Partial hepatectomy versus radiofrequency ablation for hepatocellular carcinoma: Confirming the trial that will never be, and some comments on the indications for liver resection
Authors: Pietro E. Majno, Gilles Mentha, Vincenzo Mazzaferro
Journal: Hepatology (2010)

After reviewing the decision analysis study of Cho et al.,1 which concludes that radiofrequency thermal ablation (RFTA) and hepatic resection are to be considered equally effective for the treatment of very early hepatocellular carcinoma (HCC, ≤2 cm in size), we had mixed feelings. The study was intelligent and well-constructed, but provided only confirmatory information and suggested no change in practice from what was already done in our units and in many other units where the EASL-AASLD (European Association for the Study of the Liver–American Association for the Study of Liver Diseases) guidelines are slightly bent to take into account the good results of RFTA for small tumors.2 A consideration prevailed: despite its immaterial nature (implicit in decision analysis) and the lack of multidisciplinary input (that we regret), the study offered the soundest comparison between RFTA and resection that is realistic to hope for. HCC, hepatocellular carcinoma; RCT, randomized controlled trial; RFTA, radiofrequency thermal ablation. Since their introduction, ablative techniques have challenged the supremacy of surgical resection for early HCC, more from the results of well-conducted observational studies with sufficient follow-up than from randomized controlled trials (RCTs), which are very difficult to organize. The efficacy of optimal percutaneous ethanol injection was obviously very similar to the one of optimal surgical resection.3, 4 RFTA then arrived on the scene, with studies showing that the risks of seeding were essentially linked to unselected indications,5 a RCT proving RFTA's supremacy to percutaneous ethanol injection,6 and more recent studies providing a data on intermediate-term results.7 In current practice, however, many surgeons still resist, moved sometimes by genuine concern about cases inappropriate for ablation, but often by reluctance to change, and by more selfish fears of dwindling referrals and loss of control. Does the study by Cho et al. give the final word on the equivalence between RFTA and resection? For the group of patients presenting with Child A cirrhosis and a very early HCC (some 5% of total referrals for HCC, at present), and probably for larger ones where RFTA can be optimally effective (HCC <3 cm), we believe so. The average results of liver resection and ablation for patients perfectly suitable to each procedure are very similar in terms of overall survival. We should no longer ignore this fact simply because RCTs are missing, and the study by Cho et al., which was constructed taking into account the best scenarios for resection and the worst scenarios for ablation, although limited to HCC up to 2 cm, supports this statement. (A word of caution: the radiological literature needs to be as thorough as the surgical one in confirming that the good results of pioneers, serving as assumptions in the study, can be generalized). Individual components belonging to each patient nuance the picture, because they influence the results of each treatment making it better or worse than average (e.g., whether the tumor is central or peripheral, close or distant from bile ducts, in a patient who is lean or overweight, presenting with or without portal hypertension, etc.). The weight of these components can be more important in the final outcome than small differences in average results between the two treatments. Sensitivity analysis in Markov models allows one to appreciate the influence of individual components on the final results (sometimes bringing into light factors that are not obvious, nor directly linked to the treatment, such as the incidence of de novo recurrence, the possibility of RFTA retreatment and age on the final outcome, which are far more important than seeding or surgical mortality (the readers are invited to look for the instructive Tornado diagrams in the supplementary material of the study). It is therefore on the basis of these individual components, if they are present, that the choice of which treatment is most appropriate should be made. We may underestimate the relevance of individual components, generally for two reasons: excessive empiricism and excessive rationalism. Excessive empiricism gives too much weight to our perceptions and experience. This attitude is generally mixed with ignorance of our colleagues' work (e.g., surgeons may overestimate the difficulty of an ablation, and hepatologists may overestimate operative risk). On the other hand, excessive rationalism gives too much importance to things that can be quantified more easily, underestimating other entities because they cannot be measured or explained, and that are therefore not taken into account by the RCT. It is noteworthy that body size and the central or peripheral location of tumors, components with a large impact on ease of surgery or of RFTA and on complications, are rare or absent in the literature and guidelines, with few exceptions.8 Excessive empiricism and rationalism can be neutralized by multidisciplinary management that we regard as compulsory, at least for difficult cases (competence and a collegial state of mind should expedite the management of the easy ones). By preferring RFTA to resection, we may underestimate the relevance of information on markers of tumor behavior. Most of the information on pathology components and gene profiling associated with tumor recurrence originates from surgical specimens. This information may be crucial to plan the treatment in the long term, in particular for very early HCC. The identification of tumors prone to recur despite their presentation as small nodules can help to select the best candidates for preventive liver transplantation.9, 10 If the question of the supremacy between resection and ablation is settled both in the theoretical arena and in most of our practices, what should be the next effort of surgical, or better, multidisciplinary, clinical HCC research? Resection of solitary large tumors (exceeding 5 cm in size) is no longer a promising field: patients with large solitary tumors benefit from surgery because surgeons have learned to do it with very low mortality, because patients with operable large tumors are a self-selected group with a low tendency to multifocal disease, and plainly because other treatments are less effective. This point is settled as well: even if these patients are not, structu sensu, in an early stage because they do not qualify for transplantation, no upper limit of size for surgical resection appears in the BCLC flowchart, and we hope that patients do not escape surgical referral only because their tumors are too large. We believe that the most meaningful challenge for surgery concerns patients with intermediate HCC, and in particular patients with two or three nodules (stage B) and with macroscopic vascular invasion (stage C) (Fig. 1). Barcelona Clinic Liver Cancer classification of hepatocellular carcinoma. The therapeutic flow-chart has been modified to include both current and possible future indications for surgery, alone or in combination with transarterial therapies and ablative techniques. The aim of the cartoon is to produce prospective investigations: each modification of the original layout is so far suggested only by case series and cohort studies. LDLT, Living donor liver transplantation; OLT, orthotopic liver transplantation; PEI, percutaneous ethanol injection; RF, radiofrequency; PS, performance status; TACE, transarterial chemoembolization; ttc, treatment and care. Some patients with two or three nodules may benefit from liver resection.11, 12 Which ones? The clue may be in understanding that for many of these patients, local control of the disease is the realistic aim of treatment and that surgery should be considered only as one of the ways to achieve it. As such, it is relevant and probably relatively easy to compare resection to multimodal transarterial chemoembolization–RFTA in terms of overall survival and costs (and the role of targeted adjuvant or neoadjuvant therapies on either or both arms?). Some patients with portal thrombosis survive for a long time after surgery and apparently benefit from resection.13 However, the clues to which ones are not obvious. The burden is on more optimistic surgeons to oppose the skepticism of more conservative hepatologists, stepping up from anecdotal reports that have shown predictable low mortality and occasional long-term survival, to well-planned observational studies. The counterpart of such laudable academic efforts—a prerequisite for evaluating whether surgical endeavors are worth the trouble—may be the commitment from hepatologists and interventional radiologists (and surgeons, of course) to present these patients for multidisciplinary discussion.