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Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial)
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https://doi.org/10.1016/j.hpb.2020.01.008
ORIGINAL ARTICLE
Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial) Charing C.N. Chong1, Kit F. Lee1, Sunny Y.S. Cheung1, Clement C.M. Chu2, Anthony K.W. Fong1, John Wong1, Joyce W.Y. Hui2, Andrew K.Y. Fung1, Hon T. Lok1, Eugene Y.J. Lo1, Stephen L. Chan3, Simon C.H. Yu2, Kelvin K.C. Ng1 & Paul B.S. Lai1 1
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, 2Department of Imaging & Interventional Radiology, and 3Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong
Abstract Background: Microwave (MWA) and radiofrequency ablation are the commonly used local ablation for hepatocellular carcinoma (HCC). Studies comparing both techniques are scarce. The aim of this study was to compare the efficacy of MWA versus RFA as a treatment for HCC. Methods: Patients with HCC who were suitable for local ablation were randomized into MWA or RFA. All patients were followed up regularly with contrast-enhanced computed tomography (CT) performed at 1, 3, 6 and 12 months after ablation. Both patients and the radiologists who interpreted the postprocedure CT scans were blinded to the treatment allocation. Treatment-related morbidity, overall and disease-free survivals were analyzed. Results: A total of 93 patients were recruited. Among them, 47 and 46 patients were randomized to MWA and RFA respectively. Patients in two groups were comparable in baseline demographics and tumor characteristics. With a median follow-up of around 30 months, there were no significant difference in the treatment-related morbidity, overall and disease-free survivals. MWA had a significantly shorter overall ablation time when compared with RFA (12 min vs 24 min, p < 0.001). Conclusions: MWA is no different to RFA with respect to completeness of ablation and survivals. It is, however, as safe and effective as RFA in treating small HCC. Received 5 November 2019; accepted 20 January 2020
Correspondence Charing C.N. Chong, Department of Surgery, 4/F Clinical Science Building, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. Tel: +852 3505 1496. E-mail: [email protected]
Introduction Liver cancer is the fifth most common cancer and second most common cause of cancer death in men worldwide, with an increasing annual incidence in both developing and developed countries.1 The majority (70%–90%) of primary liver cancers occurring worldwide are hepatocellular carcinoma (HCC). In the United States, the age-adjusted incidence rates of liver cancer have tripled from 1975 to 2011.2 This increase may be
Source of support: Donation from medical fund from Shun Tak District Min Yuen Tong of Hong Kong for the purchase of microwave applicators.
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attributable to the increases in chronic HCV infection or possibly increases in the prevalence of obesity and diabetes mellitus.3 Only around 10–20% of patients with HCC are suitable for curative liver resection. Many of the inoperable patients undergo palliative treatments or supportive care. Background liver cirrhosis is one the major factors that limits resectability. Local ablation therapy is a form of local treatment for HCC. It involves the introduction of chemicals like alcohol or heat energy like laser, radiofrequency and microwave into tumors to cause necrosis of the tumor. It can preserve more non-tumor liver parenchyma and is regarded as a curative treatment especially for small size HCC in patients with liver cirrhosis.
