This study received no grant or financial support, and none of the authors have any conflicts of interest to declare.

Transcription

1 LIVER TRANSPLANTATION 20: , 2014 ORIGINAL ARTICLE Pilot Study of High-Intensity Focused Ultrasound Ablation as a Bridging Therapy for Hepatocellular Carcinoma Patients Wait-Listed for Liver Transplantation Kenneth S. H. Chok, 1 Tan To Cheung, 1 Regina C. L. Lo, 2,3 Ferdinand S. K. Chu, 4 Simon H. Y. Tsang, 1 Albert C. Y. Chan, 1 William W. Sharr, 1 James Y. Y. Fung, 2,5 Wing Chiu Dai, 1 See Ching Chan, 1,2 Sheung Tat Fan, 1,2 and Chung Mau Lo 1,2 1 Department of Surgery, 2 State Key Laboratory for Liver Research, 3 Department of Pathology, 4 Department of Diagnostic Radiology, and 5 Department of Medicine, The University of Hong Kong, Hong Kong SAR, China The objective of this study was to investigate the outcomes of high-intensity focused ultrasound () ablation as a bridging therapy for patients with hepatocellular carcinoma (HCC) who had been wait-listed for deceased donor liver transplantation (DDLT). Adult patients with unresectable and unablatable HCCs within the University of California San Francisco criteria who had been wait-listed for DDLT were screened for their suitability for ablation as a bridging therapy if they were not suitable for transarterial chemoembolization (). Treatment outcomes for patients receiving ablation,, and best medical treatment (BMT) were compared. Fifty-one patients were included in the analysis. Before the introduction of ablation, only 39.2% of the patients had received bridging therapy ( only, n 5 20). With ablation in use, the rate increased dramatically to 80.4% ( 1, n 5 41). The overall dropout rate was 51% (n 5 26). Patients in the BMT group had a significantly higher dropout rate (P ) and significantly poorer liver function as reflected by higher Model for End-Stage Liver Disease scores and higher Child-Pugh grading. Clinically relevant ascites was found in 5 patients in the group and 2 patients in the BMT group, but none was found in the group (P and P , respectively). The and groups had comparable percentages of tumor necrosis in excised livers (P ), and both were significantly higher than that in the BMT group (P and P , respectively). In conclusion, ablation was safe even for HCC patients with Child-Pugh C disease. Its adoption increased the percentage of patients receiving bridging therapy from 39.2% to 80.4%. A randomized controlled trial for further validation of its efficacy is warranted. Liver Transpl 20: , VC 2014 AASLD. Received October 10, 2013; accepted April 9, Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high prevalence in Asia and with an increasing incidence in Western countries. 1 It is the third most common cancer causing deaths in Hong Kong. 2 The resectability rate for HCCs is just 20%, and hence the prognosis for the majority of HCC patients remains poor. 3,4 Liver transplantation (LT) is the only surgical treatment option for HCC patients with Child-Pugh C disease. It can eliminate liver tumors as well as the diseased cirrhotic liver. However, because of the grave scarcity of liver grafts, patients on the LT waiting list have to suffer a long Abbreviations: AFP, alpha-fetoprotein; BMT, best medical treatment; DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma;, high-intensity focused ultrasound; INR, international normalized ratio; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; mrecist, modified Response Evaluation Criteria in Solid Tumors; RFA, radiofrequency ablation;, transarterial chemoembolization; UCSF, University of California San Francisco. This study received no grant or financial support, and none of the authors have any conflicts of interest to declare. Address reprint requests to Kenneth S. H. Chok, M.B.B.S., Department of Surgery, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong SAR, China. Telephone: ; FAX: ; kennethchok@gmail.com DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2014 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 CHOK ET AL. 913 and indefinite wait, during which their disease may deteriorate. There are different bridging therapies for keeping patients on the wait list long enough for liver grafts. At our center, only transarterial chemoembolization () with lipiodol has been regarded as a bridging therapy. Aimed at hindering disease progression, it is effective in improving survival and controlling symptoms, as shown in many studies. combines the effects of targeted chemotherapy and ischemic necrosis induced by arterial embolization. A prospective randomized controlled trial of at our center demonstrated its significant survival benefit. 