Radiofrequency ablation in liver tumours

Transcription

1 Annals of Oncology 15 (Supplement 4): iv313 iv317, 2004 doi: /annonc/mdh945 Radiofrequency ablation in liver tumours S. Benoist & B. Nordlinger Department of Digestive and Oncologic Surgery, Ambroise Paré s Hospital, Boulogne, France Introduction Hepatic malignancies are extremely common and often present a therapeutic dilemma. Worldwide, hepatocellular carcinoma (HCC) is one of the most widespread solid cancers, with an estimated incidence of at least one million new patients per year [1]. Similarly, colorectal carcinoma is common in the western world and liver metastases develop in nearly 40% of patients with this cancer and represent the major cause of death in this disease [2]. Surgical resection of metastatic liver tumours is considered to be the optimal treatment modality that can, to date, ensure long-term survival and cure in some patients [3]. Similarly, when feasible, surgical resection or liver transplantation should be considered first for primary liver tumours [4]. Unfortunately, only 20% of patients with liver tumours are suitable for surgery [5, 6]. In patients with unresectable disease, several non-resectional procedures have been assessed in order to provide local control. In this setting, tumour ablative techniques have been developed in recent years and include cryotherapy, radiofrequency (RF) ablation and laser hyperthermia. Among these techniques, RF has become the most widely used ablative technique for primary and secondary liver tumours [7 15]. This paper will review the technique, indications, complications and results of RF for the treatment of the two most common hepatic tumours, i.e. HCC and colorectal liver metastases. Background and basics of RF tissue ablation Technical features During the application of RF energy, a high frequency alternating current ( khz) moves from the tip of an electrode into the tissue surrounding the electrode. The RF current induces ionic agitation, which in turn results in heating. As the temperature within the tissue becomes elevated above 608C, cells start to die, resulting in a region of necrosis surrounding the electrode [16]. Different types of electrode designs are available, including a water-cooled cluster of three parallel 19G electrodes (Tyco Healthcare, Mansfield, MA, USA), two expanding electrodes (Radiotherapeutics and RITA Medical Systems, Mountain View, CA, USA) and a stiff electrode (Berchtold, Tuttlingen, Germany). A comparison, in an experimental model, between different types of electrodes, showed no major difference concerning the volume of induced necrosis [17]. The thermal injury to the tumour is inversely related to blood flow in the tumour due to washout effect. Tissue perfusion has a direct impact on the volume of necrosis that can be induced [8, 16]. Occlusion of liver vessels, either the portal vein, the hepatic artery or both, has been shown to increase the volume of necrosis, but it requires a laparotomy [8, 18]. Occlusion of the hepatic artery of the liver segment involved by the tumour is also possible through a percutaneous approach using angiographic balloon or transhepatic portal balloon [19]. The area of necrosis induced by RF ablation should be 1 cm larger than the size of the tumour, similar to the surgical margin obtained after surgical resection. Tumours less than 3 cm at their greatest diameter, can be destroyed with one placement of the needle electrode, with an array diameter of cm, when the electrode is positioned in the centre of the tumour [13, 20]. For larger tumours, multiple placements or deployment of an electrode array may be necessary to destroy completely the tumour [13, 21]. However, for such larger tumours, completeness of tumour destruction may be more uncertain [22]. RF approach RF ablation of liver tumours can be performed percutaneously, under laparoscopy or during laparotomy. There are no studies comparing these three routes. The indications of these approaches are different and their choice is individualized. The percutaneous approach is less invasive than laparotomy, which can be a problem in a patient with liver cirrhosis. It can be performed under general or local anaesthesia as an outpatient procedure, carries a lower morbidity and complication rate and is less expenzive [7, 11, 13, 16]. However, lesions located in the dome of the liver near the diaphragm or close to the stomach or colon are not always accessible by a percutaneous approach due to the risk of injury of adjacent organs. Thus, a percutaneous approach is indicated in patients with small HCC and underlying cirrhosis or in patients with recurrent liver metastases after a first surgical resection. The laparoscopic approach requires a high level of skill. It is guided by laparoscopic ultrasound and allows a good evaluation of the number and location of liver tumours. It also allows a survey of the peritoneal cavity to exclude the presence of extra-hepatic disease, which is not possible by the percutaneous approach. The laparoscopic approach can be q 2004 European Society for Medical Oncology

