Frontline Resection or Liver Transplantation in Patients with Single-Nodule Hepatocellular Carcinoma.

Patients with single-nodule hepatocellular carcinoma (HCC) may be candidates for local ablation, surgical resection or liver transplantation (LT). Although all these therapeutic options are considered potentially curative, the risk of tumour recurrence is heterogeneous and a significant proportion of patients undergoing local ablation or surgical resection will recur beyond LT criteria within the first 3 years, with a dismal prognosis. In the current issue of Liver International, Filippo Pelizzaro et al. on behalf of the Italian Liver Cancer (ITA.LI.CA) group, present a retrospective multicenter study including 512 patients with a single-nodule HCC ≤5 cm who underwent frontline liver resection.1 The authors had excluded patients with tumour reappearance earlier than 3 months (n = 80), arguing that these could actually correspond to overlooked HCC nodules during the pre-surgical workup rather than a true recurrence. After a median follow-up of 4.2 years, HCC recurrence occurred in 286 patients (55.9%) and most importantly, a significant proportion of patients had HCC recurrence beyond LT criteria (18% of patients from the whole cohort when considering Milan criteria and 15.2% when considering up-to-seven criteria). Independent predictive factors for non-transplantable recurrence were tumour diameter ≥4 cm, elevated alpha-fetoprotein, microvascular invasion, and satellite nodules.1 According to the Barcelona Clinic Liver Cancer (BCLC) staging system, patients with a preserved functional status, normal liver function and absence of portal hypertension who are diagnosed with a single-nodule HCC are usually considered for local ablation or surgical resection depending on the diameter and location of the nodule, as well as the local expertise.2 Although complete radiological response after ablation could be achieved in the vast majority of patients, tumour recurrence rates are as high as 70%.3 Liver resection could be considered more appropriate than local ablation for nodules larger than 2 cm or in smaller nodules if there is no contraindication for an eventual LT, but still, HCC recurrence may occur in 50%–70%.3, 4 Adjuvant therapies could decrease this risk in the future but their efficacy needs to be confirmed.5 In contrast, LT is associated with reduced HCC recurrence rates (around 10% in single-nodule HCC under Milan) and 5-year survival rates around 80%.6 In a setting in which decisions are made within multidisciplinary teams in a multiparametric therapeutic hierarchy, which ranks therapeutic options according to their survival benefit,7 LT would be the first-line therapy for patients with cirrhosis and single-nodule HCC. However, as the incidence of HCC continues rising and the imaging techniques become more sensitive, the number of patients with single-nodule HCC who are potential candidates for LT would probably exceed the number of donors available, and would certainly preclude the access to LT of patients with other indications. Wherever available, salvage living donor LT may not eliminate the risk of HCC recurrence but it could increase patient survival compared with the other treatment strategies, such as hepatic re-resection, radiofrequency ablation, trans-arterial chemoembolization, or percutaneous ethanol injection.8 In any case, salvage LT is superior to repeat liver resection for treating patients with transplantable, intrahepatic HCC recurrence.9 The rationale under frontline liver resection in single nodule HCC is to avoid LT in patients who would never experience HCC recurrence in order to allocate donors for more urgent LT indications and to avoid transplant-derived morbidity and mortality. The key is to identify patients with a priori low risk of recurrence for frontline resection and patients with high risk of recurrence, particularly non-transplantable recurrence, in whom LT should be offered as the first-line therapy. Pelizzaro et al. identified tumour size ≥4 cm and serum alpha-fetoprotein ≥20 ng/mL as the most relevant predictors of tumour recurrence beyond Milan Criteria, each of them able to double the risk per se. For patients with HCC between 4 cm and 5 cm, and serum alpha-fetoprotein >100 ng/mL the risk of recurrence beyond Milan criteria was 58.5% at 5 years,1 which is unacceptable taking into account that LT would offer 13.3% recurrence rates at 5 years in patients with similar features.10 In doubtful cases, a positron emission tomography could be useful to evaluate the biological behaviour of the tumour preoperatively. Indeed, tumour avidity for fluorodeoxyglucose in the positron emission tomography is more frequent in poorly differentiated HCCs with microvascular invasion11 and it has been consistently associated with increased risk of tumour recurrence and shorter overall survival.12, 13 Although there is no agreement on the optimal threshold of standardized uptake value to discourage