5 Nonetheless, is not applicable in certain situations, 6 so other forms of bridging therapy must be developed. High-intensity focused ultrasound () ablation is a relatively newly developed treatment. It is the only treatment modality that is completely extracorporeal. 7 It is based on the unique characteristic of ultrasound beams ( MHz), which can be focused at a distance from the radiating transducer. induces cell death by both thermal coagulation and a cavitation effect (Fig. 1). The ability to induce immediate cell death at a distance from the ultrasound source makes ablation an attractive option for treating HCC without the need for surgery or the insertion of ablation instruments. Initial clinical results for ablation obtained from researchers in China are encouraging in terms of significant tumor shrinkage and the prolonged survival of patients Our previously published data from a retrospective analysis showed that could achieve favorable radiological responses from unresectable HCCs without significant morbidity or mortality even in select patients with Child-Pugh C cirrhosis. 12,13 In addition to good radiological responses, satisfactory rates of tumor necrosis according to histological examinations of excised livers have also been found in a few transplant recipients. 13,14 The good safety profile of ablation provoked the initiative of performing a prospective pilot study, a major step before any randomized controlled trial, to determine its efficacy in treating patients with unresectable HCC on the LT waiting list. This study also compared treatment outcomes of patients undergoing ablation, patients undergoing, and patients undergoing the best medical treatment (BMT) during the same study period, with pathological examination used as the gold standard for comparison. PATIENTS AND METHODS This pilot study was a single-center, prospective trial conducted at Queen Mary Hospital by the Department of Surgery of the University of Hong Kong. The study period was January 2011 to June It is registered at HKClinicalTrials.com, and the protocol number is HKCTR The study protocol was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (reference number UW ). All adult patients Figure 1. Microscopic examination of the effects of on a tumor (HCC with partial tumor necrosis). A viable tumor (A) is shown and ghost shadows of tumor cells are observed in the necrotic area (B). with unresectable and unablatable HCCs within the University of California San Francisco (UCSF) criteria who had been wait-listed for deceased donor liver transplantation (DDLT) were recruited. 15 The diagnosis of HCC was based on elevated levels of alphafetoprotein (AFP) and a typical appearance on imaging according to the criteria of the European Association for the Study of the Liver 16 (a patient with cirrhosis and with 2 image scans showing a focal lesion > 2cm with arterial hypervascularization or with 1 image scan showing a focal lesion > 2 cm with arterial hypervascularization and a serum AFP level > 400 ng/ml). Patients who had extrahepatic disease or refused to participate were excluded. Patients with satisfactory liver function were offered first. We regarded the following as contraindications to : Child- Pugh C disease, portal vein thrombosis, hepatic artery thrombosis, renal failure, clinically relevant ascites, arteriovenous shunting, and severely impaired liver function [hepatic encephalopathy, international normalized ratio (INR) > 1.5, and serum total bilirubin level >50 lmol/l]. 6 When was precluded by poor liver function, a screening ultrasound session was offered, and if ultrasound localization was impossible, BMT was offered. We regarded a serum total bilirubin level >100 lmol/l and subcutaneous tissue thicker than 3.5 cm (which would absorb a substantial amount of energy from the energy pathway) as contraindications to therapy. For the sake of patient homogeneity in the study, patients who finally underwent living donor LT were excluded. Ablation The JC Haifu system (Chongqing Haifu Technology, Chongqing, China) was used. A single hepatobiliary surgeon and a single radiologist, both accredited by Chongqing Haifu Technology and experienced, carried

