Non-invasive markers of liver cancer, would it be advisable to screen older people?

According to World Health Organisation (WHO) data for 2020, liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death, after lung cancer and colorectal cancer (https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.p…). Although recent years have seen a decrease in the incidence of most tumours, in the case of liver cancer the number of patients diagnosed per year has not only not decreased, but has increased. A common characteristic of patients is that they are over 60 years of age at the time of diagnosis and, in fact, advanced age is considered a risk factor for the development of all types of cancer, but it is particularly important in liver cancer.

In the case of hepatocarcinoma (HCC), for years there have been follow-up programmes for subjects belonging to certain risk groups, i.e. patients with alcoholic cirrhosis or hepatitis B or C viral infection, to facilitate early detection, but despite this, a significant percentage of cases are still diagnosed late.

In the case of cholangiocarcinoma (CCA), they often appear in patients with no previous diseases, although risk factors have been identified that predispose to a greater or lesser extent to the development of this type of tumour, notably the presence of biliary cysts and gallstones, chronic diseases affecting the biliary tract, or parasitic infections or hepatitis B or C virus infections. Alcohol and tobacco consumption, diabetes and non-alcoholic fatty liver disease are less associated with the development of CCA, but are so frequent that they are expected to be the main risk factors for older people diagnosed with this type of tumour in the coming years. 

The OLD-HEPAMARKER project aims to identify minimally invasive markers for the early diagnosis of liver cancer, with a special focus on ACC. To date, markers with potential usefulness for early diagnosis of these tumours have been identified and will be validated in a large population of elderly patients with ACCC that is being selected, but when reliable diagnostic markers that can be tested in hospitals become available, it is important that the population in which the tests should be performed is identified: should all those over 65 years of age be tested even if they have no risk factors, or should all those over 60 years of age be tested if they have any risk factors, or should all those over 60 be tested if they have any risk factors?

In the framework of the European Network for the Study of CCA (ENS-CCA), information has been collected from more than 2200 patients with this disease from 11 countries (almost 25% from Spain) and the analysis of the data is providing valuable information for different purposes: (i) to identify new risk factors, (ii) to determine whether older patients (>85 years) have different characteristics from younger older (65-85 years) and younger (<65 years) patients, and (iii) to select which groups of older patients should be monitored to detect as early as possible whether they have liver damage that could progress to CCA. The full data from the first study will be presented for the first time at this year's Cholangiocarcinoma Foundation meeting, which is also being held online (https://cholangiocarcinoma.org/2021-annual-conference/agenda/).

In this study, the mean age of patients with biliary cancer at diagnosis was 66 years, with a slight predominance of men versus women. As shown in figure 1, 55% of patients were overweight/obese, 22% had diabetes, 39% had high blood pressure, 7% had viral hepatitis and 19% had biliary diseases. In addition, 33% of patients were frequent users of tobacco and 20% of patients used alcohol on a daily basis, although the figures could be higher.

Figure 1. Risk factors identified in the European-wide study of patients with cholangiocarcinoma. BMI, body mass index.

Some of the risk factors could be eliminated or reduced, such as the use of intoxicants, but many people do not consider drinking "a little" alcohol at meals and "a little extra" at weekends, nor do they consider giving up smoking until a doctor tells them to do so because of a serious health problem. As for alcohol, until recently it was said that "moderate" consumption is beneficial to health, and this message can lead to confusion, but in recent years medical societies are making it clear that alcohol consumption, even in small quantities, cannot be recommended. Its association with the development of various types of cancer is very high, especially hepatocarcinoma.

There is no doubt that avoiding being overweight would also be desirable, and although physical exercise may be reduced in some older people, any type of exercise, even moderate, should be part of the healthy habits to be maintained throughout life (Figure 2), together with a balanced diet. 

Figure 2. Recommendations to reduce the risk of biliary tumours in the elderly and to detect them early to promote cure.

This should include regular medical check-ups and, in the future, screening for early detection of liver tumours, and screening of older people in a similar way to what is currently done for breast or colon cancer. In fact, analysis of data from the European registry confirms that when tumour detection is performed at less advanced stages, and surgical removal is possible, patient survival increases, even if they are very old, so efforts to make minimally invasive liver cancer markers available as soon as possible need to be expanded.

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