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Editorials |
1 From the Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. Received January 15, 2001; accepted January 18. Address correspondence to the author (e-mail: sgoldber@caregroup.harvard.edu).
Index terms: Editorials • Liver neoplasms, 761.323 • Liver neoplasms, therapy, 761.1269 • Microwaves, 761.1269 • Radiofrequency (RF) ablation, 761.1269
Traditionally, local tumor removal has required major surgery. Recently, improvements in imaging technologies have enabled the development of minimally invasive tumor therapies, which rely on imaging guidance for the accurate percutaneous placement of needle-like applicators (1,2). The potential benefits of minimally invasive, image-guided ablation of focal neoplasms, as compared with conventional surgical options, include (a) the ability to ablate and/or palliate tumors in nonsurgical candidates; (b) reduced morbidity and costs and improved quality of life; and (c) the ability to perform these procedures on an outpatient basis.
Historically, the greatest attention has been given to the clinical potential of image-guided ablation procedures for the treatment of small primary liver tumors and colorectal metastases to the liver (3–5) because of the substantial morbidity and mortality associated with standard surgical resection combined with the large number of patients who cannot tolerate such surgery. Over 5,000 radio-frequency (RF) ablation procedures to treat focal liver tumors have been performed during the past 5 years (5–10). This fact alone (ie, rapid adoption without complete validation and comparative outcome studies) attests to both the scope of the clinical need and the less-than-ideal alternative treatment options for these patients. More recently, the clinical potential of these techniques for the treatment of neoplasms in other sites, including the kidney (11), breast (12), bone (13–15), lung (16), and retroperitoneum, has been reported (17).
The two main approaches that have been used to induce image-guided, percutaneous tumor ablation are direct injection of cytotoxic chemical agents and deposition of thermal energy (1,2). Initial studies focused on direct injection strategies, with the greatest clinical attention given to percutaneous ethanol instillation (PEI), for which several investigators have achieved results comparable to those of surgical resection (65% 5-year survival) for small focal hepatocellular carcinomas (ie, lesions smaller than 3 cm) (18,19). Recent attempts to improve the results of ablative injection therapy have included strategies involving many different thermal energy sources, such as RF (3–10), microwave (20–22), laser (23,24), and ultrasonography (US) (25). Tumor destruction with these methods is achieved primarily by subjecting the entire tumor volume to cytotoxic temperatures, which have been demonstrated to be 50°C–54°C for 4–6 minutes (26). The results of preliminary clinical studies (2–10,20–24) in small liver tumors suggest that local tumor control can be achieved in 80%–90% of cases in which the tumors are smaller than 2.5 cm in diameter.
Results of the study performed by Shibata et al (20) reported in this issue of Radiology suggest that minimally invasive image-guided therapy with thermal ablation has reached a new milestone: There is sufficient interest and belief in the technique to warrant direct comparison of technologies—in this case, between RF and microwave techniques. Until recently, the relative novelty of these techniques has resulted in most investigators studying and reporting on individual devices or techniques. Given the large number of potential energy sources used to achieve thermal ablation (eg, RF, microwave, laser, etc) and the different strategies for applying them (eg, multitined electrodes [9,10], pulsed-energy delivery [24,27], and probe cooling [6,28]), important questions as to which modalities and modifications are most appropriate for given clinical scenarios have emerged.
The study by Shibata et al (20) is also particularly beneficial in that they report data from a single, relatively uniform population of patients with small focal hepatomas. Shibata et al (20) are to be commended for being one of the first groups to perform a randomized prospective study of thermal ablation in a single uniform patient population. This study design limited many of the biases seen in previous retrospective series (6–10,21–24), because many clinicians have reported the results of series of tumor ablations in mixed patient populations (with substantial referral bias) and with varied ablation techniques. This, in turn, limited the conclusions that could be drawn and the comparisons that could be made among the studies.
The findings of Shibata et al (20) demonstrated clinically favorable equivalent efficacy when RF and microwave ablation techniques were compared: Both techniques achieved 90% or greater local tumor control during a follow-up period of 6–27 months (mean, 18 months). This finding is not surprising given the disease process studied. In all likelihood, many ablative technologies can be used to achieve similar positive clinical outcomes for the treatment of small hepatocellular carcinoma nodules. This assertion is based on the equivalent survival rates observed when surgery was compared with PEI (18,19) and on early RF and microwave data that mirror the results of both surgery and PEI (21,29,30). In all likelihood, the realities of tumor biologic features (ie, tumor presentation and growth rate) have at least as great an effect on our ability to completely ablate a tumor as do the specific thermal ablation technologies.
