Metastatic carcinoma of the liver is far more common than primary malignant hepatic tumours. Until 1980, the treatment of metastatic carcinoma of the liver was largely expectant. The last 12 years have, however, seen a dramatic change in the management of this disease. Patients who have developed liver metastases are now assessed with a view to resection or chemotherapy. In addition, patients who have undergone curative resection for colorectal cancer and who are at risk of developing metastatic liver cancer are now routinely screened by sonography and serial estimation of carcinoembryonic antigen to detect hepatic metastases before they have developed beyond curative hepatic resection.

Because of the portal venous circulation, blood-borne metastases from gastrointestinal carcinomas usually appear first in the liver; spread of other carcinomas, such as those originating from breast and lung to the liver is usually indicative of widespread disseminated disease. Hepatic metastases from colorectal cancer are common, sometimes solitary, and slow to progress; they may occur without evidence of dissemination elsewhere. For this reason, patients with metastases from colorectal cancer form a special group. This is also true of patients with metastases from carcinoid or neuroendocrine tumours of the gastrointestinal tract and pancreas, in whom disabling symptoms attributable to the secretion of peptides and other vasoactive substances may occur. In patients with the carcinoid syndrome, hepatic resection to relieve symptoms may be indicated, while chemotherapy and embolization may are often effective in the treatment of the Zollinger–Ellison and VIPoma syndromes.

Although patients with unresectable hepatic metastases occasionally survive for more than 5 years, the median survival is under 6 months. Much depends upon the site and nature of the primary tumour and the extent of disease at the time of presentation.

Metastases from cancer of the colon and rectum are slower to develop than metastases from carcinomas elsewhere. The median survival of patients with hepatic metastases from colorectal cancer is 177 days compared with 75 days for patients with metastases from carcinoma of the stomach and 54 days for patients with metastases from carcinoma of the pancreas. The survival of patients with hepatic metastases from carcinoid tumours and other tumours of neuroendocrine differentiation may be very prolonged.

As would be expected, the greater the proportion of the liver affected by metastases the shorter the survival of the patient. The extent to which the liver is affected by metastatic disease can be assessed by ultrasound or CT imaging, or by palpation at laparotomy. In either case, it is important to assess the approximate proportion of the liver that is replaced by metastases and whether the distribution of the metastases is such that curative resection may be contemplated. Three groups are described, according to the percentage of liver tissue replaced by metastases: less than 25 per cent replacement, 25 to 75 per cent replacement, and greater than 75 per cent replacement of the liver parenchyma. For patients with liver metastases at the time of resection of a colorectal cancer, the mean survival is 3.4 months for those with greater than 75 per cent hepatic replacement compared with 6.2 months for patients with less than 25 per cent hepatic replacement. Similarly, patients with widespread metastases have a mean survival of 3.1 months, compared with 10.6 months for patients with multiple but potentially resectable metastases and 16.7 months for those with solitary metastases.

The grade of the tumour also has a bearing on the prognosis. The mean survival of patients with metastases from colorectal cancer that are well or moderately differentiated on histological examination is 13 months, compared with 7 months for patients with poorly differentiated tumours. The histological grade of hepatic metastases, determined by Broder's classification confirms a mean survival of 11 months for grades 1 and 2 compared with 7.6 months for grade 3 and 5.5 months for grade 4.

Hepatic metastases may be an incidental finding during the preoperative assessment or at laparotomy in a patient with a carcinoma. The presence of hepatic metastases is a contraindication to surgical resection of gastric, pancreatic, or oesophageal carcinoma. The presence of hepatic metastases increases the morbidity and mortality of surgical resection for colorectal cancer. The operative mortality rate may be as high as 22.7 per cent for patients undergoing resection of a carcinoma of the colon or rectum in the presence of liver metastases compared with 4.6 per cent for those without liver metastases.

Some patients may develop symptoms and signs attributable to the liver metastases. Acute abdominal pain from necrosis of or haemorrhage into a hepatic metastases may be confused with acute cholecystitis, right ureteric colic, or appendicitis. Hepatic metastases may also present with a mass, fever malaise, jaundice, and pruritus.