3 914 CHOK ET AL. LIVER TRANSPLANTATION, August 2014 out all the procedures. Details of the procedure have been described elsewhere. 12 In brief, the administration of general anesthesia was necessary to prevent deep visceral pain and to ensure the immobilization of the patient. After anesthesia had been induced, the patient was carefully positioned in a prone or right lateral position so that the skin overlaying the lesion was in contact with a degassed water tank. The tumor was located by an ultrasound probe, which was incorporated into the treatment device. A treatment plan was devised with 3-dimensional reconstruction of the tumor boundary with 5-mm-separated sections. With the movement of the high-intensity ultrasound focus in successive sweeps from deep regions to shallow regions of the tumor, the targeted region in each planned section was ablated. This process was repeated section by section until the whole tumor was completely ablated. During the ablation of each section, real-time ultrasound images obtained before and after each exposure were immediately compared to determine whether echogenic changes (ie, grayscale changes), which indicated the extent of coagulation necrosis, had covered the desired treatment area. Tumors situated at the liver dome might require rightsided artificial pleural effusion (usually 800 ml of normal saline was instilled). The presence of gross ascites facilitated ablation because the water medium made ultrasound visualization clearer. Magnetic resonance imaging was performed 1 month after ablation. If residual disease was found, another session of ablation was offered as long as the patient s subcutaneous tissue was 3.5 cm thick on imaging (previous ablation might have caused significant tissue edema and rendered ultrasound localization impossible). Cisplatin was used as the chemotherapeutic agent and was delivered with lipiodol, and this was followed by Gelfoam particle embolization. Selective cannulation and embolization of the feeding arteries of the tumors were performed whenever possible. Technical details of the procedure have been described elsewhere. 4 was usually repeated every 2 to 3 months until the development of tumor progression, liver intolerance, or other severe complications. Prioritization Adjustment Scheme for HCC Patients on the LT Waiting List (Modified From the United Network for Organ Sharing) Since October 1, 2009, HCC patients have been given a prioritization adjustment on the LT waiting list to reflect the urgency of tumor progression. 17 The adjustment is modified from the guidelines of the United Network for Organ Sharing of the United States. All adult patients with T2 HCCs are assigned a new Model for End-Stage Liver Disease (MELD) score of 18 after a 6- month wait on the list as long as there has been no tumor progression beyond T2. During the 6-month wait, the patients continue to receive necessary bridging therapies as clinically indicated. Two bonus points are added to the score with every subsequent 3-month wait. For patients with T2 HCC and decompensated liver function (MELD score > 18), the baseline score is taken as their calculated MELD score, and 2 bonus points are added to the score with every subsequent 3- month wait. Patients whose disease is beyond T2 but still within the UCSF criteria will have their MELD score frozen. Patients whose disease has progressed beyond the UCSF criteria will be delisted. Our center does not adopt any down-staging protocol. Pathological Examination of Excised Livers Each excised liver was examined grossly for the number of tumor nodules and the maximum dimensions of each nodule. Representative tissue in each case was submitted for histological examination. Hematoxylin and eosin sections were reviewed by an anatomical pathologist to assess the percentage of tumor necrosis. Statistical Analysis Pearson s chi-square test or Fisher s exact test was used to compare categorical variables. The Mann- Whitney U test was used to compare nonparametric continuous variables, which were presented as medians and ranges. The Student t test was used to compare parametric continuous variables, which were presented as means and standard deviations. The Kaplan-Meier method was used for survival analysis, and the log-rank test was used for variable comparisons. P values < 0.05 were regarded as statistically significant, and all P values were 2-tailed. The primary endpoints were the dropout rate, the tumor necrosis rate in excised livers, and the radiological response according to the modified Response Evaluation Criteria in Solid Tumors (mrecist). 