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Factors Influencing the Local Failure Rate of Radiofrequency Ablation of Colorectal Liver Metastases

¹ Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands
² Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
³ Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
⁴ Department of Surgery, Amphia Ziekenhuis, Molengracht 21, 4818 CK Breda, The Netherlands
⁵ Department of Surgery and Radiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Ziekenhuis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
⁶ Department of Surgery, VU Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
⁷ Department of Surgery, Maxima Medical Center, De Run 4600, 5504 DB Veldhoven, The Netherlands
⁸ Department of Surgery, Medisch Spectrum Twente, Haaksbergerstraat 55, 7513 ER Enschede, The Netherlands

Correspondence: Address correspondence and reprint requests to: F. H. van Duijnhoven; E-mail: f.h.van_duijnhoven{at}lumc.nl.

	ABSTRACT

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Background: The prognosis of patients with colorectal cancer is poor, especially when there is distant metastatic disease. Local ablation of tumor by radiofrequency ablation (RFA) has emerged as a safe and effective new treatment modality, but its long-term efficacy may be hindered by renewed local tumor growth at the site of RFA. The objectives of this study were to identify risk factors for local RFA failure and to define exclusion criteria for RFA treatment of colorectal liver metastases.

Methods: A total of 199 lesions in 87 patients were ablated with RFA. Factors influencing local failure rates were identified and compared with data from the literature.

Results: The local failure rate was 47.2%, and the average time to local disease progression was 6.5 months. Factors that significantly correlated with increased failure rates were metachronous occurrence of liver metastases, large mean lesion size, and central tumor location.

Conclusions: Because accurate electrode placement is pivotal in achieving adequate tumor necrosis, RFA should not be performed percutaneously when electrode placement is impaired. We suggest that lesions >5 cm and lesions located near great vessels or adjacent organs should be treated with open RFA, thus allowing vascular inflow occlusion and complete mobilization of the liver. Lesions that are difficult to reach by electrodes should be approached by an open procedure.

Key Words: Liver metastases • Radio frequency ablation • Local tumor control • Colorectal cancer

	INTRODUCTION

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Colorectal cancer is one of the most common malignancies in the Western world, with 500,000 new cases presenting each year. In 25% of patients, liver metastases are present at the time of diagnosis,¹ and eventually >70% of patients will develop liver metastases.^2,3 Unfortunately, only 20% of patients are eligible for curative resection of liver metastases, and a large group of patients remains for whom the development of new treatments is of the utmost importance.^4,5 These patients may benefit from local ablative techniques such as radiofrequency ablation (RFA). Needle electrodes are inserted directly into the tumor and deliver a high-frequency (200 kHz to 20 mHz) alternating current to the tissue, thus causing hyperthermia of the tissue and coagulative necrosis.

In recent years, RFA has emerged as a promising treatment option for colorectal liver metastases. Initially, reports about its efficacy were mainly positive, and no large studies into the complications of RFA were conducted. Several studies have proven RFA to be feasible and relatively safe, with tumor response rates of 52% to 95% and median survival of 30 to 37 months.^6–12 With increased follow-up time and the availability of larger patient groups, however, it became evident that although RFA may be very useful, there are also less favorable considerations.¹³ Complications do not occur very often (7.1%–9.5%),^14–17 but when encountered, they may be serious and may require surgical intervention, thus limiting the applicability of RFA to more specialized centers. Also, studies with longer follow-up showed that renewed local tumor growth at the RFA-treated site is considerable, with rates as high as 39% (Table 1).^12,18 The occurrence of serious complications and the high number of local RFA failures emphasize the need for a more precise identification of risk factors for both the occurrence of complications and local tumor growth after RFA treatment. In the current literature, the identification of these risk factors for local RFA failure is mostly limited and is often not statistically validated (Table 2). The purpose of this study, therefore, was to identify independent, validated risk factors for local tumor progression after RFA by using multivariate adjusted statistic analysis and to propose exclusion criteria for RFA treatment of colorectal liver metastases.

	PATIENTS AND METHODS

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The mean age of patients was 62 years, and distribution between the sexes was 57 men/30 women. Further patient characteristics are listed in Table 3.

Radiofrequency Ablation
RFA treatment was defined as the RFA procedure during which target lesions were treated with tumor ablation. RFA treatment was performed either percutaneously or during laparotomy under ultrasound (laparotomy) and/or CT (percutaneous) guidance. Electrodes were placed by aiming at a 1-cm ablation margin. Treatments were performed by either experienced intervention radiologists or hepatobiliary surgeons. Three different commercially available radiofrequency generators and four types of electrode systems were used in the participating treatment centers: a single electrode with deployable tines (RITA Medical Systems, Mountain View, CA, or Radiotherapeutics, Sunnyvale, CA), a linear monopolar electrode (Radionics, Burlington, MA), or a triple-electrode cluster consisting of three triangularly configured electrodes (Radionics). Specific RFA protocols designed by each of the three manufacturers were used for each system according to manufacturer recommendations.