The presence of hepatomegaly, ascites, and peritoneal spread adversely affects the prognosis of hepatic metastases. The survival of patients with hepatomegaly is 7.7 months, compared with 14.3 months if the liver is not palpable. Ascites, if present, is associated with a survival of 3.8 months compared with 13 months if absent. Of the biochemical estimations, the serum alkaline phosphatase is the most important with regard to prognosis. The survival of patients with colorectal cancer liver metastases is 2.8 months if the alkaline phosphatase level is elevated compared with 6.2 months if normal.

Hepatic metastases detected as a result of routine screening after apparently curative resection of a colorectal cancer are associated with a better prognosis, first because the early detection of hepatic metastases gives the best chance of surgical resection and the only hope of cure and second, because the earlier the metastases are detected, the longer the patient will survive with his metastases. The best method of screening is as yet undetermined. Examination of the liver by ultrasound at yearly intervals is currently the favoured method. However, it is interesting to note that the majority of patients undergoing hepatic resection for metastases from colorectal cancer are detected on investigation of an elevated carcinoembryonic antigen level, and very few from isotope or sonographic imaging.

The majority of patients with hepatic metastases present with disease that has spread beyond surgical resection: only about 5 per cent of patients with hepatic metastases from colorectal cancer are suitable for surgical resection. The survival of patients undergoing resection of hepatic metastases is 25 per cent at 5 years, and 1 to 2 per cent of patients with colorectal cancer could therefore be cured by resection of their hepatic metastases. As 24000 patients a year are registered with a diagnosis of colorectal cancer in England and Wales, approximately 1200 patients may benefit from resection of hepatic metastases and 300 patients a year could be expected to be cured.

Resection, or some other new modality, such as alcohol ablation, are the only hopes of cure. Hepatic resection for metastases is, however, associated with an operative mortality of 5 per cent and serious morbidity of up to 30 per cent. While the postoperative stay may be as short as 13 days, it may be several months before the patient regains his preoperative strength and vigour. Before considering hepatic resection, the potential benefits must be weighed against the risks. The patient must be in good general health and fit enough to withstand major abdominal surgery. Advanced age in its own right is not a major contraindication to hepatic resection for colorectal cancer metastases, although few such resections have been performed in patients over the age of 80. Local recurrence and metastases other than those in a resectable portion of the liver are also a contraindication to hepatic resection. Several studies have analysed subgroups of patients undergoing hepatic resection for colorectal metastases in order to identify factors which may indicate a better prognosis.

Features relating to the primary colorectal carcinoma have proved disappointing in determining the prognosis after resection of hepatic metastases. Hepatic metastases from Duke's A colorectal carcinomas are very rare. Opinion is divided as to whether patients with liver metastases from Dukes' C colorectal carcinomas fare worse than those with metastases from Dukes' B carcinomas (Table 1) 361.

The histological grade of the primary tumour or its metastases would be expected to have a bearing on the prognosis. The mean survival after resection of metastases from poorly differentiated tumours is 7.1 months compared with 17.9 months for moderately or well-differentiated tumours. In another series, none of nine patients with poorly differentiated tumours undergoing resection of hepatic metastases survived to 3 years while the 5-year survival of 77 patients with well or moderately differentiated tumours was 20 per cent. However, as few patients with poorly differentiated tumours undergo resection of hepatic metastases, statistical significance is difficult to demonstrate. The primary site, whether colon or rectum, the age and gender of the patient, and the preoperative carcinoembryonic antigen level do not have any significant effect on prognosis following resection of hepatic metastases. Patients with symptomatic hepatic metastases fare worse than patients whose disease is asymptomatic. However, as patients who have developed symptoms from their metastases may be presumed to have more advanced disease, the better survival of asymptomatic patients may be attributable to a lead time bias.

The success of resection of metastases from colorectal cancer depends on the technical ability to resect with a wide margin the portion of the liver containing the disease. Most reports show trends towards a better prognosis in patients with solitary metastases compared with those with multiple metastases, or less than four metastases compared with more than four. Similarly, survival is marginally better in patients with metastases less than 5 cm in diameter. However, failure to resect all the metastatic cancer, direct involvement of adjacent structures by the hepatic metastases, or involvement of the portal triad lymph nodes is associated with a significantly worse prognosis. Similarly, the 5-year survival of patients whose hepatic resection margin is less than 5 mm is 9 per cent, compared with 23 per cent for patients with a greater resection margin.

Following resection of hepatic metastases, approximately one-third of patients develop recurrence in the liver alone. Such patients should be reassessed with a view to a second resection; several successful repeat hepatic resections have been performed.