18 The secondary endpoint was short-term dropout-free survival. The survival analysis was based on the intention-to-treat principle. RESULTS Fifty-two patients were recruited, but 1 patient was excluded because of a refusal of transplantation. Twentyfive patients underwent DDLT and were analyzed. Twenty-one patients received ablation as the sole primary bridging therapy after listing, and 20 patients received as the sole primary bridging therapy after listing. Ten patients could not undergo either therapy because of failed ultrasound localization or poor liver function test results, and they received BMT. Figure 2 outlines the study protocol for the patients. The overall dropout rate was 51% (26 of 51 patients). The rate of patients receiving bridging therapy increased dramatically from 39.2% (only 20 patients received ) to 80.4% after the adoption of therapy [41 patients received (n 5 20) or (n 5 21)]. The dropout rates for the,, and BMT groups were 52.4% (n 5 11), 40% (n 5 8), and

4 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 CHOK ET AL. 915 Figure 2. Treatment protocol for wait-listed patients with unresectable and unablatable HCC. 70% (n 5 7), respectively (P ). The and groups were comparable in terms of most of the clinical parameters (Table 1). Patients in the BMT group had significantly worse liver function (Table 1). No patient received therapy before salvage transplantation (transplantation performed to treat HCC recurrence after tumor resection), possibly because previous abdominal wall scarring tends to make ultrasound visualization difficult. Five patients in the group and 2 patients in the BMT group had clinically relevant ascites. Only 1 patient received ablation for a second time for residual disease on magnetic resonance imaging. When we compared all patients (including dropouts) in the and groups, we found that patients in the group had significantly higher MELD scores (17 versus 10, P ), serum total bilirubin levels (47 versus 27.5 lmol/l, P ), INRs (1.5 versus 1.2, P ), and Child- Pugh grades (P ). Moreover, significantly more patients in the group had clinically relevant ascites (14 versus 3, P ; Table 2). When we compared dropouts and transplant patients, we found that the latter had significantly lower MELD scores (11 versus 15, P ), serum AFP levels (11 versus 293 ng/ml, P ), and serum creatinine levels (76 versus 83 lmol/l, P ). Moreover, significantly fewer of the transplant patients had clinically relevant ascites (7 versus 15, P ; Table 3). Four patients in the group and 3 patients in the group had 75% to 100% necrosis (P ). Patients in the 3 groups had comparable cancer staging (Table 4). Tumors in the group had better radiological responses according to the mrecist criteria than tumors in the BMT group (P ; Table 5). The BMT group had the highest dropout rate among the 3 groups (P ; Fig. 3). A competing risk analysis led to a similar finding (P ; Fig. 4). At the time of the writing of this article, all transplant patients were alive with no recurrence of disease. DISCUSSION In Hong Kong, because deceased donor liver grafts are extremely scarce, HCC patients are eligible and hence listed for DDLT only if their tumors are unresectable

5 916 CHOK ET AL. LIVER TRANSPLANTATION, August 2014 TABLE 1. Clinical Data for the 3 Groups of LT Patients P Value (n 5 10) (n 5 12) BMT (n 5 3) BMT BMT Sex: male/female (n/n) 8/2 10/2 3/0 >0.99 >0.99 >0.99 Age (years)* 60.5 (49-65) 58 (45-67) 62 (45-63) Diagnosis (n) Cirrhosis Primary biliary cirrhosis Chronic active hepatitis Salvage transplantation (n) Real MELD score* 12 (9-18) 10 (6-12) 23 (14-25) Hepatitis B virus (n) Hepatitis C virus (n) Waiting time for LT (days)* 416 ( ) ( ) 278 ( ) Donor age (years)* 56.5 (22-77) 44.5 (27-60) 43 (42-65) AFP (ng/ml)* 7.5 (1-244) 6 (2-817) 1090 ( ) Total bilirubin (lmol/l)* 27.5 (15-82) 19 (3-40) 179 (61-365) INR* 1.35 ( ) 1.2 ( ) 1.5 ( ) Platelet count (310 9 /L)* 40 (21-151) 70.5 (32-161) 47 (33-100) Aspartate aminotransferase (U/mL)* 49.5 (24-104) 46.5 (20-81) 58.5 (45-72) Alanine aminotransferase (U/mL)* 29 (20-138) 30.5 (16-194) 33 (12-45) Creatinine (lmol/l)* 76 (58-101) 72.5 (56-106) 78 (70-82) Child-Pugh class (n) A B C Presence of ascites (n) > *The data are presented as medians and ranges. Ascites that required repeated abdominal paracentesis. and unablatable and are within the UCSF criteria. Among those listed, 20% to 30% have substantial disease progression. 