Cancer staging should serve to estimate the prognosis, select the most appropriate primary and adjuvant therapy for each stage, and assist in comparing results of different treatments or coming from different patient series. Ultimately, an accurate cancer stage can help physicians in managing oncologic patients and scientists in exchanging unambiguous information. According to the European Association for Study of the Liver (EASL) recommendations, a staging system for HCC should take into account four issues: tumour burden, degree of liver function impairment, general condition, and treatment efficacy[13,15]. Indeed, staging of HCC is complex and, currently, there is no universally accepted staging system. The consensus conference of the American Hepato-Pancreato-Biliary Association (updated in 2010) re-proposed the use in clinical practice of different systems for different patients: as survival of early stage patients is greatly modified by treatment, prognostic prediction must include treatment-related variables; conversely, as treatment may not be a key predictor in advanced stages, it may not be a crucial variable of a prognostic index for patients with these tumors. Nowadays, clinicians can choose among several staging systems, although it should be underlined that only the BCLC staging system provides a treatment algorithm linked to the HCC stage.
Early stage tumors
According to the BCLC definition, a very early HCC is represented by single nodule < 2 cm, and an early HCC is a tumor fulfilling the Milan criteria at imaging techniques (one nodule ≤ 5 cm or 3 nodules each ≤ 3 cm, without vascular or lymph nodal invasion). In CTP class A patients, survival after hepatic resection for early HCC reaches 70% at 5 years, and up to 90% for very early HCC; however, whether to prefer, in these patients, hepatic resection over liver transplantation, or percutaneous treatments such as radiofrequency ablation (RFA), still remains a matter of debate[69,70]. Thus, the actual role of hepatic resection should be viewed in the light of such competing strategies.
The literature comparing the results of hepatic resection versus RFA for early HCC encompasses a number of retrospective studies, some case-control studies and only two randomized controlled trials (RCT), both coming from the Eastern world[71,72]. The first one, conducted on 161 CTP class A patients with a solitary tumor ≤ 5 cm, reports similar survival rates after surgery (90 patients) and percutaneous treatments (71 patients), with 4-year survival rates of 68% and 64%, respectively (5-year survival rates were not reported). Also, DFS was not affected by the treatment adopted either in the whole population or in the subgroups of patients with tumors < 3 cm and between 3.1 cm and 5 cm. The second RCT was conducted on 230 patients with HCC meeting the Milan criteria, 6.1% of whom belonging to CTP class B. The authors found that resection (115 patients) was significantly superior to RFA (115 patients) in terms of both 5-year survival (75.7% vs 54.8%, respectively) and 5-year recurrence-free survival (51.3% vs 28.7%), and this was confirmed in post-hoc analyzes focused on individuals with solitary HCCs ≤ 3 cm, those between 3.1 and 5 cm, as well as with multifocal tumors. Thus, the two RCTs provide conflicting results making it impossible to propose robust recommendations. Nevertheless, when observational studies are also considered, a trend seems to emerge toward better overall and disease-free survivals after resection. In fact, the 5-year survival rate of surgical patients with early HCC can be estimated to be around 70% while the rate of those submitted to RFA is around 60%; the difference is much more striking for the 5-year DFS, the figures being around 60% and 20%, respectively[69,70]. However, the considerable heterogeneity among studies regarding both patient selection and results does not make it possible to reach definite conclusions on this topic. Pertinently, it should be noted that a recent multicenter prospective cohort study, in patients with a single tumor ≤ 2 cm and potentially amenable to hepatic resection, reported a complete response (without local recurrence) in 97% of cases after RFA, and a 5-year survival rate up to 75%. In another study considering 104 of these patients, the 5-year survival rate achieved with resection and RFA was excellent (> 80%) and equivalent after correction to the one-to-one propensity analysis model for the confounding factors.
Therefore, it can be said that in patients with early HCC, RFA provides a worse DFS as compared with hepatic resection, so that the need for retreatment is greater. Instead, hepatic resection and RFA would achieve similar results in very early HCCs. However, the drawback of RFA in terms of radicality is somehow counterbalanced by lower mortality, morbidity and costs (shorter hospital stay) and the easy repeatability of ablation. On the other hand, Markov models indicate that in HCC early stages, hepatic resection should be considered in the case of RFA local failure and that surgery provides better quality of life-adjusted survival, due to the lower risk of local recurrent disease requiring retreatment. Taken together, these observations suggest that hepatic resection and RFA should be considered as complementary rather than competitive treatments. In cases of deep tumor location, that require a removal of a large volume of parenchyma if resected (i.e., major hepatectomy), it is reasonable to consider RFA as the preferred strategy to adopt; conversely, superficial tumor location or tumors adjacent to main vessels or biliary structures, are much better managed with hepatic resection. Nonetheless, for many experts, recommending RFA as first-line therapy for resectable small HCCs still requires a higher level of evidence. Such uncertainty is highlighted by the conclusions of the conference of the Japan Society of Hepatology held in 2009: to the question “Which treatment would you perform for 2-cm sized HCC nodules in patients with Child-Pugh A liver function?” 80% of surgeons responded “resection”, while 68% of non-surgeons responded “RFA”. Greater agreement was observed when asking about the optimal treatment of 3-cm sized nodules in patients with Child-Pugh A: 95% of surgeons and 79% of non-surgeons responded “resection”.