resection in favour of LT, a tumour-to-normal liver standardized uptake value ratio >1.5 in the positron emission tomography has been associated with increased risk of extrahepatic tumour recurrence after surgical resection.14 More specific tracers for HCC such as c-choline15 have shown promising results but there is insufficient data to recommend them systematically over fluorodeoxyglucose. In patients with HCC undergoing surgery, the pathological analysis of the resected specimen would provide additional valuable information to make clinical decisions.16 In the study by Pelizzaro et al., the presence of microvascular invasion or satellite nodules in the pathological analysis of the resected specimen was associated with 76% and 92% excess of risk of non-transplantable recurrence, respectively. The authors provided a convenient nomogram to estimate the individual risk of tumour recurrence.1 Previous studies have identified additional pathological risk factors of tumour recurrence such as invasion of the surgical margin and poor histological tumour differentiation.17 There is controversy about how to combine preoperative information with pathological data to identify candidates for upfront LT or ab initio LT, instead of a follow-up with salvage LT as a safety net which will inevitably fail in at least one in five patients.18 In a recent study, Lima et al. trained and internally validated the NTR score aimed to predict non-transplantable recurrence in patients with HCC undergoing liver resection.18 Unlike Pelizzaro et al., patients with more than one HCC nodule entered the study provided that the tumour was considered resectable. The NTR score combined serum alpha-fetoprotein >400 ng/mL, albumin-bilirubin grade (ALBI) and tumour burden score, thus sharing most predictors with the study by Pelizzaro. Higher NTR score was associated with incrementally worse 5-year non-transplantable recurrence rates (low 11.3%, medium 28.8%, high 37.5%). Another multicenter study including 293 patients with early-stage HCC under Milan criteria undergoing upfront liver resection19 found underlying liver cirrhosis, tumour diameter larger than 3 cm and multiple lesions as risk factors with incrementally worse non-transplantable recurrence rates: 4.5% without risk factors, 13.3% in presence of 1 risk factor, and 20.5% in presence of 2 or 3 risk factors. The authors concluded that patients with ≥2 risk factors would be better candidates for upfront LT instead of liver resection, even though the reported non-transplantable recurrence rates for this subpopulation were lower than that observed in the high-risk groups of Pelizzaro et al.1 and Lima et al.18 Immunotherapeutic agents may improve survival in patients with unresectable HCC20, 21 and they have become first-line therapies in advanced HCC. The question of whether the use of adjuvant immune checkpoint inhibitors before resection or LT would confer additional survival benefits in patients with HCC needs to be elucidated. Several randomized trials are ongoing in this setting22 and their results are highly anticipated. In the LT setting, where the use of immunotherapy either before or after LT could increase the risk of graft rejection, more preclinical and clinical studies are required to explore the mechanism of the crosstalk of checkpoint inhibitors and immunosuppressive agents to minimize the risk of post-LT HCC recurrence. Taking the evidence as a whole, liver resection may not be the optimal therapeutic option for all patients with compensated cirrhosis and single-nodule HCC, even if technically feasible. A proposed algorithm to identify candidates for upfront resection or LT is shown in Figure 1. In brief, LT should be considered as the first-line therapy for patients with single-nodule HCC larger than 4 cm or with smaller tumours showing serum alpha-fetoprotein >100 ng/mL. In borderline patients, a positron emission tomography could aid decision making. The remaining patients could undergo upfront liver resection but ab initio LT should be considered in patients with microvascular invasion, satellite nodules or invaded surgical margin.16 The accumulation of other poor prognostic histological factors could also justify ab initio LT. These recommendations are aimed to minimize the probability of non-transplantable HCC recurrence but their implementation may be subjected to the local availability of donors and transplant policies, including the possibility of living donation. In the era of personalized oncological therapies, transplant teams should provide the patient and his/her relatives with transparent and objective information in a way that they understand the prognostic implications of each therapeutic pathway in order to make informed decisions and to establish therapeutic alliances. None. MR-P has received lecture fees from Astellas, Chiesi, and Advanz, outside of the present work. LR has no conflict of interest to disclose. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.