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Please cite this article as: Chong CCN et al., Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial), HPB, https://doi.org/10.1016/j.hpb.2020.01.008
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Radiofrequency ablation (RFA) is the most commonly used local ablation therapy for HCC.4–7 It involves the placement of a RFA needle into the tumor by either the percutaneous route, laparoscopic route or during open operation. The heat energy generated causes coagulative necrosis of tumor according to the size of needle used and the duration of treatment applied. The procedure is usually well tolerated with mortality less than 1% and morbidity less than 10%. Our previous experience showed that complete ablation was achieved in 82.3% of patients with a mean tumor size 2.4 cm.8 Microwave ablation (MWA) is another type of local ablation therapy that has been used for more than 20 years.9 It has received attention again in recent years because of the progress in microwave technology. Currently, frequencies of 915 and 2450 MHz are being used for microwave tissue ablation. The advantage of microwave as compared with RFA is that heating by microwave is primarily active and the transmission of microwaves in the living tissue is not limited by tissue desiccation and charring.9,10 The heat-sink effect has been shown to be reduced with MWA.11,12 Furthermore, there is no need to apply earth plates on body of patient as in RFA. So it can avoid the potential complication of earth plate burn injury. The new generation of MWA system has been used in many centres in Europe, North America and Australia.13–16 We have applied MWA as a treatment of liver cancer since early 2009. Clinically it can create a larger zone of ablation in a shorter period of time. Complete ablation can be achieved in 95.8% of patients with a mean tumor size 3.7 cm.17 Whether microwave ablation is as safe and effective as, or even better than, RFA in treating HCC remains unclear. Several cohort studies have reported similar safety and efficacy outcomes when
Table 1 Inclusion and exclusion criteria for the current study
Inclusion criteria:
Exclusion criteria:
Age >18 years
Informed consent not available
Unresectable HCC and tumor amendable for local ablation
Pregnant female patients
Resectable HCC but patient opts for local ablation
Tumors unfavorable for local ablation (e.g. tumor close to porta hepatis)
Maximum diameter of tumor 5 cm
HCC with history of rupture
Maximum number of tumor nodules 3
Concomitant hepatectomy
Absence of extrahepatic metastasis
Patients with chronic renal failure
Absence of radiology evidence of major vascular or bile duct invasion Child’s A or B liver function Karnofsky performance status 70%
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compared with RFA.18–25 The only prospective randomized controlled study on this topic was focused on percutaneous ablation only.26 We, therefore, conducted this randomized control trial in patients with HCC who need local ablation therapy in order to compare the efficacy of MWA with RFA.
Method This was a prospective randomized study conducted in a tertiary referral teaching hospital with a specialized hepatobiliary surgery and interventional radiology team. The team had experience of more than 300 local ablations for liver cancers. Patients with the diagnosis of HCC based on histology or the typical imaging appearance and raised alpha-fetal protein (AFP) were screened for eligibility. Selection of patients for recruitment into this study was performed by the principal investigator or co-investigators within the team according to the following inclusion and exclusion criteria stated in Table 1. This study is registered at ClinicalTrials.gov, number NCT01340105. Randomization was made by a computer generated random number list. Cases were stratified into two groups: percutaneous ablation and surgical ablation (laparoscopic and open ablation). Eligible patients were randomized to either MWA or RFA after thorough workup and informed consent was obtained. Treatment procedures Percutaneous RFA and MWA were performed by an interventional radiologist under local anesthesia in the Department of Imaging & Interventional Radiology under ultrasound or CT guidance. For RFA, cool-tip RFA needles (Covidien, Boulder, CO, USA) of various sizes were used depending on the tumor size. Cluster cool-tip needles tended to be used for treatment of larger tumors. The choice of needle was determined by the interventional radiologist performing the procedure. For MWA, percutaneous microwave needle (Microsulis Medical Ltd, Denmead, UK) was used for tumor ablation with various power and duration setting depending on tumor size. For both RFA and MWA, the ablation zone was planned to include a 1 cm ablation margin around tumor. For tumors that were not suitable for percutaneous ablations (e.g. tumors next to adjacent viscera) or tumors that were not accessible by a percutaneous route (e.g. tumor at dome of liver), surgical ablation was be performed. The procedure was undertaken by surgeons with intra-operative ultrasound guidance in the operation theatre under general anesthesia. A laparoscopic approach was used if possible, otherwise laparotomy and open ablation were performed. The same models of needles described above for percutaneous RFA and MWA were used in surgical ablation. Concomitant procedures like lysis of adhesions and cholecystectomy were sometimes performed to facilitate the ablation of tumors. Again, the aim was to obtain a 1 cm ablation margin around the tumors.