19,20 Bridging therapy is an important tool for hindering tumor growth and progression. Previously at our center, only was considered as a bridging therapy. Although it has been shown to be an effective treatment in various randomized controlled trials, 5,21 contraindications (eg, severe liver dysfunction, renal failure, refractoriness after multiple sessions, hepatic artery complications, and gross ascites) are common. To supplement the treatment gap, therapy is a good alternative. Our previous retrospective studies have found that it is a safe procedure even for patients with Child-Pugh C disease. 12,13 Unlike radiofrequency ablation (RFA), ablates without creating vascular adhesion around the ablation site. This is certainly a tremendous advantage. The presence of vascular adhesion will increase the blood loss and operation time in subsequent LT, and this is particularly detrimental to critically ill recipients. In this study, 1 patient in the group had 99% tumor necrosis (Fig. 5). Most of the patients could not undergo because of contraindications, and therapy filled this treatment gap effectively without jeopardizing the patients safety. Neither nor therapy resulted in any major complications except for mild nausea and upper abdominal discomfort. The overall dropout rate of wait-listed LT candidates (51%) is very high in Hong Kong because of the severe shortage of liver grafts. In the present study, 18 patients dropped out because of tumor progression, and 8 patients did not survive the wait (Table 6). The effect of bridging therapy is diluted by the long waiting time and the high incidence of dropout. In general, there is no difference between treated patients and untreated patients whose wait for transplantation is less than 6 months. 22 Although living donor LT is an alternative to DDLT with comparable outcomes, suitable living donors are not always readily available. Furthermore, donor volunteerism and donor safety are our utmost concerns. The Kaplan-Meier plot of dropout-free survival (Fig. 3) and the competing risk analysis (Fig. 4) showed that patients in the BMT group had the poorest outcomes (P and P , respectively). With the very long wait, this might just reflect the natural history of the disease. Although the difference between the and BMT groups was not statistically significant, the curve representing the BMT group drops abruptly, whereas the curves representing the other 2 groups run parallel. The difference could not be

6 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 CHOK ET AL. 917 TABLE 2. Clinical Data for the 3 Groups of Patients With and Without Transplants Whole Group (DDLT Only) P Value (n 5 21) (n 5 20) BMT (n 5 10) BMT BMT Sex: male/female (n/n) 16/5 17/3 10/ Age (years)* 58 (38-66) 57.5 (45-67) 59 (45-64) Diagnosis (n) >0.99 > Cirrhosis Primary biliary cirrhosis Salvage transplantation (n) > Real MELD score* 17 (7-52) 10 (6-14) 20 (9-28) <0.001 Hepatitis B virus (n) > Hepatitis C virus (n) Waiting time for LT (days)* 315 ( ) ( ) 175 (10-465) Preoperative parameters* AFP (ng/ml) 22 (1-167,770) 12 (2-3314) 207 (3-27,220) Total bilirubin (lmol/l) 47 (8-547) 27.5 (3-45) 72.5 (18-490) <0.001 INR 1.5 ( ) 1.2 ( ) 1.45 ( ) <0.001 Platelet count (310 9 /L) 62.5 (17-151) 61 (27-161) 58.5 (33-103) Aspartate aminotransferase (U/mL) 64 ( ) 46.5 (20-358) 108 (45-151) Alanine aminotransferase (U/mL) 51 (19-304) 31 (16-194) 40.5 (12-91) Creatinine (lmol/l) 82 (58-366) 75 (56-109) 80 (60-109) Child-Pugh class (n) A B C Presence of ascites (n) *The data are presented as medians and ranges. Ascites that required repeated abdominal paracentesis. TABLE 3. Comparison of LT Recipients and Dropouts Whole Group (DDLT Only) Recipients (n 5 25) Dropouts (n 5 26) P Value Sex: male/female (n/n) 21/4 22/4 >0.99 Age (years)* 60 (45-67) 58 (38-66) 0.46 Diagnosis (n) 0.45 Cirrhosis Primary biliary cirrhosis 2 0 Salvage transplantation (n) Real MELD score* 11 (6-25) 15 (7-52) 0.01 Hepatitis B virus (n) Hepatitis C virus (n) Duration on waiting list (days)* 346 ( ) ( ) 0.02 Preoperative parameters* AFP (ng/ml) 11 (1-1260) 293 (2-167,770) 0.05 Total bilirubin (lmol/l) 28 (3-365) 45 (8-547) 0.01 INR 1.3 ( ) 1.4 ( ) 0.05 Platelet count (310 9 /L) 55.5 (21-161) 65.5 (17-144) 0.92 Aspartate aminotransferase (U/mL) 47.5 (20-194) 79 ( ) Alanine aminotransferase (U/mL) 30 (12-194) 56 (19-304) 0.01 Creatinine (lmol/l) 76 (56-106) 83 (60-366) 0.03 Child-Pugh class (n) A 14 5 B 8 9 C 3 12 Presence of ascites (n) *The data are presented as medians and ranges. Ascites that required repeated abdominal paracentesis.

