Targeting liver cancer in China

He looks tired as he rushes into his office at 4pm and finally sits down. He has just completed interventional treatment on three patients with liver cancer in the afternoon, having already seen around 30 patients in the morning: a busy, but typical day in the centre.

In China, every year nearly 400,000 people are diagnosed with liver cancer, and around 368,000 people die from it;1 and although China contains less than 20% of the world’s population,2 it experiences almost half of all new liver cancer cases.1,3 Hepatocellular carcinoma (HCC) represents approximately 90% of all cases of primary liver cancer4 and develops predominantly in those people with cirrhosis, or scarring, due to chronic hepatitis B or C.5

The Jiangsu province in East China is at the epicentre of China’s liver cancer epidemic: not only does this region have a high incidence of hepatitis B, the warm, wet climate further increases people’s risk. Certain moulds that flourish in these humid conditions produce a highly carcinogenic substance called aflatoxin, which can sometimes be spotted because it turns rice yellowish: “The rice is more susceptible to becoming contaminated in the South-east, due to the climate,” says Professor Ren.

He didn’t set out to study liver cancer, but these unusual features of the disease in China piqued his interest. And as his career has progressed, there has been a subtle shift in the type of patients coming through his doors: now, as well as being kept busy with a constant stream of new patients, he sees a growing number of cancer survivors returning for check-ups and tweaks to their ongoing treatment.

Earlier diagnosis, together with the availability of new and more effective treatments, means that people with HCC are surviving for longer than ever before. Over the past decade, strides have also been made in understanding the biology of HCC – including identifying the key genetic changes responsible for initiating and driving tumour growth.

Liver cancer certainly hasn’t been cured, but progress has been made nevertheless. Professor Ren remembers learning about liver cancer when he was younger and being aware of the particularly poor prognosis for those diagnosed with the disease: “Without modern imaging techniques patients were seldom found at the early-stage. Added to that, there were no efficient therapies for patients at the advanced stage, the only option was chemotherapy but liver cancer was not efficacious to it.”

In the 1970s China began work to improve the prognosis for a range of cancers, including liver cancer. The government launched a research programme to study cancer and set up the Cancer Prevention and Control Office (CPCO). One of the most important things it did was launch a liver cancer screening programme in high incidence regions, making it one of the first countries to do so. “At that time, most patients diagnosed with liver cancer were in the advanced stage of the disease and would live for only several months. However, with the introduction of an assay, which measures the levels of alpha-fetoprotein (AFP), a protein that is elevated in many people with the disease, some patients were found at an early-stage,” says Professor Ren.

One problem is that many of the signs and symptoms of liver cancer, such as jaundice, rapid weight loss and liver enlargement (which may present as pain and swelling of the abdomen) don’t occur until the later stages of the disease. The liver plays an essential role in breaking down nutrients from the diet and filtering toxins from the blood, but it can continue to function well, even if only part of it is working. At the early-stage there are few obvious symptoms so they can easily be dismissed or overlooked.

Today, doctors have advanced imaging equipment, such as MRI or CT scanners, which they can use to detect tumours, but back then, many regions of China didn’t even have ultrasound machines. Instead, doctors travelled to the coastal area of Southeast China, with the support of the local government, to organise the adults in their communities – most of whom worked in the fields – to provide a blood sample, which could be tested for AFP. Levels of AFP are elevated in 50-70% of people with HCC, so measuring for AFP enable them to be referred for further diagnostic tests, meaning treatment can be started before they even show typical symptoms. The latest developments in screening methods, such as using ultrasound imaging in combination with measuring AFP levels twice a year, in the HCC high-risk population have become more efficient, especially for hepatitis B and C carriers, or patients who have liver cirrhosis.

After China introduced liver cancer screening, the five-year survival rate for these early-stage patients climbed to 60-70%, whereas previously, most would die within a few months due to late-stage diagnosis. Recognising China’s progress in liver cancer prevention and treatment, in 1979, the National Cancer Institute of America presented Professor Tang Zhaoyou, a senior expert from Zhongshan Hospital, and then chairman of the Liver Cancer Institute of Zhongshan Hospital of Fudan University, with a Golden Award.

However, even with screening in place, many patients were still diagnosed at a late-stage and / or with severe liver cirrhosis and had to be treated with palliative therapy, making their survival prospects grim.