Resection of metastases from carcinoma of the lung, stomach, or pancreas carries a poor prognosis and is not justified. Resection of metastases from carcinoma of the breast may be justified if the patient is symptomatic and if hormonal therapy or chemotherapy fails to control symptoms; long-term survival has been reported. Patients with metastases from carcinoid tumours and other neuroendocrine tumours may benefit greatly from palliative resection to alleviate symptoms due to the secretion of vasoactive substances and peptides. Such metastases may have a well-defined plane around them which allows the metastasis to be enucleated. Although such resection is palliative, the survival may be measured in years and the relief of symptoms dramatic.

Despite two decades of intense clinical investigation, colorectal cancer metastatic to the liver remains highly resistant to systemic chemotherapy. Only the fluoropyrimidines (5-fluorouracil (5-FU) and flurodeoxyuridine) have shown a consistent therapeutic activity, and numerous studies have not demonstrated any other agent to be superior to these drugs. A large number of trials have evaluated the efficacy of combination chemotherapy but often promising initial results have not been reproduced. A report of 10 different chemotherapeutic treatments in 848 patients with colorectal cancer showed that none was superior to 5-FU. Systemic 5-FU induces an objective response in 15 to 20 per cent of treated patients, without prolonging life. A similar response rate of 23 per cent for hepatic metastases has been observed.

There is substantial evidence, mainly for tumour cell cultures studies, to suggest that antitumour agents have a steep dose–response relationship. Hepatic artery or portal venous cannulation and regional chemotherapy will result in higher regional concentrations of chemotherapeutic agents in the liver. Thus, hepatic artery or portal venous infusion of 5-FU may be indicated in patients with unresectable liver metastases in whom there is no evidence of local recurrence or dissemination elsewhere. Although the metastases in the liver are thought to originate from dissemination via the portal venous circulation, once developed, they derive their chief blood supply from branches of the hepatic artery. One prospective randomized trial has reported a response rate of 34 per cent following hepatic artery infusion of 5-FU compared with 23 per cent following intravenous administration of 5-FU. However, no effect on survival has yet been demonstrated.

In distinction to the treatment of patients with metastases from colorectal cancer, chemotherapy may have an important role in their prevention. A trial, of postoperative portal venous perfusion of 1 g of 5-FU compared with no adjuvant treatment in 257 patients suggests that untreated patients are at twice the risk of dying than treated patients. The results of a multicentre trial of adjuvant perioperative 5-FU are awaited.

Liver metastases can be treated by embolization of their blood supply. A cannula is introduced into the femoral artery and advanced until the coeliac axis has been cannulated. An angiogram is then performed and the vessels supplying the metastases identified. If possible, these vessels are then superselectively cannulated. Absolute alcohol, gelfoam, or steel coils may be introduced to occlude the blood supply.

Embolization is most effective for patients with hepatic metastases from neuroendocrine tumours since it reduces the symptoms attributable to the secretion of vasoactive substances. Embolization via the hepatic artery has not been shown to improve survival of patients with metastases from carcinoma of the colorectum and other gastrointestinal malignancy.

Apart from occasional complications of arterial puncture, haematoma formation, arterial dissection, and thrombosis, embolization of a hepatic metastasis may result in pain, fever, and leucocytosis. This post-embolization syndrome affects up to 50 per cent of patients undergoing this procedure and may last for a week. Septicaemia or hepatic abscess may develop in up to 10 per cent of patients.

The efficacy of radiotherapy in the treatment of metastases in the liver is limited by the radiosensitivity of normal hepatocytes and the relative insensitivity of metastatic carcinomas. The maximum dose which can be administered before inducing radiation hepatitis is 35 Gy; this dose is too low for curative irradiation of metastatic carcinomas. Radiotherapy is occasionally useful in the palliation of severe pain from hepatic metastases but does not prolong survival.

Because hepatic metastases derive their blood supply mainly from the hepatic artery, simple ligation of the hepatic artery or full arterial devascularization of the arterial supply to the liver has been attempted in the treatment of patients with liver metastases. Metastases that are highly vascular, such as carcinoid tumours, may show a better response. A transient decrease in tumour size without improved survival has been reported following hepatic artery ligation and devascularization. The rapid re-establishment of arterial flow through collateral supply limits the efficacy of this technique.

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