Liver cancer changes face: from fighting viruses to metabolic challenge

For decades, the scientific and clinical narrative of primary liver cancer in Italy remained linked to the spread of chronic viral hepatitis. The epidemiological panorama we observe today, however, tells a profoundly different story. Thanks to the extraordinary success of compulsory vaccination for Hbv, introduced over thirty years ago, and the revolutionary efficacy of the new antiviral therapies for Hbv and Hcv, we are witnessing a trend reversal. The once predominant viral component is gradually giving way to Masld, i.e. steatotic liver disease associated with metabolic dysfunction. In this new scenario, obesity, type 2 diabetes and metabolic syndrome have emerged as the main drivers of liver carcinogenesis in our country.

The implications of this transformation go far beyond a simple statistical analysis: we are faced with a paradigm shift that challenges our established surveillance protocols for early detection of neoplasia. In fact, unlike patients with viral-based cirrhosis, for whom we have now standardised surveillance programmes, individuals with metabolic disease present an insidious challenge, since they can develop cancer even in the absence of overt cirrhosis.

This data overturns many of the certainties acquired over the years and requires us to radically rethink early diagnosis strategies, extending clinical attention to populations that until now were considered low risk. It will be necessary to implement innovative surveillance methods, capable of maintaining high sensitivity even in contexts where current methods are less effective, while guaranteeing economic sustainability on a large scale. The search for new diagnostic tools is, in this sense, one of the most urgent priorities for Italian hepatology.

On the therapeutic front, too, the current landscape has become extremely complex, but at the same time promising. A first change concerns therapies that act on the neoplasm in a targeted manner, without the need for invasive surgery. These treatments are no longer relegated exclusively to advanced stages, but are successfully employed in less advanced forms of the disease, often integrated in multimodal protocols with locoregional therapies. This approach makes it possible to attack the tumour while preserving the integrity and function of the organ, leading to an improvement in prognosis that was difficult to envisage with traditional approaches alone.

The real revolution, however, lies in the change in philosophy of systemic therapies. We have moved rapidly from the era of single molecularly targeted drugs to that of immunotherapeutic combinations. The use of anti-angiogenic agents combined with immunotherapy, or the use of different immunotherapeutic drug combinations, is no longer limited to extending long-term survival. These therapeutic schemes are paving the way for neoadjuvant and conversion strategies, allowing patients initially deemed inoperable to regress to definitive curative treatments such as surgical resection or liver transplantation.