As already stated, the role of hepatic resection in early stage HCC should be viewed in the light of competing strategies, and liver transplantation (LT) represents the most attractive alternative option because it removes both detectable and undetectable tumor nodules together with the pre-neoplastic cirrhotic background. However, LT use should be viewed in the context of shortage of available grafts, and decisions must consider, together with the benefit for the individual patient, the collective benefit of all potential liver recipients. Liver transplantation achieves excellent results in patients with limited tumor burden. Patients with HCC fulfilling Milan criteria have a 5-year survival of about 70%, with recurrence in less than 10%. This survival well matches post-transplant survival of most other indications for LT[80,81]. This is a critical point, recalled by Recommendation No. 7 of the International Consensus Conference on Liver Transplantation for HCC, held in Zurich in 2010, which states that LT should be reserved for HCC patients who have a predicted 5-year survival comparable to non-HCC patients. When compared to LT, partial hepatectomy would seem to be inferior in terms of long-term survival, but most surgical series rely on patients who underwent resection of a wide spectrum of tumor extent, frequently beyond the Milan criteria. Notably, factors precluding LT, such as large or multifocal tumors and vascular invasion, are often included in series analyzing resection results, and are associated with early recurrence and shorter survival. There is evidence that hepatic resection and LT can indeed achieve similar post-operative and intention-to-treat survivals in patients respecting Milan criteria. Thus, when patients with more limited disease are selected, the results of hepatic resection are much more favorable, approaching the 5-year survival rate of 70% reported after LT[19,83-85]. It should be considered that this figure is the end-result currently achievable thanks to both improved diagnostic imaging and therapies for recurrences, including salvage LT, that have been shown to significantly prolong survival after partial hepatectomy. Thus, the combination of resection and salvage LT seems to be a reasonable strategy to adopt for resectable HCC within Milan criteria. This strategy could also increase the proportion of grafts offered to non-HCC candidates on the waiting list.
Beyond the early stages of the tumor
Beyond the early stages, there is debate on the ability of the current staging systems in segregating patients into homogeneous prognostic strata able to assist clinicians in selecting the optimal treatment strategy. The BCLC intermediate stage (BCLC-B) includes patients in Child-Pugh class A or B, with multi-nodular or large HCC, and preserved performance status. This definition includes a very heterogeneous patient population, according to either tumor extent (from bifocal HCC to subtotal tumor replacement of liver parenchyma) or liver function (from perfectly compensated to decompensated cases with ascites and hyperbilirubinemia). The recommended treatment modality for this HCC stage by both EASL and American Association for the Study of Liver Diseases guidelines is trans-catheter arterial chemoembolization (TACE). Instead, due to the heterogeneity of this stage, patients are best served when the treatment decision is individualized and taken within a multidisciplinary team[88,89]. Indeed, retrospective analyses have shown that, in BCLC stage B patients, hepatic resection yielded better survival rates than TACE[90-92]. Stage B, but even stage C, patients can tolerate hepatic resection showing low mortality, acceptable morbidity, and survival benefits. The reported 3-year survival rate ranges from 56% to 74% for stage B and from 28.6% to 67% for stage C patients[90-92]. Especially in stage B, resection is superior to the TACE in terms of survival[57,91]. A very recent case-control study, conducted on a population of 603 patients (1:2 ratio), has shown that in patients with a portal vein tumor thrombus (PVTT) within segmental branches (type I) or the right or left portal vein (type II), resection provides a significant survival benefit in comparison to TACE. In particular, in the presence of type I PVTT, the 5-year survival rate was 37.9% after resection and only 3.6% after TACE; in the presence of type II PVTT, the corresponding figures were 17.2% and 0%, respectively. These results suggest a revision of the BCLC recommendations. Although the BCLC staging classification has been claimed as standard HCC classification in Western regions, its validation across Eastern and Western regions is required and some refinements are probably needed before it can accepted for universal application. Indeed, most Asian experts state that the BCLC staging system does not satisfy the needs of surgeons and physicians in real clinical practice: when participants of the Japan Society of Hepatology were asked if they usually follow the BCLC treatment algorithm, 70% responded “no”. It should also be noted that resection is not excluded as an option for HCCs beyond the early stages in the Asian treatment algorithms and in real clinical practice about half the physicians include resection as a treatment choice, albeit in cases of advanced HCC[79,95].