Liver metastasis (Secondary liver cancer) is not the end of the road in the era of modern liver surgery & transplantation
Cancer deposits within the liver from a site outside the liver are called liver metastases or secondary liver cancers. In fact more than 50% cancers in the liver do not originate in the liver cells but are metastasis from other sites.
Liver is the third commonest site for development of secondary deposits from cancer anywhere in the body. For cancers originating in the stomach, intestine, pancreas, gallbladder/bile duct, colon and rectum; it is the second commonest site after local lymph nodes.
Why is the liver a common site for liver metastasis?
The liver receives blood from the arterial system like other organs and tissues. Additionally nutrient rich blood from the gastrointestinal tract also enters the liver through the portal vein. This dual blood supply exposes the liver to greater risk of receiving circulating tumor cells from cancers anywhere in the body.
The microscopic structure of the liver is unique. it has blood spaces called sinusoids that have lining like blood vessels; but with with gaps in between the adjacent cells. This allows cancer cells that arrive via blood to slip outside the wall into the liver substance more easily than in other organs.
The sinusoids described above are also lined by special immune cells called Kupffer cells that specialise in extraction of abnormal cells and proteins from the blood flowing in the sinusoids. Kupffer cells also extract cancer cells arriving via blood which helps them gain access to the liver.
Metastasis is fortunately an inefficient process!
Fortunately, metastasis is not an efficient process. Less than one in a million cells that reach the liver would develop into metastasis.
Once cells arrive in the liver they usually remain dormant in the absence of conducive environment for them to grow by stimulating factors or factors that enable them to received extra blood and nutrients that help them grow rapidly into metastasis. In certain cancers like breast cancer, the cancer releases factors in the blood that creates sites called pre-metastatic niches within the liver where , if the cancer cells reach, they have higher chances of developing into metastasis.
Cancer cells that come out of dormancy become cell clusters called micro-metastasis. Micrometastasis remain dormant within the liver unless they acquire potential to grown budding blood vessels (angiogenesis), which transforms them into metastatic deposits.
How many cancer patients develop liver metastasis?
As a result of improvement in survival for most cancers, cancer patients are surviving significantly longer for the last three decades than earlier.Advances in radiological techniques have increases the sensitivity of detection of liver metastasis than conventional techniques. In particular metabolic imaging like FDG-PET scanning has increased detecttion of metastasis by more than 25% in most cancers.
It is believed that more than 30% cancer patients will have liver metastasis detected during their lifetime and if autopsy is performed for all patients dying of cancer, 65% would have metastasis in the liver. Importantly in 15-30% of these patients, liver is the only site of metastatic deposits.
More than 30% of patients with cancer in colon and rectum have liver metastasis when the cancer is first detected (synchronous) and more than 70% develop liver metastasis after treatment of their colonic or rectal cancer (metachronous).
Liver metastasis is the end of the road....myth or fact?
Traditionally the detection of liver metastasis has been considered the end of the road for many years. Barring liver metastasis from slow growing and indolent neuroendocrine tumours, patients with liver metastasis are likely survive less than 2 years after diagnosis.
In the modern era of multidisciplinary cancer management, systemic chemotherapy has become more effective, safe and molecular targets within cancer cells have been identified in some cancers for specific non-cytotoxic targeted therapy. With these advances, survival even after detection for liver metastasis has progressively improved but yet long term survival (>5yrs) has been unachievable by this modality alone for most cancers. However chemotherapy alone cannot cure liver metastasis unless all cancer cells are conlusively shown to be killed within the metastasis. Sadly more than 50% liver metastasis that show reduction in size or completely disappear on scans (ghost lesions), have viable tumor cells under the microscope.
With improvements in technology, safe anaesthesia practices, better imaging and greater experience in liver surgery, the procedure has become safer and is regularly being performed with near 0% mortality.Liver surgery has been therefore increasingly applied to metastatic liver disease in the hope that removal of liver metastasis would help in prolonging survival. Despite good safety profile, long term survival with surgery alone has also been disappointing. Surgery is unable to treat micrometastasis, circulating tumor cells and dormant cells because they cannot be detected on current imaging modalities...therefore systemic therapy has to be married to surgery when treating liver metastasis for most patients if long term survival is to be achieved.
With greater experience, combination of systemic therapy and surgery has been introduced for management of liver metastasis with much better outcomes over the last 15 years with survival exceeding 50% at 5 years for liver metastasis from colon, rectum, breast, ovary/testis, neuroendocrine cancer using peri-operative systemic therapy and surgery in selected patients.
All over the world, surgeons haveperformed liver transplantation for patients with large metastasis from slow growing neuroendocrine tumors that are not amenable to excision, with good results (even better than for hepatocellular carcinoma) and this is accepted universally. One of the most famous recipients of a liver transplant for such metastasis was late Steve jobs of Apple.
Recently a group from Norway showed excellent results after liver transplantation for liver metastasis from colorectal cancer and the idea is evoking interest all over Europe. However this is yet to gain acceptability elsewhere.
A perusal of published literature on liver surgery for liver metastasis brings forth the following points
- Liver resection, if safely performed, to remove all existing liver metastases is useful for all cancers
- Patients should be selected based on medical fitness, extent of tumor in liver & experience of treating team
- It must be part of multidisciplinary strategy that includes systemic therapy & interventional radiology
- Best survival is obtained after complete excision of liver metastasis is obtained if the metastases are few in number, confined to the liver, if the metastasis are sensitive to chemotherapy and appear many years after the primary tumour has been treated.
Therefore in the modern era, in selected patients, liver metastasis is definitely not the end of the road. This statement is particularly true for patients with liver metastasis from cancer of the colon or rectum, neuroendocrine tumors, breast cancer, testicular & ovarian cancer and gastrointestinal stromal tumors (GIST).
All patients with liver metastasis benefit from liver directed therapy, choosing the appropriate therapy and at the right time is important for optimum outcome.
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