7 918 CHOK ET AL. LIVER TRANSPLANTATION, August 2014 TABLE 4. Tumor Characteristics for the 3 Groups P Value (n 5 10) (n 5 12) BMT (n 5 3) BMT BMT Tumors (n)* 1 (1-3) 2 (1-3) 2 (1-2) Largest size of tumors (cm)* 2.85 ( ) 2.5 ( ) 2.5 (2-5.5) Vascular permeation (n) >0.99 >0.99 Stage (n) I II IIIA Milan criteria: within/beyond (n/n) 6/4 5/4 2/1 > UCSF criteria: within/beyond (n/n) 7/3 6/3 3/0 > Follow-up duration (months)* 6.3 ( ) 13.3 ( ) 3.5 ( ) Recurrence of HCC (n) Graft survival (%) year No data 2 years No data 3 years - - No data Patient survival (%) year No data 2 years No data 3 years - - No data Necrosis in excised liver (n) %-100% %-74% %-49% %-24% *The data are presented as medians and ranges. Two patients did not have a tumor on explant pathology. One patient had 100% necrosis, and no pathological staging was assigned. American Joint Committee on Cancer staging system (6th edition, 2002). TABLE 5. Radiological Responses in the 3 Groups P Value (n 5 21) (n 5 20) BMT (n 5 10) BMT BMT Tumor response according to mrecist criteria Complete response Partial response Progressive disease Stable disease determined because the sample size was too small, as reflected by the high likelihood ratio (22 log likelihood ). can extend the survival of patients with stage B disease (Barcelona Clinic Liver Cancer classification) from a median of 16 months (untreated cases) to a median as high as 19 to 20 months according to randomized controlled trials and a meta-analysis of pooled data, 5,21,23 but patients with a poor response to before transplantation have significantly shorter survival. 24 However, most preserved good responses are reflected in the radiological Response Evaluation Criteria in Solid Tumors or biological markers (eg, AFP) without histological proof. Whether the same observation applies to therapy is still a challenging question.

