Microwave ablation in skilled hands. A treatment opportunity gaining room in the field of single HCC 3–5 cm

SEE ARTICLE ON PAGE 66 In this issue of Hepatology, a multicenter Chinese study reports microwave ablation (MWA) to be apparently noninferior to laparoscopic liver resection (LLR) in terms of overall survival (OS) for single HCC sized 3–5 cm (Wang et al., Hepatology 2022), corresponding to the early HCC stage.[1–4] Patients at risk for HCC are submitted to semiannual ultrasound surveillance in order to detect HCC as early as possible and, consequently, to apply curative treatments, which would instead become precluded if tumors are discovered at a more advanced stage. Traditionally, curative treatments are considered to be represented by liver transplantation (LT), surgical resection, and thermal ablation.[2–4] Unfortunately, LT can be offered only to a limited proportion of patients, even when HCC is found at an early stage, for several reasons, including shortage of donors, patient comorbidities, and others. Surgical resection has been initially held as the unique reference treatment for patients who are not transplant candidates,[5] with ablation, primarily in the form of radiofrequency ablation (RFA), proposed for patients who are not surgical candidates.[6] However, in the past decade, RFA and surgery became equally recommended in the subset of patients in the very early Barcelona Clinic Liver Cancer stage, corresponding to tumors <2 cm,[3,4] based on the demonstration of comparable OS with the two treatments, despite higher recurrence rates with ablation.[7] Single tumors 2–3 cm in size were considered instead to represent a gray zone in terms of comparative survival benefit,[7,8] while surgery remained the preferable treatment for single HCC >3 cm in size, attributable to both better OS and recurrence‐free survival (RFS).[7,8] Thermal ablation with RFA appeared, in fact, insufficiently able to achieve complete necrosis with increasing tumor size[8,9] and in locations close to the capsule and large vessels,[4,10] translating into shorter survival. However, in the most recent years, significant technological improvement became mature in both the surgical and interventional fields, raising the question of whether the above recommendations still remain valid. Surgery benefitted from the possibility of less‐invasive approaches, such as laparoscopy[3,4] and nonanatomical resections. Ablation benefitted from the introduction of MWA[11] to provide larger necrosis with decreased local recurrence, artificial ascites, or chest fluid to prevent heat damage to surrounding structures or imaging reconstruction to better target the lesion, enabling safer, more‐complete ablations regardless of the thermal ablation method.[12] Such improvements in interventions have started challenging the surgical priority in tumors smaller than 3 cm,[13] including recent randomized trials,[14] and are now expanding to single tumors 3–5 cm in size.[1] Should we change therefore our treatment approach following the results provided by Wang et al.?[1] Should we propose to our new patients with single HCC 3–5 cm to freely choose between laparoscopic surgical resection or MWA whenever they are both technically feasible? Probably not yet, although a step in a new direction appears to have been made. The main reason for not having reached enough evidence yet to change our approach lays in the retrospective nature of the study. Study patients were offered either resection or ablation in real life, following a multidisciplinary discussion.[1] Therefore, it is impossible to verify for which reason patients were considered better served by one rather than the other technique. Operators providing either surgical or interventional treatments were all extremely skilled, with a median of >10 years of independent operations. However, we do not know how often the alternative to an extremely skilled operator would have been a much less experienced operator, given that the data are coming from noncontrolled real life. However, more important than this, an obvious trend exists to the allocation of more‐fragile patients to ablation. Patients submitted to MWA were, in fact, older, with slightly more compromised performance status, suffering more often from cirrhosis, more frequently affected by diabetes, and with slightly higher bilirubin and lower platelet count, similarly to other contemporary studies.[15] The researchers decided indeed to carry out a propensity score adjustment to restrict the analysis to a subgroup of comparable subjects, finally including less than half of the total surgical population. Probably, only a restricted population of patients is really identically suitable for both resection and ablation, and indeed a recently published randomized trial comparing surgery to ablation[14] had to be prematurely terminated because of insufficient recruitment of patients eligible for randomization. Ablation will likely remain offered as the reference technique to more‐fragile patients, in keeping with the multidisciplinary choices.[1,15] Why are then the present data[1] useful nonetheless? They reassure physicians that MWA, deployed by the most skilled operators, provide no worse of an outcome than resection, even for larger‐than‐usual single HCC; thus, we should not force indications for surgery, even laparoscopic, for patients not perfectly suitable for it. For the remaining well‐fit, compensated patients with single HCC 3‐5 cm, suitable for surgery, the question remains open: Shall ablation be offered only to patients held unsuitable for resection, or shall both techniques be offered with the same ranking of priority? The obvious answer would be: We need a randomized controlled trial. Despite that such a study would be obviously deserved and welcome, we will hardly see any such study in the near future because of practical reasons. The study population of such a noninferiority study would imply a very large, multicenter investigation extended over many centers, with many years of recruitment and follow up. Moreover, all physicians must accept that their patients are randomized, including surgeons to whom patients could have been referred. All of them must convince their patients not to be operated on right away, but rather randomized. Such a prospective, randomized study is likely to remain a dream rather than becoming reality, and, in fact, a recent randomized study addressed to patients with HCC <3 cm in size was prematurely concluded because of insufficient recruitment.[14] Given that, for the above reasons, a randomized study will not come early, or not at all, we must make a decision on the current evidence. We must then consider that MWA ablation provides comparable survival, but shorter RFS. MWA appeared to be more cost‐effective than LLR, but the costs of treating a higher number of recurrences were not considered. We could also benefit from subgroup analysis of the current data to help toward deciding whether, in any subgroup, MWA could be proposed with great confidence as a very valid alternative to surgery. According to the hazard ratios of the subgroup analysis and the clinical consistency of the finding, the only relevant information to this end appears to be that MWA seems preferable over resection in older patients (>70 years of age). Interestingly, in the subgroup of patients with alpha‐fetoprotein >400 ng/dl, no benefit was observed not only in OS, but also in progression‐free survival with resection.[1] It could be speculated on that such an unfavorable prognostic marker already alludes to a distant dissemination of cancer cells, making less effective a local capacity of complete tumor resection. At last, it must be kept in mind that microwave devices do not provide identical outcomes over the various manufacturers and models. Therefore, the findings reported in the study by Wang et al.,[1] in which all cases were treated with the same type of equipment, cannot be immediately translated to any other type of an MWA device. In conclusion, MWA appears to have gained room in the field of single HCC 3–5 cm when performed by skilled operators, and it will be more often considered within the multidisciplinary discussions, to provide the best individualized treatment strategy for any given HCC patient. CONFLICT OF INTEREST Dr. Piscaglia advises for, consults for, and is on the speakers' bureau for Roche. He consults for and is on the speakers' bureau for Eisai, Ipsen, MSD, and Esaote. He advises for Bracco, AstraZeneca, Tiziana Life Sciences, Roche, and Exact Sciences. He is on the speakers' bureau for Samsung.