2 iv314 useful in tumours located centrally in the liver near major intrahepatic blood vessels since it allows a more precise positioning of the RF needle [23]. The laparoscopic approach is also indicated when the tumour is adherent to structures that may be damaged by thermal ablation such as the colon, stomach or duodenum [7, 16]. Laparotomy is more invasive than the percutaneous approach, but allows inspection of the peritoneal cavity to rule out extra-hepatic disease. When combined with peroperative ultrasound, it can detect small liver lesions, which may have been overlooked during preoperative imaging work-up. The RF ablation can also be combined with liver resection: e.g. resection of a large tumour in one lobe can be combined with RF ablation of small deposits in the opposite lobe [7, 13, 24]. Monitoring the effectiveness of the procedure and follow-up Ultrasound has been used to assess the completeness of the procedure, but the hyperechogenic image seen during thermal ablation does not correlate with the coagulative damage [7, 8] and the image becomes heterogeneous within minutes. Both computed tomography (CT) scan and magnetic resonance imaging (MRI) seem to be more reliable [7]. Contrast-enhanced CT scan is the preferred examination for follow-up. A peripheral rim, which represents an inflammatory reaction to the thermally damaged cells, must resolve within 1 month. After this delay, persistent or new perilesional enhancement is considered to be residual or recurrent tumour, in particular when it increases in size during follow-up [7]. Comparable images are obtained with MRI. More recently, fluorodeoxyglucose positron emission tomography (FDG-PET) scan has been assessed for the follow-up of local ablative treatment [25]. In the study, the positive predictive value and the negative predictive value of FDG-PET scan for detection of local recurrence was 80% and 100%, respectively [25]. Morbidity and mortality of RF ablation Overall, RF ablation of liver tumours is well tolerated. Common side-effects following the procedure include minimal right upper quadrant discomfort, transient fever and nausea and usually asymptomatic right pleural effusion. Deterioration in liver function tests is also common with complete recovery within 1 week [11]. The morbidity rate varies from 2% to 10% and the mortality rate is below 1.5% [9, 12, 15, 18, 26 28]. In a recent meta-analysis including 3670 patients with hepatic malignancies treated by percutaneous, laparoscopic or open RF ablation, the mortality and the morbidity rates were 0.5% and 9%, respectively [26]. The complication rate and mortality were comparable for the three RF ablation approaches. The causes of death were hepatic abscess, liver failure, cardiac complications and peritoneal haemorrhage. Deaths related to colon perforation have also been reported [27, 29]. The more frequently encountered complications were hepatic abscess, abdominal bleeding, biliary tract injuries, liver failure and pulmonary complications [26, 27, 29]. Several risk factors for complications can be identified. Complications after RF ablation for HCC are more common in patients with a stage C cirrhosis according to the Child Pugh classification [26]. Portal vein thrombosis occurs more frequently in patients with a cirrhotic than in a non-cirrhotic liver, especially in case of combined blood flow occlusion [27]. Liver abscess occurred more frequently in patients with a bilioenteric anastomosis [27]. Subcapsular tumours carry a higher risk of abdominal bleeding, especially with a percutaneous approach. This complication may be prevented by careful cauterization of the electrode tract. Central tumours predispose to biliary tract and central vessel damage and there is a consensus that tumours closer than 1 cm to the main biliary duct are a contraindication for RF. Thermal damage to neighbouring organs is found exclusively in the percutaneous approach. The knowledge of these risk factors should help to lower the complication rate of RF ablation. In many centres, RF ablation has now replaced cryoablation because of its lower complication rate. RF ablation of hepatocellular carcinoma Indications and contraindications RF ablation is a minimally invasive and safe technique for the non-surgical treatment of HCC. It is usually performed by a percutaneous approach under ultrasound or CT scan guidance. It is indicated as first-line treatment in patients with a cirrhotic liver and a small HCC (<5 cm) confined to the liver that is unresectable due to limited liver reserve or compromised liver function [12]. The technique is difficult for patients with multiple tumours (more than three) because of the need of repeat puncture. Another indication is a tumour recurrence within a liver remnant after curative liver resection, where further resection is not possible because of limited liver reserve. In this situation, RF ablation is indicated if the tumours are relatively small, limited in numbers and confined to the liver [12]. A third potential indication of RF ablation is in patients with HCC waiting for liver transplantation [30]. RF ablation could be used to reduce the risk of progression of the disease during this period, which could contraindicate liver transplantation. RF ablation is contraindicated in patients with important ascites, coagulopathy that cannot be corrected and obstructive jaundice due to a potential risk of bleeding and bile peritonitis. There is an increased risk of bleeding when the tumours are located at, or protruding from, the liver surface [12, 19]. Results for HCC Most of the data published on RF ablation of HCC have a limited follow-up (Table 1). In the series including more than 40 patients, local recurrence rate at the ablation site following RF ablation varied greatly, ranging from 4% to 30% [14, 31 36].