A breakthrough came in 2006, when a new class of drugs called tyrosine-kinase inhibitors became available to patients. Unlike chemotherapy, which kills all rapidly growing cells, these ‘targeted therapies’ act on specific molecules that tell cancer cells to grow and spread. “In the past we could do nothing about advanced stage liver cancer and the efficacy of chemotherapy was not good,” says Professor Ren. However, thanks to these new targeted agents, average survival rates have increased from several months to closer to a year. New targeted agents are currently being tested in HCC patients, for example some novel immunotherapies, which enhance the body’s natural ability to recognise and destroy cancer cells, have been approved for use in subsets of HCC patients.

Meanwhile, progress is also being made in preventing the disease. “In the past, in the high incidence areas, people washed clothes and vegetables in the river and used the water obtained from the same river for drinking and cooking. Some families even lived on boats on the river,” says Professor Ren. Not only did these humid conditions promote the growth of aflatoxin-producing moulds, but drinking polluted water also increases the risk of HCC and other cancers of the digestive system. “In the 1980s, we realised the problem and the strategy to ‘improve water, prevent mildew and hepatitis’ was put in place,” says Professor Ren. People were encouraged to use tap and well water for drinking and to improve grain storage conditions. In the 1990s, the Chinese government also began vaccinating infants against hepatitis B, which is responsible for more than 80% of Chinese liver cancer cases, and it introduced universal vaccination of infants in 2002.

The hepatitis B virus is mainly transmitted through direct contact with blood and infected body fluids and causes cirrhosis of the liver, which increases the risk of HCC, as well as damaging the DNA in liver cells more directly.

Although the overall incidence of liver cancer in China has not significantly declined, it is now starting to fall in adolescents in some high-incidence areas, which Professor Ren attributes to vaccination.

Indeed, Taiwan recorded a halving in the incidence of childhood HCC in the decade after it introduced universal hepatitis B vaccination in 1984 and, as this cohort has aged, this decrease in cases has been observed in adolescents, and now young adults.

However, many adults are already infected with the virus and average life expectancy in China is increasing, which means that more people are living to an age where advanced liver cancer begins to manifest itself. Anti-viral drugs can reduce the risk of developing HCC, but other etiologic factors exist, including hepatitis C infection, alcohol intake, diabetes mellitus and non-alcoholic liver disease.

Greater public awareness of HCC is essential – as is equipping Chinese physicians with the skills to recognise and treat it. Thanks to the work of the Chinese Liver Cancer Society, the China Anti-Cancer Association and the Chinese Medical Association, a series of guidelines for liver cancer and hepatitis were released to enable many more physicians nationwide to treat patients with the disease effectively. “In the past, liver cancer patients who were diagnosed in remote areas had to travel to Beijing or Shanghai for surgery,” says Professor Ren. In 2011, the Ministry of Health also issued guidelines for the standardised treatment of liver cancer, which is enabling more patients to access high-quality care.

Even so, more research into the disease is urgently needed. Unlike some other cancers, which may be caused by a small number of clearly defined genetic mutations, liver cancer has complex mechanisms, which can vary between different disease stages and patients. Furthermore, even if tumours initially respond to targeted drugs, they may develop resistance mechanism.

“Targeted therapy or immunotherapy shows responses in some patients, but others are not responding effectively,” says Professor Ren. The challenge is now to understand why this is, and to develop tests that will match individual patients to the best treatment for their unique tumour. Additional treatments are also needed to enable those patients who develop drug-resistance to stay a step ahead of their tumours.

The prognosis for HCC patients in China and around the world has increased significantly as a result of better screening and new treatments. However, with over 815,000 new cases of HCC diagnosed each year globally,3,4 and over 369,000 in China,1,4 the work for Professor Ren and his colleagues continues.

References

1. World Health Organisation: Globocan 2020 – China Factsheet. Available at:

2. Pew Research Center. Which 7 countries hold half the world’s population? Available at:

3. World Health Organisation: Globocan 2020 – All cancers factsheet. Available at:

4. Llovet et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016; 14(2): 16018.

5. J. R. Desai et al. Systemic therapy for advanced hepatocellular carcinoma: an update. J Gastrointest Oncol. 2017; 8(2): 243-255.