Battling Asia’s war on liver cancer.
by Dr Choo Su Pin
Liver cancer, or hepatocellular carcinoma (HCC), is an Asian men’s disease. Almost 80 percent of the world’s HCC cases and deaths from HCC occur in Asia; with a four to one ratio of men to women. According to the latest World Health Organisation (WHO) figures, more than half of the 20 countries with the highest rates of liver cancer in the world are in Asia-Pacific (APAC).
The figures may be even higher as there are some countries in Asia with very high incidence of the disease but no effective registries or records; countries like Myanmar and Laos have no accurate source of data. Others, like Indonesia, have national registries which cover the big cities but do not effectively cover the less developed rural areas. It is suspected that there may be even more HCC in Asia and that people are dying in rural areas without HCC ever being identified as the cause.
HCC is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Cirrhosis is a late stage of scarring (fibrosis) of the liver caused by many forms of liver diseases and conditions, such as hepatitis and chronic alcoholism.
Like any other part of the body, the cells in the liver can undergo changes to form cancer. Scientists believe HCC possibly starts when hepatic stem cells in the liver responsible for repairing it start to multiply out of control in response to chronic liver damage but that remains the subject of investigation.
HCC liver cancer is called a primary malignancy because it starts with mutation and proliferation of cells in the liver. Cancerous cells that start from other parts of the body and spread to the liver, for example, colon cancer that has spread, does not constitute liver cancer in the strictest sense. These are known as secondary liver tumours or metastatic cancers to the liver.
People have postulated that the high HCC incidence rate in Asia might have something to do with hormones or genetics but while there has been some research to indicate some form of genetic factor among East Asians. The main reason liver cancer occurs predominantly in Asia is because Asia has the highest rates of hepatitis B infection; the biggest risk factor for developing HCC.
Apart from chronic hepatitis B and hepatitis C infection, other risk factors include tobacco smoking, obesity, diabetes, non-alcoholic fatty liver disease, alcoholic liver cirrhosis, non-alcoholic causes of cirrhosis and non-alcoholic steatohepatitis (NASH) which is an advanced form of non-alcoholic fatty liver disease. Worldwide hepatitis infection is responsible for 65 percent of HCC cases but in Asia, it accounts for 80 percent. In Europe and the United States, the majority of cases are due to lifestyle risk factors such as alcohol drinking, obesity, smoking, and hepatitis C infection from shared drug paraphernalia and the use of anabolic steroids.
Mongolia as an example of a perfect storm of risk factors. It has the highest per capita rates of HCC in the world because it has very high rates of hepatitis B and C infections and a plethora of alcoholic problems.
When the hepatitis infection rates are reduced, especially hepatitis B, there is a general decline in the number of HCC cases. Taiwan has reported a decrease in the number of HCC cases in recent years due to the fall in hepatitis B rates since they started vaccinating new born babies in the 1980s.
Singapore also introduced vaccination for babies in the 1980s and the benefits are becoming apparent. It will take one or two generations to get the issue under control but generally, there are fewer cases of HCC in young people under 40. Babies being infected by their mothers is the most common cause of hepatitis B infection so screening at birth and vaccination is the best way to reduce the rates.
Thirty years ago, hepatitis B was responsible for 80 percent of the HCC in Singapore just like the rest of Asia. Today, it is only responsible for about 50 percent of the cases. Although there has been a decline in the number of HCC cases and hepatitis B related cases, unfortunately Singapore has now seen an increase in the number of lifestyle related cases such as non-alcoholic fatty liver disease and NASH, due to increasing numbers of overweight and obese people. Fatty liver disease is now the second most common cause of HCC in Singapore, responsible for many more cases than hepatitis C and alcoholic cirrhosis combined.
Even people who are not visibly obese can develop fatty liver disease because it is related to the amount of visceral fat, the fat stored around the internal organs rather than the subcutaneous fat stored just beneath the skin. Indicators of high levels of visceral fat are having an apple body shape or having a pronounced and firm pot belly. Subcutaneous fat is also what causes fleshy thighs, love handles and other pinchable inches.
High mortality rates
The reason HCC can be so deadly is because the liver is vital to life; it is a major organ and carries out important functions such as manufacturing various essential proteins, processing and storing nutrients like glucose and ketones, and detoxifying harmful substances in your body.
The prognosis upon diagnosis is often poor because many patients are not diagnosed until the cancer is quite advanced which then limits their treatment options. If detected early for instance, before it has spread and invaded blood vessels, a resection called a partial hepatectomy can be performed to remove the tumour. With successful curative surgery, the chance of survival beyond five years is more than 40 percent.
Sometimes, a liver transplant is recommended as it removes both the cancer as well as the underlying diseased liver. Five year survival after transplant can be as high as 70 percent.
