Metastatic Liver Cancer
The liver is second only to the lymph nodes as the most common site for metastases from cancers arising in other sites in the body. For cancers that occur in the gastrointestinal tract the frequency of metastatic disease in the liver is high due to the venous drainage of the gastrointestinal organs via the portal vein which passes through the liver. Therefore, it is not surprising that for tumours such as colorectal cancer, the most common site and, frequently, the only site of metastatic disease is the liver. Other extra-abdominal tumours such as lung carcinoma, breast cancer and malignant melanoma, also spread to the liver to haematogenous dissemination. Therefore, it is clear that metastatic disease to the liver represents a significant oncologic problem.
Colorectal Cancer
Despite the existence of excellent screening and preventive strategies, colorectal cancer (CRC) remains a major public health problem in western countries. Each year worldwide approximately 400 000 people die from colorectal cancer and 700 000 new cases are diagnosed. Colorectal carcinoma is the second leading cause of death from cancer in the US. It is also the third most common malignancy in both men (after lung and prostate cancers) and women (after lung and breast cancers). Approximately 60% of patients will develop metastatic disease, which is localized to the liver alone in half of them.
Treatment options for patients with metastatic colorectal cancer (mCRC) are limited and clinical outcome is generally poor. Surgical resection in selected patients can achieve 25-45% 5-year survival. However, five-year survival in all other patient groups is less than 5%. Systemic chemotherapy can palliate symptoms and improve survival. 5-FU based chemotherapy has been the cornerstone of treatment of mCRC for more than 40 years, and new drugs, such as irinotecan and oxaliplatin, with a definite activity have more recently broadened the options for treatment.
Natural history
By the time they are diagnosed, some 25% of colon cancers will have extended through the bowel wall, whereas cancers of the rectum will have spread through the bowel wall in 50%-70% of patients and metastasized to lymph nodes in 50%-60%.The most common site of extralymphatic involvement is the liver, with the lungs the most frequently affected extra-abdominal organ. Metastatic liver tumours are largely silent until the disease is well advanced. Patients with metastatic colorectal tumours frequently die of hepatic failure due to liver metastases.
Epidemiology
The overall incidence of CRC is nearly identical in men and women. The risk of developing colorectal tumours begins to increase at 40 and rises with age. The incidence of CRC is higher in industrialised regions of the world.
Risk factors
Specific causes of CRC are unknown, but nutritional, genetic and familial factors, as well as pre-existing diseases, such as inflammatory bowel disease or certain cancers, have been found to be associated with this cancer. Risk factors for the development of CRC include high fat diet, daily alcohol use, smoking, decreased physical activity and obesity.
Prognosis
The TNM staging classification is based on the depth of tumour invasion in the intestinal wall, the number of regional lymph nodes involved, and the presence or absence of distant metastases. The pathologic stage at the time treatment is initiated is the most reliable predictive factor of outcome in colorectal cancer. Other prognostic factors, such including age at diagnosis, presurgical carcinoembryonic antigen level, gender, presence and duration of symptoms, site of disease, histological features, obstruction or perforation, perineural invasion, vascular or lymphatic invasion have not consistently correlated with overall disease and survival.
Treatment
In patients with metastatic disease, several studies of combination chemotherapy containing irinotecan or oxaliplatin have shown median survival times of longer than 20 months. The current first-line regimens containing irinotecan and oxaliplatin have become standard therapy. With the recent approval of two targeted agents, an antivascular endothelial growth factor monoclonal antibody, bevacizumab, and the human epidermal growth factor receptor-targeted mAb cetuximab, the clinical outcome for patients is improving.
Colorectal Cancer Liver Metastases
The clinical outcome of patients with metastatic colorectal cancer is frequently determined by the organs to which the cancer has spread. Involvement of the liver is associated with poor survival. The liver is the most common site of metastatic disease in colorectal cancer patients. Liver metastases are present at initial diagnosis in 20% of colorectal cancer cases, and a further 15-30% of patients will develop liver metastases within a period of 3 years.
Treatment
Only a small number of people with liver metastases from colorectal cancer are eligible for curative surgical resection. Strategies have now been developed to resect what in the near past was regarded as 'unresectable disease'. Treatment often develops through multiple stages and requires close cooperation with various specialists. Thus, the optimal management of patients with colorectal liver metastases can only be provided by a team comprising a liver surgeon, oncologist, interventional radiologist and histopathologist, who have an in-depth understanding of the latest diagnostic and therapeutic options formulated through multidisciplinary forums.
Liver Resection
Surgery is the only curative treatment for colorectal liver metastases. Liver metastases from colorectal cancer are unusual, in that surgical resection has been shown to provide long-term survival and cure. Five-year survival rates following resection range between 25% and 39%, with a median survival between 28 and 40 months in most large series. These results sharply contrast with the outcome of non-resected colorectal liver metastases, where the median survival is 5-10 months and 5 year survival extremely rare.
Surgical strategies for unresectable metastases
Although surgery is the only treatment associated with long term survival in patients with CRC liver metastases, the resectability rate has been reported to be between 15-25%. Therefore, given the improved prognosis in patients who have undergone surgical removal of the tumour, strategies have been developed in order to enable patients with initially unresectable disease to have surgery. The main cause of unresectability is the impossibility of removing the entire tumour while leaving a sufficient residual amount of functional liver parenchyma.
Down-staging chemotherapy
The concept of down-staging liver tumours is known in the management of hepatocellular carcinoma, but until recently only a few non-randomized retrospective studies and case reports had been published, in which unresectable CRC liver metastases had been down-staged and made resectable by the use of neo-adjuvant chemotherapy.
Two stage hepatectomy
In selected cases, patients with extensive bi-lobar disease can be treated by a 'two-stage hepatectomy'. Although surgery is contraindicated if complete resection cannot be achieved, this approach justifies leaving some tumour in place, if this can be completely removed at a second resection. Reports also suggest that hepatic resection should be attempted regardless of the number of metastases, providing a complete resection with clear margins is envisaged.
Portal vein embolisation
Resection of CRC liver metastases may not be technically feasible because of the size and distribution of lesions. Even if the liver tumour is technically resectable, surgery may be contraindicated if the anticipated remnant liver is too small, because of the high risk of postoperative liver failure. In these circumstances pre-operative portal vein embolisation can produce atrophy of the affected lobe and compensatory hypertrophy of the future remnant liver. Although most experience with this technique refers to patients with hilar cholangiocarcinoma, there are many recent reports of this technique applied to patients with colorectal cancer liver metastases.
Chemotherapy for Unresectable Metastases
There is renewed interest in local delivery of chemotherapy to the liver in an attempt to increase the effectiveness of chemotherapy against liver metastases.
Hepatic arterial infusion (HAI) of chemotherapy into the liver allows a high concentration of chemotherapy to be delivered directly to the site of the tumour. The rationale for HAI of chemotherapy is that liver metastases are perfused almost exclusively by the hepatic artery, whereas the normal liver is perfused by the portal vein. Further certain drugs are largely extracted by the liver during the first pass, allowing for minimal systemic toxicity. Although intra-hepatic chemotherapy with floxuridine for liver metastases has produced higher overall response rates there was no consistent improvement in survival when compared with systemic chemotherapy.
Other locoregional therapies are being developed for patients with metastases that are not amenable to curative resection. These techniques include cryotherapy, radiofrequency ablation and chemoembolisation.