Liver cancer: Approaching a personalized care

Abstract

The knowledge and understanding of all aspects of liver cancer [this including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA)] have experienced a major improvement in the last decades. New laboratory technologies have identified several molecular abnormalities that, at the very end, should provide an accurate stratification and optimal treatment of patients diagnosed with liver cancer. The seminal discovery of the TP53 hotspot mutation [1,2] was an initial landmark step for the future classification and treatment decision using conventional clinical criteria blended with molecular data. At the same time, the development of ultrasound, computed tomography (CT) and magnetic resonance (MR) has been instrumental for earlier diagnosis, accurate staging and treatment advances. Several treatment options with proven survival benefit if properly applied are now available. Major highlights include: i) acceptance of liver transplantation for HCC if within the Milan criteria [3], ii) recognition of ablation as a potentially curative option [4,5], iii) proof of benefit of chemoembolization (TACE), [6] and iv) incorporation of sorafenib as an effective systemic therapy [7]. These options are part of the widely endorsed BCLC staging and treatment model (Fig. 1) [8,9]. This is clinically useful and it will certainly keep evolving to accommodate new scientific evidence.

This review summarises the data which are the basis for the current recommendations for clinical practice, while simultaneously exposes the areas where more research is needed to fulfil the still unmet needs (Table 1).

Keywords: HCC; Liver cancer; Personalised treatment; Profiling; iCCA.

Fig. 1. BCLC staging and treatment strategy

[as per Semin Liver Dis. 2014 Nov;34(4):444–55]. The figure represents the first approach to the evaluation of the patients with expected prognosis and initial treatment option to be considered. As shown, the upper part of the scheme defines prognosis according to the relevant clinical and tumor related parameters. Bottom part depicts the decision process to select a treatment option for first consideration. As in all recommendations, final treatment indication should take into account a detailed evaluation of additional characteristics (age, comorbidities) of the patients that imply a personalized decision making. *Note that Child-Pugh classification is not sensitive to accurately identify those patients with advanced liver failure that would deserve liver transplant consideration. Some patients fitting into Child-Pugh B, and even A, may present a poor prognosis because of clinical events not captured by such system, i.e. spontaneous bacterial peritonitis, recurrent variceal bleeding, refractory ascites with or without hepatorenal syndrome, recurrent encephalopathy, severe malnutrition. **Patients with end-stage cirrhosis due to heavily impaired liver function (Child-Pugh C or earlier stages with predictors of poor prognosis, high MELD score) should be considered for liver transplantation. In them, HCC may become a contraindication if exceeding the enlistment criteria.

Fig. 2. Personalised decision making in a patient with HCC

(A) Macroscopic view of a resected HCC in a patient with cirrhosis due to HCV infection. Diagnosis was based on imaging techniques and its size was between 3 and 4 cm. Liver function was preserved, but there was clinically significant portal hypertension (hepatic venous pressure gradient = 11 mmHg). Liver transplant was contraindicated because of comorbidities and its location protruding in the liver surface precluded safe ablation (direct access without a protective rim of non-tumoral liver is associated to increased risk of bleeding and peritoneal seeding). In addition, size >30 mm is a predictor of incomplete ablation. Because of these considerations it was decided to recommend surgical resection through laparoscopy. (B) Partition of the HCC shows capsule formation and no macroscopic satellites. It is possible to differentiate the separate tumor areas and even some minute intratumoral nodules. There is a necrotic haemorrhagic area in the central part. This macroscopic heterogeneity (also identified by different differentiation degrees across the nodule) predicts a heterogeneous molecular profile if assessed by any of the currently available technologies. Increased proliferation markers will be present everywhere, but tumor needle biopsy will be at risk to fail to accurately inform about the tumor biology profile.