Liver Metastasis (Secondary liver cancer): is it the end of the road?

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

1. Liver resection, if safely performed, to remove all existing liver metastases is useful for all cancers
2. Patients should be selected based on medical fitness, extent of tumor in liver & experience of treating team
3. It must be part of multidisciplinary strategy that includes systemic therapy & interventional radiology
4. 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.

 

World Hepatitis Day 2014: Hepatitis is closer than you think....think again

Hepatitis....know it...confront it

Hepatitis is a term used for inflammation of the liver cells due to any cause

Causes of hepatitis

1. Viruses: hepatitis viruses A-H, non-hepatitis viruses: herpes, cytomegalovirus etc
2. Bacteria
3. Parasites
4. Drugs
5. Chemicals & toxins including alcohol

It can manifest in two forms

Acute hepatitis

Recurrent hepatitis

Chronic hepatitis

Common routes of transmission of hepatitis are through contaminated food and drink (feco-oral route), through blood & blood products (parenteral route) and sexual contact.

Transmission through placental circulation from pregnant infected mother to child in the womb is called vertical transmission.

Acute hepatitis is characterised by abdominal discomfort, low-moderate grade fever, nausea, lethargy and loss of appetite. Most viral infections are associated with feeling of uneasiness, weakness, body pain before development of jaundice (prodrome). Jaundice is the hallmark of acute hepatitis and is usually detected by yellow discolouration of eyes and passage of dark yellow urine. Liver function tests show raised bilirubin level (mainly conjugated) accompanied by elevated liver enzymes (AST, ALT and frequently ALP). Urine shows elevated bile salts. Massive elevation of enzymes >1500 IU is rare. High fever usually indicates concurrent inflammation within the biliary system (cholangitis).

Acute hepatitis is a self-limiting disease and in most cases with supportive care, complete uneventful recovery results over a period of a few weeks. Recovery may be prolonged in elderly patients, pregnant women, those receiving medication to reduce immunity or those who have pre-existing liver damage from alcohol, fatty liver or other causes.

Alcoholic hepatitis is a unique form of hepatitis that occurs after years of large consumption of alcohol. It usually follows a binge of alcohol but can occasionally seen in early phases of abstinence. 

It is a severe form of hepatitis that causes a systemic inflammatory state often associated with infection, kidney dysfunction and progression to liver failure. The underlying liver is usually pre-cirrhotic or frankly cirrhotic in patients with alcoholic hepatitis. Many patients with alcoholic hepatitis have muscle wasting and nutritional defects making them prone to infections and multi organ failure leading to significant mortality despite supportive care.

In less than 5% cases, the liver damage caused by inflammation overwhelms the body immunity and the capacity of the liver to repair and regenerate. In such situations patients may progressively and rapidly develop cardinal features of liver failure : Deep jaundice  Mental changes (Encephalopathy & Clotting dysfunction. This syndrome is called Acute liver failure if patient had normal liver to start with and Acute on chronic liver failure if patient has a recognised or unrecognised chronic liver disease to start with.

Both are very severe conditions and if condition does not respond to medical measures, can be fatal.

Chronic hepatitis is usually the result of persistent or recurrent damage or the failure of immunity to clear the acute infection or insult. Chronic hepatitis is seen in 20-30% most of which is due to hepatitis B or C virus infections. Common hepatitis virus A is never chronic while less common hepatitis can rarely cause chronic infection.

Chronic hepatitis can follow an indolent course being asymptomatic for years before detection. Until liver damage has exceeded the reserve of the liver, liver function tests may be normal apart from subtle alterations.

The chronic inflammation in the liver can lead to development of primary liver cancer ( hepatocellular carcinoma) in unto 4% patients with chronic hepatitis every year.

Chronic inflammation can also lead to progressive scarring and changes in the micro architecture  of the liver leading to fibrosis and eventually cirrhosis. Once cirrhosis develops, the average survival is less than 10 years in most cases. Progressive damage can lead to features of chronic liver failure like jaundice, accumulation of fluid in abdomen (ascites), clotting deficiency and mental changes (hepatic encephalopathy). Reduction in liver function reduces immunity leading to increased propensity for infections and strain on other organ systems. In such a state average survival is less than one year.

Once cirrhosis develops the risk for developing hepatocellular carcinoma doubles to 8% per year.

As in most diseases, prevention is better than cure

Prevention of hepatitis

1. Consumption of safe food and drink
2. Vaccination: hepatitis B, hepatitis A
3. Avoid alcohol & IV drug abuse
4. Avoid unprotected high-risk sexual activity
5. Avoid contaminated syringes, needles, blood and blood products
6. Manage body weight & keep diabetes in check

Early detection of hepatitis

1. Periodic health checks
2. Screening of high risk patients
• children of parents with liver cancer or hepatitis
• siblings & spouses of patients with liver cancer or hepatitis
• patients receiving blood products (haemophiliacs, thalassemics) or dialysis
• iv drug abuse history
• high risk unprotected sexual activity & commercial sex workers
• healthcare workers
• patients with suppressed immunity or those on immunity reducing drugs

Treatment of hepatitis

1. Most cases of acute hepatitis need only supportive care
2. No specific treatment available for most viral hepatitis except hepatitis B and C
3. Inciting cause should be detected, avoided and treated accordingly
4. If acute or acute on chronic liver failure results patients should receive ICU management including ventilator support: some patients who don't respond can be salvaged by urgent liver transplantation
5. Measures to prevent developing chronic hepatitis & cirrhosis should be taken
6. Patients with chronic hepatitis should be aggressively followed for detection of cirrhosis or development of cancer
7. Early cases of liver cancer can be cured by liver surgery if there is no cirrhosis. If thesre is cirrhosis, liver transplant is the best option
8. Patients with complications of liver cirrhosis can be salvaged with liver transplant
9. Measures to prevent recurrence of hepatitis should be instituted even after transplant