Thursday, February 17, 2011

Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas

Patients and Methods
Supporting Information


Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: A long-term cohort study

Discussion Only

This long-term cohort study of RFA treatment for HCC in patients with cirrhosis sheds important light on the clinical behavior of this highly prevalent and frequently fatal form of cancer.1-3 As in previous studies,6, 10-12, 16-18 RFA of the initial HCC nodules produced CRs in over 98% of the cases, with a local recurrence rate of about 15%, even if the technique used was not performed to obtain safety margins. The latter requires multiple electrode insertions and overlapping thermal lesions28 that are difficult to create even for skilled operators. The local recurrence rate might have been slightly higher if the 83 patients (11.7%) followed for less than a year had longer follow-ups. This possible underestimation is offset, however, by the operational definition of local recurrence adopted in the study that included all tumor growth within 2.0 cm of the original ablation zone. Viable tumor tissue within or continuous with the ablation zone probably does reflect treatment failure caused by suboptimal electrode placement or undetected satellites that escape ablation due to the convective effect of portal blood flow outside the tumor.29 However, viable tumor tissue within 2.0 cm from the ablation zone but not continuous with it, particularly when it is detected more than 1 year after treatment, may well represent de novo carcinogenesis unrelated to the outcome of the ablation.18

As in previous studies, immediate posttreatment CR and local recurrence rates were better than those reported after percutaneous injection therapies.33 The local recurrence rate observed for HCC nodules ≤2.0 cm is similar to that reported after surgical resection of HCCs of the same size,14 and only minor differences exist between the overall local tumor control rates achieved with RFA and surgical resection for nodules more then 20 less then 30 mm.13, 15 However, these differences, which can be eliminated with just one additional RFA “clean-up session,” need to be weighed against the relative risks of procedure-related death and morbidity. In fact, RFA is consistently mortality-free,6, 10, 11 and fewer than 1.0% of our procedures were associated with major complications.10-12, 16-18 These rates are slightly higher than those reported for percutaneous injection therapies,5, 33 but they are far lower than those observed after surgical resection.34

Although RFA provided excellent local tumor control, ≈1 out of 3 patients developed some type of nonlocal recurrence each year, leading to a cumulative proportion of recurrence of almost 80% at 5 years. This figure is entirely consistent with the recurrence rates reported for RFA, other percutaneous ablative therapies,10-12, 16-18, 33 and surgical resection of HCCs ≤3.0 cm.14-16 These findings demonstrate that, regardless of how the first nodules are treated, recurrence and progression are the rule for HCC. However, the disease often remains confined to the liver for long periods, and this offers opportunities for radical ablation. In this setting, keeping a patient tumor-free calls for repeated interventions, therefore, the versatility and noninvasiveness of the treatment method is almost as important as its local efficacy. Like other minimally invasive techniques, RFA offers distinct advantages with respect to surgical resection in terms of repeatability. Over 65% of all recurrence episodes in our cohort were managed with repeated RFA treatments. In contrast, only 7.7%-31.0% of first recurrences and a negligible percentage of subsequent recurrences are eligible for repeated resections.15, 19

As previously reported,10-12 liver function influenced overall survival, despite the limited differences evaluated in our cohort (Child-Pugh classes ranging from A5 to B7). Overall survival was also significantly related to early recurrence (i.e., ≤24 months after treatment) and to local recurrence. This may reflect the limitations of radiologic tools in staging seemingly early stage tumors.14 However, the strongest independent predictor of death (overall and tumor-specific) was first recurrence in the form of advanced nonlocal disease, which precludes curative treatment. In some cases the early development of advanced disease may reflect tumor understaging; however, in most cases it likely reflects the intrinsic biological potential of the primary tumor that cannot be currently established before treatment. Conversely, the low risk associated with limited nonlocal recurrences—the most common event observed during follow-up—may be attributed to their early detection and to the efficacy of RFA in their local control.
The observed cumulative survival curves are entirely comparable with those reported in other series of HCCs treated with percutaneous ablative therapies6-12, 16-18, 33 or surgical resection.13-15 Recently, randomized clinical trials showed that RFA is superior to percutaneous chemical injection in terms of both local tumor control and survival.33 Conversely, no significant differences in survival rates (overall or disease-free) were found after RFA or surgery.35, 36 However, meaningful comparison of mortality data associated with surgical and nonsurgical treatment of HCC is extremely difficult, because most patients will experience several episodes of recurrence and surgical and nonsurgical approaches differ greatly in terms of their repeatability.

Collectively, our findings indicate that the clinical course of HCC, even in very early (T1) and early stage (T2), varies widely and can be only partially predicted by current staging systems, which are mainly based on size and number of tumor nodules.21, 22 Differences in the clinical outcome of HCCs diagnosed at the same stage in patients with preserved liver function may reflect biological differences of the tumor and cirrhotic liver tissue.37, 38 This study also shows that mortality unrelated to cancer progression has an important impact on the survival of HCC patients, who in Western countries are generally elderly.3, 4, 32

In conclusion, our ability to select optimal treatment strategies for patients with cirrhosis with HCCs is currently limited by three factors: (1) unpredictability of tumor progression and de novo carcinogenesis37,38; (2) tumor understaging14; and (3) substantial risk of HCC-unrelated death. Safe, effective, and minimally invasive treatments, thus, seem to be the most reasonable approach for HCC patients. Our experience indicates that RFA should be the treatment of choice for patients with one or two small HCCs, whereas surgical resection can be reserved for patients with preserved liver function whose tumors cannot be treated with RFA or in which RFA did not produce CR. It is important to recall that RFA failure does not preclude subsequent surgical resection, whereas surgery can compromise the residual liver function, making subsequent RFA useless. On the other hand, neither RFA nor surgical resection is appropriate in the group of patients who, although successful treated for early/very-early (T1, T2) HCC, develop advanced nonlocal recurrences shortly after treatment (Table 3). To improve our ability to define effective individualized strategies for the management of this complex disease, future research should focus on the identification of tumor cell markers and/or genetic profiles associated with specific patterns of HCC growth.

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