8 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 CHOK ET AL. 919 Figure 4. Competing risk analysis comparing the cumulative probabilities of dropping out for the 3 groups. Figure 3. Kaplan-Meier plot of dropout-free survival. Figure 5. right). Magnetic resonance images of a patient before treatment (left) and 1 month after treatment (complete ablation; TABLE 6. Reasons for Dropping Out (n 5 11) (n 5 8) BMT (n 5 7) Tumor progression (n) Death (n) Liver decompensation due to sepsis 2 Uncontrolled bleeding from gastrointestinal tract 2 Intracerebral hemorrhage 1 Ruptured HCC 2 Gangrenous stomach and duodenum 1 As shown in Table 5, the group had the best radiological responses among the 3 groups. However, there was a discrepancy between radiological responses and final histological results. The small sample size may be the reason. This study was only a pilot study; another study with a larger cohort will be required after the safety profile has been established. On the other hand, the time between transplantation and the last treatment was too long (9.7 versus 1.45 months, P < 0.001), so the effect of bridging therapy was diluted. treatment is not always repeatable because of anatomical limitations (eg, when the

9 920 CHOK ET AL. LIVER TRANSPLANTATION, August 2014 subcutaneous tissue is too thick), whereas can be repeated every 6 to 12 weeks, and this results in a higher necrosis rate. RFA is another commonly used loco-ablative therapy. It can achieve a complete necrosis rate of 46% to 74%, which is much higher than that achieved with (22%-29%). 24 However, other outcome measures are highly variable between different treatments, and a clear superiority of loco-ablative treatments over has not emerged so far. 25,26 RFA is regarded as a potentially curative treatment, so it is not considered a kind of bridging therapy at our center. A previous study by our center reported that both and RFA achieved no survival benefit for patients with unresectable HCCs. 27 This could be explained by the fairly high rate of residual disease in the RFA group as well as the multifocal nature of HCC. The role of ablation as a bridging therapy is still under investigation. It may fill the treatment gap for patients who have contraindications to. In this study, the group had a significantly higher percentage of tumor necrosis in comparison with the BMT group, so treatment must have some role in controlling tumor growth. Tumor necrosis is rarely seen in patients who cannot receive any treatment as bridging therapy. Although theoretically therapy certainly has potential benefits, actual long-term survival outcomes and longer follow-up are needed for a definite answer. Other measures must also be explored because approximately one-fifth of our patients (n 5 10) still could not receive any treatment while they were awaiting transplantation. However, the adoption of treatment boosted the rate of patients receiving bridging therapy from 39.2% to 80.4%, and the treatment produced coagulative necrosis in almost all treated patients. Three of the 10 patients in the group had 75% to 100% tumor necrosis. Whether this good result can translate into good patient survival can be known only after a longer follow-up. Short-term outcomes were excellent for both the group and the group. The drawbacks of this study included its small sample size and heterogeneous patient population. Moreover, it was a single-center study and inevitably had a selection bias. As shown in Tables 2 and 3, patients in the group, in comparison with those in the group, were in an inferior initial situation as reflected by the poorer liver function test results. Therefore, the insignificant dropout-free survival reflected the natural disease course. Results obtained in this study have stimulated more interest in the subject. This pilot study will be fleshed out into a randomized controlled trial in the near future. In conclusion, the adoption of ablation increased the proportion of patients receiving bridging therapy from 39.2% to 80.4%. 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10 LIVER TRANSPLANTATION, Vol. 20, No. 8, 2014 CHOK ET AL. 921 gov/policiesandbylaws2/policies/pdfs/policy_8.pdf. Accessed April Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al.; for Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100: Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61: El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132: Llovet JM, Real MI, Monta~na X, Planas R, Coll S, Aponte J, et al.; for Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet : Pelletier SJ, Fu S, Thyagarajan V, Romero-Marrero C, Batheja MJ, Punch JD, et al. An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using Organ Procurement Transplant Network data. Liver Transpl 2009;15: Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37: Cescon M, Cucchetti A, Ravaioli M, Pinna AD. Hepatocellular carcinoma locoregional therapies for patients in the waiting list. Impact on transplantability and recurrence rate. J Hepatol 2013;58: Porrett PM, Peterman H, Rosen M, Sonnad S, Soulen M, Markmann JF, et al. Lack of benefit of pre-transplant locoregional hepatic therapy for hepatocellular cancer in the current MELD era. Liver Transpl 2006;12: Jang JW, You CR, Kim CW, Bae SH, Yoon SK, Yoo YK, et al. Benefit of downsizing hepatocellular carcinoma in a liver transplant population. Aliment Pharmacol Ther 2010;31: Chok KS, Ng KK, Poon RT, Lam CM, Yuen J, Tso WK, Fan ST. Comparable survival in patients with unresectable hepatocellular carcinoma treated by radiofrequency ablation or transarterial chemoembolization. Arch Surg 2006;141: