34, 35). Kooby and colleagues28 found a relation between 30% or greater steatosis and higher BMI in a matched control study of patients with and without steatosis. Among 325 patients with steatosis, 69% had major liver resection, and 77% had colorectal liver metastases. Steatosis was associated with infection-related complications, but not with major
Diagnosis
A heightened awareness of chemotherapy-associated hepatic injury is necessary in patients at risk of non-alcoholic fatty liver disease as a result of obesity, diabetes, or hyperlipidaemia, and in patients who have received long courses of chemotherapy. Liver-function tests are generally not helpful in diagnosis, because many patients have normal laboratory values despite substantial hepatic injury. CT is the most widely used imaging technique to investigate colorectal liver metastases and is
Duration of chemotherapy
To prevent adverse outcomes from chemotherapy-associated liver injury, extended preoperative chemotherapy should be avoided. Nakano and colleagues35 reported an increased risk of sinusoidal dilatation with six or more cycles of oxaliplatin. Karoui and colleagues31 investigated outcomes after major hepatectomy under total vascular exclusion with or without preoperative chemotherapy (fluorouracil with or without irinotecan and/or oxaliplatin). None of the patients who had surgery alone had
Perioperative strategies
Patients with suspected chemotherapy-associated liver injury who need major hepatic resection should have assessment of their functional future liver remnant to minimise postoperative complications. Methods to predict the function of the expected remnant liver include biochemical tests for hepatic clearance of compounds such as indocyanine green, used widely in Asia, and measurement of the future-liver-remnant volume, which is used more in Europe and North America. The future-liver-remnant
Biological treatments
In addition to cytotoxic chemotherapy, targeted biological molecules are increasingly being used for the systemic treatment of colorectal liver metastases. Unlike cytotoxic chemotherapy, biological treatments are not associated with specific histological changes in the liver, although further investigations are needed. Bevacizumab is a monoclonal antibody against VEGF that has resulted in increased response rates in patients with stage IV colorectal cancer and improved progression free survival
Conclusion
Advances in systemic therapy for metastatic colorectal cancer have led to more patients being treated with chemotherapy before hepatic resection. For patients with initially unresectable metastases, preoperative therapy can lead to a decrease in size of metastases and render these patients resectable. For patients with initially resectable metastases, progression free survival improves with perioperative chemotherapy compared with surgery alone. The cytotoxic drugs used for colorectal liver
Search strategy and selection criteria
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