Interventional radiology as a fine art
Article Outline
The era of new systemic treatments of hepatocellular carcinoma (HCC) has yet to come. Hepatocarcinogenesis and liver cancer could be subjected to biomodulation in the near future [1] but up to now the treatments of HCC are still local or locoregional and rely on either surgery, percutaneous ablation, or different variants of chemoembolisation [2], [3].
Progresses in the field have been slow but not negligible. Although still debated, indications for liver transplantation or resection have been refined and mostly restricted [4].
In western countries where underlying liver disease is present in almost all cases of HCC and reaches the stage of cirrhosis in 90%, interventional radiology has taken a predominant position as a curative or palliative option [2], [3].
New percutaneous ablation techniques now enable to destroy small tumors with a margin of surrounding parenchyma up to 8–10
mm [2]. But curiously results are still reported without taking into account techniques and operator’s skill. Radiofrequency ablation (RFA) which is almost universally considered as the best ablative technique is more diverse than surgery and more rapidly improving. However, technical requirements that seem now evident for surgery have still to be admitted for RFA, particularly experience and skill of the operator. Comparisons between techniques and probes have been scarce [5]. In the near future multipolar multiprobe RFA will make well-limited large tumors eligible for the technique and more importantly allow ablation of small tumors detected by screening using a safety margin [6]. These new techniques have yet to be evaluated taking into account the operator’s experience a factor that undoubtedly influences their efficacy.
Recent progresses have been observed also in the field of intra-arterial treatments. The manuscript by Varela et al. in this issue [7] is a good example of these new developments. Using drug eluting beads that slowly release chemotherapy while simultaneously inducing a calibrated arterial obstruction, the BCLC authors have raised the suggestion for a higher treatment effect with a potential reduction of side effects. Hence, conventional transarterial chemoembolisation using the old empirical mixture of Lipiodol® and chemotoxic agents is being challenged by the usage of drug eluting beads and of crystal spheres loaded with Yttrium-90 a novel technology with marked antitumoral effects that deserves proper investigation [8].
As mentioned , these new treatments show a powerful antitumoral activity, but there is uncertainty about their safety and ultimate impact on survival. Hence, we are obliged to make a reflection on how to properly evaluate them versus conventional therapy and what criteria have to be used to indicate each of them for the most suitable patients. To these questions, the usual academical answer is: by performing large randomized studies. But is it realistic? Will they provide a major contribution to the field of HCC?
The answer is at least ambiguous. The treatments of HCC considered as curative or potentially curative have never been subjected to this kind of evaluation. For ethical reasons no trial comparing transplantation, resection or percutaneous ablation versus conservative care has ever been performed [9]. A limited number of trials compared resection versus percutaneous ablation [10] or alcoholisation versus RFA [11], [12], [13]. These trials have endorsed the conclusions of previous well-matched case-control studies but did not deliver any strong definite answer concerning selection criteria of patients for each technique and the particular weight of operator’s skill in the results.
The only field where numerous middle-sized randomized studies have been performed using a conservative care arm has been chemoembolisation [14]. The example is worth a reflection as no clear-cut conclusions have been drawn. All trials performed in France have been negative but even so, chemoembolisation is still widely used reflecting a limited confidence in trial results. Recent metanalysis including the studies from France, Asia and Spain concluded that the procedure increased survival in treated patients but that the overall benefit was limited [15]. More importantly, discrepancies appeared among trial results and if a recent still unpublished randomized trial with negative results would be taken into account [16] the difference in survival may probably become non-significant. It is obvious that the heterogeneous selection of patients for each trial (patients from France had mostly alcoholic cirrhosis conversely to viral liver disease in Spain or Asia) coupled with marked differences in the treatment application may have prompted such a confusing situation, but this just stresses the difficulty of running a powerful trial to compare new technology vs conventional approach. Such a trial would sure have to be multicentric and likely multinational to recruit enough number of patients and allow to determine what subgroups of patients really benefit from the treatment.
Even if such a trial was designed and conducted, the findings would not be widely assumed, if not highly significant favoring one arm and the debate would keep going. Why would this happen? Firstly as previously discussed interventional radiology is an operator dependent technique with several technical variants of the same procedure. Since these are numerous enough, the partisans of a given technique would contest a negative result. Secondly and more importantly is that HCC is a very particular cancer where tumoral response to treatment and survival could be dissociated and be divergent. The outcome of the underlying liver disease may interfere with the results of any antitumoral treatment as almost all of them may damage the non-tumorous liver parenchyma [17]. Even in apparently well-designed randomized trials the status of the non-tumorous liver remains largely imprecise. In the best cases the underlying cirrhosis is stratified according to the Child–Pugh classification. This is clearly not enough as the degree of liver fibrosis, portal hypertension activity and steatosis may also influence the outcome. The example of liver resection could be useful to take into consideration as it has been clearly shown that morbidity and mortality in patients with cirrhosis is deeply influenced by the cause of the underlying liver diseases. HBV patients have the best postoperative prognosis, intermediate HCV cases and alcoholics have the worst outcome at a similar Child–Pugh stage. The importance of high preoperative aminotransferases serum activity has also been emphasized [4].
Accordingly, how should we proceed to advance our knowledge if randomized studies could no longer be the more effective answer? As said, too much heterogeneity in techniques, too many potential patient profiles and too many confounding parameters. It is likely that the sole viable answer will come from pooling large randomized trials into a metanalysis taking into account individual data. This has not yet been done for chemoembolisation and in any case, the realization of the trials would need a long time in contrast with the rapid evolution of techniques, but their information would clearly be better than that derived from case-control studies in which patients are matched according to an insufficient number of factors [18].
The liver cancer community has therefore to reflect on the way to evaluate these new techniques and better define their potential indications. An anonymous database recruiting patients treated in different parts of the world in specialized centers might be an option if the data collection is precise enough to provide details concerning the tumor itself and the state of the non-tumorous parenchyma. Data collection should be extensive and on an intention to treat basis thus, including all patients selected for treatment in all centers. This database could give an estimation of the therapeutic value of each technique and help to identify the target HCC patients who would definitely benefit from treatment and those in whom the uncertainty still remained and hence, be candidates for research of a proper size. Until all this collaborative study is performed we will still benefit from phase 2 studies as the one by Varela et al.
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PII: S0168-8278(07)00003-7
doi:10.1016/j.jhep.2007.01.001
© 2007 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