3 iv315 Table 1. RF ablation for hepatocellular carcinoma Authors Year No. of patients Size of lesions (cm) Mean follow-up (months) Local Recurrence Other liver (%) Survival rate (%) 1 year: 2 years: 3 years Rossi et al. [31] <_ : 86: 68 Curley et al. [14] mean: Buscarini et al. [32] <_ Chan et al. [33] <_ Lencioni et al. [34] < : 98: - Harrison et al. [35] mean: Guglielmi et al. [36] <_ : 63: 45 It is clearly established that tumour size is a risk factor for recurrence after RF ablation [12, 28, 35]. A complete necrosis can be achieved in 90% of the lesion less than 3 cm. Tumours larger than 5 cm have a lower percentage of complete necrosis and a higher rate of recurrence [35, 36]. Other risk factors for local recurrence are a high pre-treatment alpha-fetoprotein level, tumour alpha-fetoprotein production and hepatitis C infection [12, 35]. It suggests that in addition to treating the primary tumour, other therapies aimed at the liver s inflammatory state might also be important in achieving a durable response after RF ablation. RF has been compared with percutaneous ethanol injection in two randomized trials and shown to have a higher complete ablation rate in fewer treatment sessions but also a higher complication rate [37, 38]. A major problem of RF ablation is tumour recurrence in the remnant liver, which ranges from 30% to 50% [14, 31, 35, 36]. Several hypotheses can explain this high intrahepatic recurrence rate. Lesions less than 1 cm in diameter may have been overlooked. HCC can invade the tributary of the portal branches and shed tumour emboli into the neighbourhood of the same liver segment. One way to decrease intrahepatic recurrence rate would be to administer adjuvant treatment after RF ablation. To date, only one prospective randomized study has shown that treatment with interferon-alpha could prevent recurrence after RF ablation of HCC [39]. Another potential problem of RF ablation is tumour seeding, especially for subcapsular and poor differentiated tumour. This risk could be reduced by performing thermocoagulation of the needle track while removing the needle. Despite the high locoregional recurrence rate, the overall survival rate after RF ablation of HCC [5, 31] is comparable to that reported after surgical resection, ranging from 66% to 73% at 3 years [4, 5]. Whether RF ablation for small HCC could provide similar long-term survival to surgical resection needs to be tested in a prospective randomized study. RF ablation of liver metastases Only surgical resection can offer long-term survival rates in 25% 30% of patients. Only 10% 20% of patients with liver metastases fulfil criteria for resection and are amenable to surgery. The trend is to be more aggressive and to widen the indications for surgical resection [6]. RF has been developed in recent years for the treatment of liver metastases. Its efficacy has not been tested in randomized trials and the use of RF ablation should be restricted at the moment to the treatment of unresectable liver deposits. The basic idea is to use it in patients with a limited number of intrahepatic deposits that are not totally resectable due to their location in the liver. Tumour ablation can be used alone or in combination with liver resection, some metastases being resected and others ablated [6, 7, 13, 24]. All the metastatic disease has to be treated. Another potential indication of RF ablation is patients with liver recurrence after hemi-hepatectomy [40]. Table 2. RF ablation for liver metastases Authors Year No. of patients Size of lesions (cm) Mean follow-up (months) Local Hepatic or extra-hepatic Survival rate (%) 1 year: 2 years: 3 years Curley et al. [18] mean: Wood et al. [41] mean: De Baere et al. [42] mean: : -: - Gillams & Lees [43] mean: : 60: 34 Solbiati et al. [20] mean: : 69: 46 Bowles et al. [44] mean: Pawlik et al. [9] <_ : 70: 50 Mutsaerts et al. [10] mean:

4 iv316 The results of RF ablation of colorectal liver metastases are difficult to evaluate. In many studies, several different types of tumours are included. Some patients have received chemotherapy and others not, which can bias the interpretation of the primary effect of RF treatment. In addition, results on local tumour control are often reported differently, either as the number of failures on a lesion basis, or as a number of patients with local recurrence in relation to the total number of patients treated. As shown in Table 2, it seems that for lesions up to 3 cm, RF is effective and can result in local tumour control in more than 90% of patients. For lesions larger than 3 cm, local recurrence rate at the site of treatment is more than 30% [21, 44]. The risk of recurrence was not related to the number of lesions ablated or RF ablation approach (laparotomy, laparoscopy or percutaneous) [13]. The development of new hepatic tumours or extrahepatic disease is a crucial problem of RF ablation and occurs in 30 60% of patients [9, 18, 20, 42, 43]. Thus, RF ablation may not be sufficient by itself and may require combination with chemotherapy. Since RF ablation is safe and effective to induce necrosis of liver metastases up to 3 cm in diameter, it must now be proven that this local effect can be translated into a survival benefit for the patient. This would require clinical trials comparing RF ablation with what is considered the standard treatment. In theory, two types of studies may be performed. In the first type of study there is a comparison between RF ablation and surgical resection in patients with resectable metastases. Such a study has recently been started in France (essai FFCD ). Another type of study concerns patients with unresectable liver metastases for whom standard treatment is palliative chemotherapy. A trial organized by the European Organization for Research and Treatment of Cancer (CLOCC trial) compares chemotherapy alone with chemotherapy plus RF ablation. It is likely that in the near future, most patients with liver metastases will receive multi-modality treatment including surgical resection, RF ablation and systemic chemotherapy. Conclusion It is now clearly demonstrated that RF can safely and efficiently destroy small liver lesions and that is has its place in the management of hepatic malignancies. However, the impact of RF on the survival of patients with primary liver tumours or liver metastases remains to be demonstrated in welldesigned clinical trials. It is of utmost importance that surgeons and medical oncologists enrol their patients in the ongoing studies. References 1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340: Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. 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