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Originally published as JCO Early Release 10.1200/JCO.2005.10.911 on January 31 2005 © 2005 American Society of Clinical Oncology.
Radiofrequency Ablation of Colorectal Liver Metastases: Where Are We Really Going?University Hospital, Aintree and Royal Liverpool University Hospital, Liverpool, United Kingdom The use of radiofrequency ablation (RFA) for the treatment of colorectal liver metastases has been approved by the US Food and Drug Administration for several years, and this therapy is now being adopted worldwide.1-4 However, US Food and Drug Administration approval of medical devices and techniques relates only to safety and feasibility, and does not relate to proven clinical benefit, which is necessary for approval of new drugs and their indications. RFA appears to be beneficial in the treatment of primary hepatocellular carcinoma, where its use has received the tentative support of the UK National Institute for Clinical Excellence.5,6 There is also growing interest in its use at other sites of colorectal cancer, including the treatment of lung metastases.7,8 RFA is being used increasingly as an adjunct to surgical resection of colorectal liver metastases,9,10 as an alternative to resection if the disease is deemed inoperable at laparotomy,11 with some authors even arguing equivalence of outcome when compared with surgical resection of low-volume liver disease.12 With the evolution of more powerful generators (commercial generators can now produce 300 W of energy, sufficient to destroy a sphere of tissue of 6 to 7 cm diameter in 10 to 20 minutes), and better results achieved by hepatic inflow occlusion,13 the responses of liver tumors to RFA destruction are now highly predictable and reproducible.14 The report by Berber et al15 in this issue of Journal of Clinical Oncology, therefore, is both timely and welcome. This study reports one of the largest prospective series of patients with colorectal liver metastases treated with RFA. The authors present an honest and frank assessment of the use of this technique, with the first large-scale study addressing predictive factors for patients undergoing this treatment. By 2003, 1 year after completion of the study period, the widely accepted definition of surgical resectability of colorectal liver metastases was essentially any number of metastases (uni- or bilobar) as long as no more than 70% of liver (five to six of the eight liver segments) needed to be removed.16 One might therefore be concerned about the definition of resectability of liver metastases employed at this particular center, in view of the fact that only 44 patients underwent liver resection during the 5-year study period, whereas 328 patients underwent laparoscopic RFA. However, the 135 consecutive patients recruited to the study already fall into a poorer prognostic group, including recurrence after previous liver resection, disease progression while receiving chemotherapy, or presence of extrahepatic disease.17,18 The authors are to be congratulated on attempting to perform laparoscopic RFA, rather than percutaneous RFA in patients after previous liver resection, bearing in mind the difficult dissection frequently encountered by experienced liver surgeons at open surgery in these patients. Berber et al15 have shown that predictive factors for better survival after RFA include a preprocedure serum carcinoembryonic antigen of less than 200 ng/mL, dominant lesion size of less than 3 cm diameter, and three or fewer tumors. Although one might wonder why patients who fell into the latter two groups were not considered for resectional surgery rather than entry to the study, these results are similar prognostic factors for outcome after hepatectomy19-27 and cryosurgery28-32 for the same condition. Taken together, these results bear out the currently accepted rule of fives (five or fewer tumors, smaller than 5 cm diameter) when selecting patients with colorectal liver metastases for RFA treatment by whatever route of access: percutaneous, laparoscopic, or open surgery. There are concerns about taking the results of the study by Berber et al15 at face value for two reasons. First, at the time of RFA, 40 of their patients (30%) had extrahepatic disease, which apparently went untreated. In this scenario, one questions the purpose of the RFA regarding whether the treatment intention was to improve the liver computed tomography scan or to change the progress of disease and the eventual overall outcome? The second concern relates to the interpretation of outcomes after any intervention for liver-only disease in the other 70% of patients in their study. It has been clear for some time that patients with liver-only disease will do better than those with liver and extra-hepatic disease, even if they receive no treatment at all.33-37 Although the study covers a period (1997 to 2002) when the predominant chemotherapy regimen in use in the United States was the combination of fluorouracil with folinic acid, some patients in the study also received irinotecan and