Registration of Antitumor Efficacy and Risk Factors
Both local radiologists and an independent observer reviewed all CT scans separately. Two researchers monitored all RFA data by reviewing patient charts and laboratory and radiology reports. In accordance with the criteria and definitions proposed by the Working Group on Image-Guided Tumour Ablation,¹⁹ we defined local tumor growth after RFA as the appearance of viable tumor tissue at the site of treatment. When vital tumor tissue was seen on follow-up CT scans within 30 days after initial RFA and a repeat RFA procedure was performed to ablate the remaining tumor tissue within 90 days after the initial RFA, the initial RFA treatment was excluded from analysis, and only the results of the technical successful RFA procedure were analyzed.

For the purpose of this analysis, various parameters were registered that might influence the local tumor control rate: patient age and sex, occurrence of metastases (synchronous vs. metachronous), number of treated tumors, size of treated tumors, tumor location (central vs. peripheral), procedure approach (percutaneous vs. laparotomy), type of laparotomy (with or without concomitant liver resection), application of the Pringle maneuver, RFA generator, type of electrode, number of electrode applications per lesion (during one procedure), and number of applied RFA procedures per patient.

Statistics
Univariate analysis with a Cox proportional hazards model was performed on all parameters for all treated tumors. The variance of the estimated coefficients was adjusted by using a sandwich estimator,²⁰ accounting for possible correlations of event times of lesions and RFA procedures within patients. A P value of < .05 was considered statistically significant. All statistically significant parameters were then analyzed again by using a multivariate Cox model, also with robust estimates of standard errors. Here, again, a P value of < .05 was considered statistically significant.

	RESULTS

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A total of 199 colorectal liver metastases were ablated by 104 RFA treatments, either by a percutaneous approach (31 treatments) or by laparotomy (73 treatments). RFA was combined with hepatic resection in 29 laparotomies. A Pringle maneuver (clamping of vascular hepatic inflow) was applied during surgery in 14 cases, 3 of which concerned RFA in combination with hepatic resection. In 73 patients, a single RFA treatment was performed. Two RFA treatments were necessary in 11 patients, and 3 patients underwent 3 RFA procedures.

The average diameter of the ablated metastases was 2.9 cm (range, .5–11.0 cm): 63% of lesions were located in the right liver lobe, and 37% were located in the left liver lobe. Most lesions were ablated with deployable electrodes by using either the radiofrequency system by Radiotherapeutics (47.0%) or that by RITA Medical Systems (29.3%). The remaining lesions were treated with Radionics electrodes, either with the linear monopolar electrode (17.7%) or with the cluster electrode (6.1%).

The median patient follow-up was 25 months. The average patient survival was 27.8 months, and the mean disease-free survival was 15 months. Adequate follow-up was obtained for 158 lesions (79.4%). The remaining 41 lesions occurred in patients who were deceased, lost to follow-up, or without available CT or magnetic resonance imaging scans on follow-up. At the end of follow-up, local control was achieved in 85 lesions (53.8%), whereas 73 lesions showed local disease progression. This resulted in an overall failure percentage of 46.2%. The median follow-up of successfully treated lesions was 9.9 months (mean, 10.8 months; range, .7–27.0 months). The median time to local disease progression was 3.5 months (mean, 6.5 months; range, .7–34.2 months). Treatment and tumor characteristics of both groups are listed in Table 3.

Univariate analysis indicated that the age and sex of patients did not influence the local tumor control rate (Table 4). RFA treatment by laparotomy was associated with a lower local failure rate than treatment by percutaneous RFA (43.2% vs. 52.4%), but this difference was not significant (P = .32). Application of the Pringle maneuver did not significantly improve the local success of RFA (64.3% vs. 55.7%). Repeated RFA treatment seemed to influence local failure rates (72.2% after second RFA treatment vs. 43.1% after first RFA treatment), but this difference was not statistically significant (P = .085). It should, however, be noted that the number of lesions that were treated a second (n = 18) or a third (n = 3) time compares unfavorably with the 137 lesions that were treated with primary RFA; this hampers statistical significance. Neither the number of lesions that were treated in one RFA procedure nor the number of electrode applications per lesion correlated with increased local failure rates.