For slow growing lesions such as hepatomas, no difference in survival may be demonstrated, because once the lesion is completely or almost totally eradicated, other factors, such as new lesions and underlying liver disease, will likely become the primary determinants of survival rather than small foci of potential residual disease at the treatment site. Additionally, although clear differences in tissue heating have been demonstrated with different RF electrodes and laser applicators in some models, such as the normal liver (28,31,32), other factors such as improved heat retention in hepatomas (ie, the "oven effect") may minimize these differences for small lesions (29). Hence, whereas equivalent results are likely with a slow growing, easily treated tumor, with other types of tumors and larger or infiltrative hepatomas, clear differences among the various minimally invasive therapies and methodologies are likely to emerge (30).
Another important issue that needs to be addressed is that of the appropriate length of follow-up. Although in many series, including that of Shibata et al (20), promising and optimistic short- and now midrange follow-up for the treatment of liver tumors (6–10,20–24,28–30) has been reported, it should be noted that very few studies have a duration of follow-up that is adequate to rival that of surgery and PEI. Patients will need to be followed up for appropriate lengths of time based on universally accepted clinical benchmarks, which for hepatocellular carcinoma and colorectal metastases are upward of 5 years (33–36). These data have been obtained only for PEI, with which survival equivalent to that with surgical resection has been documented for focal hepatomas (18,19). Although such 5-year follow-up has not been published yet owing to the newness of the RF and microwave techniques and will undoubtedly appear in the near future, it is important to stress the legitimate concern on the part of others not to embrace this technology prior to thorough validation.
In the study of Shibata et al (20), differences in complication rates between RF (3%) and microwave (11%) ablation did not approach statistical significance. These rates are clearly lower than those with surgical resection and were undoubtedly kept to a minimum by a high degree of interventional radiologic skill, which in this study was accomplished by a single investigator. However, given the different complication percentages noted between RF and microwave ablation, it is possible that with further study, these differences will become significant, because the larger diameter microwave applicators could lead to additional bleeding complications. Alternatively, similar complication rates may be discovered given that the risks with both RF and microwave ablation are largely the same— those related to needle placement (such as bleeding, infection, and seeding) and those related to untoward thermal damage, including bowel or gallbladder perforation or hepatic decompensation (7). Regardless of the ultimate outcome, this issue further underscores the importance of generating studies of sufficient magnitude to enable one to test the significance of small but clinically meaningful differences between study populations.
Given the high rates of complete treatment of small hepatomas with thermal ablation, with low complication rates, other factors such as ease of use can potentially be added to the considerations in the decision of which type of technology to adopt. For example, the reduced number of RF sessions required to completely destroy a given sized hepatoma was the primary determinant for Livraghi et al (29) to change from PEI to RF ablation for treatment of an overwhelming majority of patients and one of the main reasons that Shibata et al (20) believed that their RF system was easier to use. However, the time required to perform an ablative session with either PEI or microwaves is shorter than that required for RF ablation (20,29). Hence, the concept of ease of use in many cases will be subjective and dependent on the clinical circumstances.
It must be stressed that the ease of use of a procedure will need to be balanced with the ability to achieve appropriate technical and clinical outcomes. However, not every touted advantage of a particular system has equal weight in the clinical realm. This applies particularly to the choice of imaging modality used to guide ablation. For example, although interventional magnetic resonance (MR) imaging guidance (especially with thermal mapping) may be more accurate than US for monitoring ablation (24,25), its use would greatly limit the number of centers capable of performing tumor ablation, with ablation procedures being relegated to only those facilities with such specialized equipment. Thus, in the "real world," the ease of use of US, being readily available, has on a practical level won out over the potential benefits of less available technologies.
Although the Shibata et al (20) study represents a good start in that it attempted to compare different technologies for the treatment of a particular indication—namely, small focal hepatocellular carcinomas—several key issues must be addressed. First, we need to acknowledge the ephemeral nature of technologic dominance, particularly that for very rapidly evolving technologies such as thermal ablation. Interest in various thermal methods ebbs and flows on the basis of successive improvements in technology.
While there is no doubt that comparisons among standardized techniques is essential and that these types of studies are warranted at this time, it must also be acknowledged that RF and microwave techniques, as well as other thermal therapies, are currently undergoing substantial modifications and improvements (1,2). As such, conclusions drawn from any one study must be tempered to avoid the inappropriate overgeneralization of results. Specifically, one can easily envision a scenario in which different microwave or RF techniques that induce different amounts of coagulation are used and that these alternative thermal ablation techniques would alter the results generated. Thus, while the use of only one particular microwave system and only one particular RF system in the Shibata et al (20) study was advantageous in that it permitted a robust comparison between the two techniques, it is important to stress that the results should not be interpreted as representative of the potential efficacy of the entire core of enabling technology (ie, other RF or microwave devices). Hence, the comparison in this study represents but a snapshot in time, and, thus, it is highly likely that further refinements in technique potentially will lead to an obsolescence of this comparison.