Unfortunately, the majority of patients are not suitable for surgery as their cancer is too far advanced by the time it is discovered. In its early stages, HCC is largely asymptomatic, people do not show any signs of illness such as fever, pain or swelling in the early stages. Very often, HCC is only picked up by chance when patients are being treated and examined for something else.
The importance of screening
There is a general lack of awareness when it comes to screening. Many high-risk patients, even those who know they are hepatitis B carriers, do not get screened regularly. There is a need for more education among high-risk groups and general practitioners to encourage regular screening.
Screening is important for early detection and prognosis for the patient. For high-risk patients, for example those with known hepatitis B or C, known chronic cirrhosis of any sort, or have fatty liver disease should insist on regular screening. Every year or two for those under 40, annually or every six months for those in their 40s and older.
In Singapore, the Ministry of Health (MOH) guidelines recommend patients with established hepatitis B or C carrier status or with liver cirrhosis would benefit from six-monthly alpha-fetoprotein (AFP) estimations and ultrasound examinations.
Increased AFP levels may indicate the presence of cancer. When the AFP concentrations of people with chronic liver disease go from normal or moderately elevated to greatly elevated, their risk of developing liver cancer increases. If a patient’s AFP levels are raised or an ultrasound detects unusual masses or unusual density, the next step is usually a CT or MRI scan or sometimes a biopsy for a more accurate assessment.
If the cancer is detected too late and a curative resection or transplant is no longer feasible, then there are various treatment options to control the cancer and prolong survival.
When the cancer is localised to the liver, loco-regional therapies like radiofrequency ablation (using heat to destroy the cancer), chemotherapy directed into the liver (TACE) or radiation directed into the liver (radiation beads released directly into the liver tumour) are used.
For more advanced stage IV liver cancer or when loco-regional therapies mentioned above are no longer feasible, oral sorafenib, a multi-kinase targeted therapy, has been shown to prolong patients’ survival. More recently, there is a new, second-line drug that has been approved in Singapore and some Asian countries, regorafenib, a multi-kinase targeted therapy which has been shown to prolong survival.
The first drug for treating advanced HCC and extending patients’ lives came out in Singapore in 2007, it was called sorafenib (Nexavar). For 10 years, it was the only drug for patients who were not suitable for surgery.
For a decade, there were no second-line drugs to offer if patients failed to respond to sorafenib or stopped responding to it after a few months. During that period, many companies were trying to find an alternative first-line drug to sorafenib. There have been 70 other drugs evaluated for patients with advanced HCC in all phases of clinical trials, but these drugs have shown no additional success over sorafenib, compelling a necessary reassessment of this complex cancer. The search for a second-line drug was not successful until Bayer came up with regorafenib (Stivarga), which was the first drug to show survival benefit in a second-line setting for liver cancer.
The data for the positive use of regorafenib as a second-line therapy for selected patients with advanced liver cancer patients was first presented in January 2017. Regorafenib is not a new drug, doctors have been using it for colorectal cancer, but its use in treating HCC is new. The median survival time for advanced liver cancer before regorafenib for patients on the first-line drug sorafenib was less than a year. The international, phase III RESOURCE trial, which studied the efficacy and safety of regorafenib as a second-line treatment after progression on sorafenib for HCC patients, found that the mean survival rate of patients involved in the trial was 26 months from the time they started the sorafenib, regorafenib progression; which is a long time for advanced liver cancer. It proved to be a significant improvement for this group of patients.
HCC is not entirely preventable, but people can certainly reduce their risk. There are some rare, non-lifestyle congenital conditions (alpha-1 anti-trypsin deficiency), and haemachromatosis, but the top four risk factors are within people’s personal control to avoid.
Compulsory vaccination at birth against hepatitis B, which is now widespread in many Asian countries, is the first and most important step. Following, lifestyle choices and hygiene also play a role in reducing HCC risk. Drink little or no alcohol, practice safe sex, eliminate the use of tobacco, drugs and do not share needles. Having multiple sexual partners and associating with sex workers significantly increase the risk of hepatitis B and C infection. Exercise and eat a healthy balanced diet to maintain a healthy weight to avoid diabetes and fatty liver disease. These choices if heeded, will dramatically reduce the rates of HCC and many other diseases.
Dr Choo Su Pin is an adjunct Associate Professor at Singhealth Duke-NUS Oncology Academic Clinic Programme, Duke-NUS Graduate Medical School Singapore. She is also an adjunct Associate Professor, Department of Medicine, Yong Loo Lin Medical School, National University of Singapore, and the Chair of the Clinical Trials Steering Committee at the National Cancer Centre Singapore.