Regarding RFA treatment, we found that the type of electrode used was of considerable importance. The average diameter of lesions treated with the Radionics clustered triple electrode was 4.4 cm, with a local failure rate after RFA of 75.0%. We believe that this high percentage can be attributed largely to the high average tumor size. RITA deployable electrodes were used to treat lesions with a smaller average diameter of 2.7 cm and resulted in a local failure rate of only 26.8% (P = .0062). The RITA electrode also compared significantly favorably with the Radiotherapeutics electrode (60.3% local failure rate; P = .0062) that was used to treated lesions with a similar average diameter (2.8 cm). The difference in local failure rates with the Radionics monopolar electrode (42.9%), treating lesions of 3.0 cm average diameter, however, was not significant. The overall P value comparing the four different RFA systems was .011 and remained significant after secondary multivariate analysis.

	DISCUSSION

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In the past decade, the use of RFA for liver tumors has increased enormously, both in specialized centers and in smaller hospitals. It offers a very welcome alternative treatment for patients with isolated liver metastases who are not eligible for resection. Application is not necessarily complicated or difficult, and initial reports on its results are promising. However, the high rate of local treatment failure, as shown in our study, warrants caution when RFA of colorectal liver metastases is considered.

Several studies have reported on the rate of local failure after RFA treatment. There is remarkable variation in these reported failure rates, which range from 2.3% to 40%. One of the reasons for these variations may be the definition and assessment of local tumor growth after RFA and follow-up time. Explicitly, we use the term local tumor growth rather than local recurrence, according to the terms proposed by the Working Group on Image-Guided Tumour Ablation.¹⁹ Tumor reappearing at the site of previous RFA is not necessarily the actual new growth of tumor at that site but may rather be the outgrowth of remaining tumor cells after incomplete RFA and should therefore be distinguished from local recurrence. Different studies, especially those performed in the early days of RFA treatment for liver metastases, do not necessarily use the same definitions and diagnostic methods. For instance, one could consider either every tumor in the liver segments containing the treated RFA lesions a local failure or only those at the exact site of earlier RFA treatment. Also, the interval between RFA treatment and local tumor growth may be of importance, because one could argue that local tumor growth after > 6 months may not be due to outgrowth of remaining tumor cells after inadequate RFA treatment but that it is in fact the growth of new tumor cells: i.e., local recurrence. Regarding diagnostic methods, it should be noted that local tumor progression after RFA usually occurs at the rim of the ablated lesion and that this progress can be difficult to visualize on ultrasound or even CT scan, especially in the first months after treatment (Fig. 1). The use of positron emission tomography scanning in detection of residual tumor tissue after RFA may become more widespread in the near future, because several studies have shown a higher sensitivity of this diagnostic method compared with CT scanning.^21,22 However, the small number of patients included in these studies and the limited clinical availability of positron emission tomography scans will hamper this development. By using the standardized terms as proposed by the aforementioned working group, these differences may be prevented, thus enabling a more reliable comparison of study outcomes.

View larger version (37K): [in this window] [in a new window]   FIG. 1. Radiofrequency ablation–treated lesion at 1 month, with residual tumor tissue at the rim of the treated lesion, as indicated by the arrow.

Nevertheless, our study clearly identifies factors that influence local failure rates. In accordance with earlier findings, we show that the size of the treated tumor is the most important factor in the efficacy of total tumor ablation with RFA,^{10,12,23–27} and local treatment failure rates correlate with increased tumor size. In our opinion, this is due to the difficulty of placing adequate overlapping electrodes in large tumors. At present, real-time imaging of the induced necrosis is not available, so careful planning of electrode placement before commencing the procedure is essential. Upcoming developments in stereotactic three-dimensional imaging techniques may be very helpful to improve electrode placement but at the same time will further complicate the RFA procedure.^28,29

The other factors that influence the rate of local tumor growth after RFA are similarly associated with an impaired ability to achieve adequate treatment margins. It is not the size of the treated tumor itself, but the difficulties in achieving sufficient necrosis in all tumor areas, that hinders adequate ablation. This is reflected in the high rate of local tumor growth after treatment of tumors located centrally in the liver, near its large vessels. The proximity of vessels restricts the placement of electrodes, and possibly not all tumor tissue is ablated as a result of a heat-sink effect.^30,31 In such instances, application of the Pringle maneuver, which consists of the temporary occlusion of inflow via the portal vein and hepatic artery, may be indicated. Our results did not show significantly increased tumor control after RFA with the Pringle maneuver, but because this maneuver was applied in only 13 patients, a definite recommendation regarding its use can at present not be made.