By the same token, while this prospective study is important because it enabled a justified comparison of treatments for small focal hepatomas, we must be vigilant not to generalize the favorable clinical results of one particular disease to those of other disease processes, such as multifocal or infiltrative hepatocellular carcinoma and colorectal metastases, that have been more refractory to thermal ablation treatment due to underlying biologic structures that limit treatment efficacy and not to generalize the clinical effectiveness of eradicating only limited focal lesions (6,30).
Unfortunately, the inappropriate overzealous generalization of the results (both positive or negative) of any study, particularly very early in the introduction of a given technology, can have marked, disproportionate implications in the way that other similar technologies are viewed in the future. To illustrate, if poor results, major complications, or technologic difficulties are observed with one type of RF device early in a center’s experience, it will be much harder to convince the practitioners at that center to try a "new and improved" type of RF ablation technology.
Despite the current clinical optimism generated from the substantial effects of thermal ablation on patient care, on the basis of the factors just discussed and the data presented by Shibata et al (20), the optimism probably is somewhat premature and the extant data are a little too sketchy for me to agree with the final conclusion of the article, in which the authors express a preference for RF ablation over microwave ablation for the treatment of hepatocellular carcinomas. Although RF ablation showed a trend toward increased technical success and reduced complications in this study, we must remind ourselves that this study was insufficient to enable the detection of differences in outcomes or complications. Additionally, preference based on more subjective criteria, such as ease of use, may be less than ideal since such criteria may vary from institution to institution and in different clinical scenarios. Hence, I favor the more conservative conclusion that at least one RF method has favorable characteristics for thermally ablating focal, smaller than 3 cm hepatoma nodules compared with an alternative microwave device.
Given the scope and complexity of these issues, no one study should be taken as gospel, and many studies will be needed to arrive at a rational consensus regarding the ideal methods for tumor ablation. Clearly, the next step should be a much larger multiinstitutional, preferably international, collaboration to recruit an appropriately large number of patients to make valid conclusions about the ultimate effect of these ablation technologies. There is no question that image-guided thermal ablation techniques can and have benefitted many patients, most of whom had limited or no other therapeutic options. However, the belief that these methods are as efficacious as conventional therapies such as surgery ideally should be withheld until such suppositions can be supported by the results of well-designed clinical trials that effectively and conclusively prove this point.
Many thermal ablation devices are being introduced into clinical practice with variable preclinical evaluation validation. Competitive technologies have enabled the ablation of tumors measuring 2–4 cm in diameter. However, due to the biophysiologic properties of tumors (ie, heterogeneity of tumor composition and blood flow [1]), virtually all methods are limited in their ability to achieve large-volume tumor coagulation in a reproducible and predictable fashion. Hence, several groups are studying techniques involving thermal ablation combined with adjuvant intravenous (37) or chemoembolic (38) materials. Additionally, in clinical practice, other factors, including ease of clinical use, duration of the procedure, cost, and device marketing, play a substantial role in determining which technologies receive the greatest attention. Given the rapid pace of the evolution of state-of-the-art ablation technologies, it is too early to confidently predict which method, if any, will be dominant for any given clinical application. It is likely that equivalent and excellent efficacy will be achieved with many image-guided thermal ablation technologies in the treatment of hepatocellular carcinomas, but further study is required to confirm this assertion.
We must never lose sight of the primary goal of the tumor ablation paradigm: to destroy focal tumors with use of image guidance in a minimally invasive way. We as physicians and our patients are primarily concerned with the ability to completely ablate and destroy tumors. The energy source used or the pharmaceutical injected to achieve this goal is of lesser concern, as long as we can safely, predictably, and reproducibly destroy the tumors. Hence, although thermal ablation with energy is currently receiving well-deserved attention, it is possible that this entire paradigm ultimately will be replaced by other strategies. However, at this point in time, we should begin to consider thermal ablation as an additional important tool in our battle against cancer. It is hoped that further technologic refinements will enable this technique to have a positive effect on a greater number of patients. Rigorous, well-controlled comparison of the various thermal ablation techniques, such as that initiated by Shibata et al (20), is necessary; however, it is likely that many devices will facilitate similar therapeutic outcomes due to underlying tumor biologic features. Additionally, further clinical study is mandatory for determining the most appropriate candidates for these therapies and matching the best technologies to particular disease states.
FOOTNOTES
See also the article by Shibata et al in this issue.
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