oxaliplatin. The authors conclude that the results of their study are encouraging and suggest a survival advantage when compared with chemotherapy alone, but they do not give any data on the use of post-RFA chemotherapy treatment at the time of additional disease progression. It would be surprising if patients at this institution were not considered for second-line therapy at the detection of disease progression after apparently successful RFA, either using standard chemotherapy regimens or entry to ongoing clinical trials. The overall median survival for all patients in study by Berber et al15 of 28.9 months after RFA is similar to that of previously published series.38,39 Although the median survival was better for patients with fewer or smaller tumors, and compares favorably to historic controls of chemotherapy alone,37,40-43 these outcomes must be viewed in the light of more recent data using systemic oxaliplatin and irinotecan in first-line therapy. These recent studies44-46 have demonstrated median survivals exceeding 20 months for systemic chemotherapy alone in patients with considerably greater tumor burdens, including extrahepatic disease, at the time of presentation than the patients studied by Berber et al.15 In addition to the evolving accepted definition of liver metastasis resectability during the accrual to the study by Berber et al, it is now evident that a significant proportion (20% to 30%) of patients previously considered inoperable can be now be considered resectable with curative intent, with 30% alive and disease free after 5 years, using both oxaliplatin- and irinotecan-based chemotherapy regimens.45-50 Present directions in technologic advancement of destructive therapies for colorectal liver metastases are focused on faster and more powerful delivery systems. Cryosurgery has now been largely replaced by RFA, and industry is now developing electrolytic ablation technology51,52 and microwave destruction systems.53-55 Although these early phase I and II studies are interesting and promising, one remaining and fundamental question remains unanswered: What exactly is the place of nonsurgical destructive therapy in the treatment of colorectal liver metastases? The philosopher Abraham Maslow once said, "If the only tool you have is a hammer, then you tend to see every problem as a nail." This brings us back to the question posed by the introduction to this editorial: Just because something can be done, should it be done? The two crucial questions that must be addressed are whether destructive therapy (using whatever modality) is equal in curability to surgical resection for resectable colorectal liver metastases,12,56 and what additional survival benefit does destructive therapy have over modern systemic chemotherapy in the treatment of nonresectable disease? Only one attempt has so far been made to address the first question prospectively. This trial opened recently in France and has so far had little success in recruiting patients. The second question is currently being examined by the European Organisation for Research and Treatment of Cancer Intergroup Study 40004 (chemotherapy plus local ablation versus chemotherapy). In this study, patients are randomly assigned to either oxaliplatin with fluorouracil and leucovorin, or oxaliplatin with fluorouracil and leucovorin plus RFA, with a primary end point of overall survival and secondary end points of total eradication of disease, progression-free survival, and conversion to resectability with curative intent. This trial opened in Europe in late 2003, and so far only 70 patients of the 400 patients needed for the trial design have been randomly assigned. If this trial fails to complete its necessary recruitment, then it is highly unlikely that we will ever again be afforded the opportunity to address this question. At a time when purchasers of health care are looking ever-increasingly at the evidence base of our proposed treatments, then the need for randomized trials that evaluate the appropriateness of destructive therapies for colorectal liver metastases has never been greater. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Curley SA, Izzo F, Delrio P, et al: Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: Results in 123 patients. Ann Surg 230:1-8, 1999[CrossRef][Medline] 2. Jiao LR, Williamson RCN, Habib NA: Radiofrequency comes of age in liver surgery: Ablative technique and adjunct to resection. HPB 5:3-5, 2003 3. Gillams AR: Radiofrequency ablation in the management of liver tumours. Eur J Surg Oncol 29:9-16, 2003[CrossRef][Medline] 4. Erce C, Parks RW: Interstitial ablative techniques for hepatic tumours. Br J Surg 90:272-289, 2003[CrossRef][Medline] 5. Giovannini M, Moutardier V, Danisi C, et al: Treatment of hepatocellular carcinoma using percutaneous radiofrequency thermablation: Results and outcomes in 56 patients. J Gastrointest Surg 7:791-796, 2003[CrossRef][Medline] 6. 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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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