When access is limited because of a location of tumors high up in the liver, this may also result in inadequate ablation. These lesions should be approached by an open procedure that allows complete mobilization of the liver. In light of this theory, we expected local failure rates after percutaneous RFA to be higher than those after an open procedure, because the latter allows for better electrode accessibility and visibility. This was indeed the case, because the incidence of local failure after percutaneous treatment was almost 10% higher than after laparotomy, but these findings were not significant. The relatively small number of patients who were treated with percutaneous RFA (31 patients vs. 73 patients with RFA by laparotomy) may partly explain these results, and more pronounced differences might be seen with more treated patients.

Hypothetically, the type of electrode used for RFA may also influence local recurrence, because there are two types of electrodes in use: electrodes with expandable needles that induce spherical necrotic lesions with diameters ranging from 2 to 7 cm and single electrodes that result in a cylindrical necrotic lesion with a diameter of up to 3 cm. Expandable electrodes may improve the ablation of large tumors that require multiple electrode insertions, because overlapping margins can be more safely achieved. This is partly confirmed by the results of our study, although we did not explicitly find differences in local tumor control between expandable (Radiotherapeutics or RITA Medical Systems) and linear (Radionics) electrodes. We did, however, find significant differences between the electrode types. The deployable RITA Medical Systems electrodes showed the lowest local failure rate of only 26.8%, as opposed to failure rates > 60% for the Radiotherapeutics deployable electrode and the Radionics clustered triple electrode. Of course, both the small number of lesions treated with the cluster electrode (n = 8) and the fact that the triple electrode is specifically used for larger lesions should be taken into account when interpreting these results. The difference between these deployable electrodes, however, is remarkable, because >40 lesions were treated with each system. Although the expandable electrodes are similar in design, the method used to determine the end point of tumor ablation is different in both generators. The treatment end point of the Radiotherapeutics system is determined by impedance measurements: tissue necrosis is considered to be complete when impedance reaches a certain level, with a corresponding reduction in power (roll-off). The treatment end point of the RITA Medical Systems generator, conversely, is heat based: at the tips of the expandable tines, thermocouples measure local temperatures at the rim of the induced lesion. Tissue necrosis is considered to be complete when sufficiently high temperatures are induced throughout the spherical lesion and maintained for certain duration.

Arata et al.³² evaluated the correlation of the roll-off technique with tissue necrosis. In RFA of 20 hepatic tumors, 3 of which were liver metastases from colorectal carcinoma, roll-off was achieved in 11 lesions. Local recurrence occurred in only one of these lesions but was observed in five of nine lesions treated without achieving roll-off. With only three colorectal metastases included in this retrospective analysis, it may be possible that the roll-off technique does not adequately predict tissue necrosis after RFA of colorectal liver metastases. Of course, even though our analysis corrected for within-patient correlation, we should consider the possibility that the use of varying RFA systems is institution related. Therefore, we cannot conclude without restrictions that certain electrode systems are more effective than others.

Considering the above-mentioned pitfalls and problems when striving for local tumor control with RFA, we advise that application of RFA should not be lightly embarked on. It requires specialized experience and skills to insert all electrodes properly, especially in larger tumors or tumors located near large vessels or adjacent organs. If the tumor is not completely ablated, there will be no positive effect on overall or disease-free survival, thus depriving the procedure of its effectiveness. Because placement of electrodes is essential, adequate treatment planning is of pivotal importance. CT scans and ultrasonography may contribute to achieving this goal, and future three-dimensional stereotactic electrode placement may further improve RFA results. We would also recommend an extensive pretreatment work-up with abdominal and thoracic CT scans, preferably within 2 weeks before treatment. This will avoid nonbeneficial treatment with its associated risk of complications for patients with nonresectable extrahepatic disease.

In summary, we suggest the following exclusion criteria for treatment of liver tumors with RFA: nonresectable extrahepatic disease, tumor size > 5 cm, tumor location near central vascular structures, or tumors in difficult locations in patients who are not eligible for on open procedure. Differences in anti-tumor efficacy of the various available RFA electrode systems need to be further assessed in a randomized, prospective setting before any specific recommendations can be made regarding these systems.

Considering the disappointing rate of local tumor control with RFA, resection of liver metastases is always preferable and is associated with significantly higher survival rates.³³ In addition, the efficacy of RFA is highly dependent on adequate electrode placement. We therefore strongly believe that assessment of patient suitability for RFA, hepatic resection, or both should always be performed in a multidisciplinary setting. Resectability of liver metastases should be determined by a hepatobiliary surgeon before RFA is considered. Application of RFA, possibly in combination with hepatic resection, should then be performed by an experienced radiologist.

Received for publication August 10, 2005. Accepted for publication November 3, 2005.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Duijnhoven, F. H. Articles by Tollenaar, R. A. E. M. Search for Related Content PubMed PubMed Citation Articles by van Duijnhoven, F. H. Articles by Tollenaar, R. A. E. M.