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Please cite this article as: Chong CCN et al., Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial), HPB, https://doi.org/10.1016/j.hpb.2020.01.008
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Post-ablation management Patients were closely monitored after ablation treatment and any complications were documented. Serial blood tests, especially liver function tests, were performed. Patients were discharged once they were fully mobilized and tolerated oral diet, with evidence of improvement of liver function. Any in-hospital or 30day mortality after local ablation was documented. Long-term assessment All patients were followed up regularly by the investigators in the outpatient clinic. A triphasic contrast enhanced CT scan were performed at 1, 3, 6, 12 months after ablation to determine the completeness of ablation therapy and to document any local-regional recurrence. The radiologists who interpreted the post-procedure CT scans were blinded to the type of ablation. Chest X-Ray was performed 3 monthly for the first year after ablation to exclude lung metastasis. Serum AFP and liver function test were checked at 1, 3, 6, 12 months after ablation to monitor disease progress and liver function status. Patients with incomplete ablation or recurrent diseases were treated accordingly, which included repeat local ablation, transarterial therapy or systemic therapy. After the first year, patients were followed-up 4-monthly and then every 6 months after the second year. Outcome measures The primary outcome measure was the completeness of ablation as revealed by post-ablation CT scans at 1 month, with reference to AFP level. Other secondary outcomes included treatmentrelated mortality, morbidity, hospital stay, recurrent disease as documented by subsequent CT and AFP level, overall and disease-free survival. A juxta-vascular lesion was defined as a lesion located within 5 mm from a blood vessel of diameter 3 mm or more.27 Adherence with protocol was assessed by review of the operation records and clinical case notes. Sample size calculation We determined the sample size by comparing the complete ablation rate between microwave and RFA at 1-month as the primary endpoint. According to our previous experience, microwave ablation could achieve 95.8% complete ablation for tumors with mean size of 3.7 cm.17 Since the same inclusion and exclusion criteria were used in this study, we assumed the mean tumor size of 3.7 cm and that the complete ablation rate for RFA would be 75%. Using a two-sided test with a power of 80% at an alpha value of 0.05, 42 patients were needed in each arm to detect an improvement of complete ablation rate from 75% to 95% by microwave ablation. Considering a potential drop-out rate of 10% post-randomization 46 patients needed to be recruited in each treatment arm.
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Statistical analysis All data were prospectively collected by a research assistant and registered in a computer database. Comparison between treatment arms was based on an intention-to-treat analysis. Statistical analysis was performed by Chi-square test or Fisher’s exact test to compare discrete variables and Mann–Whitney U test for continuous variables. Survival was calculated from the time of procedure using Kaplan–Meier method. Survival analysis was performed using the Log-rank test and Cox-regression in univariate and multivariate analysis. A p-value < 0.05 was considered significant.
Results Fig. 1 shows the CONSORT diagram of the study flow. From April 2011 to March 2017, 152 patients fulfilled the inclusion and exclusion criteria. Among them, 56 patients refused to participate and a total of 93 patients was recruited and randomized. Three patients in the RFA group had tumors which were found to be smaller than 2 cm on operative ultrasound and hence were excluded. Finally, 47 patients in MWA group and 46 patients in RFA group were analyzed. Patients’ baseline demographics were shown in Table 2. Patients in two groups were comparable in terms of age, etiology and child’s grading. The mean size of the tumor in MWA group and RFA group were 3.1 cm and 2.8 cm respectively (p = 0.154). Juxta-vascular lesions were found in 24/ 47 (51.1%) patients in MWA group and 18/46 (39.1%) patients in RFA group (p = 0.248). Perioperative outcomes Concerning the perioperative outcomes, the median numbers of ablation cycles were 2 in both groups. MWA was associated with a significantly shorter ablation time when compared with RFA (12 min vs 24 min, p < 0.001). Nevertheless, the total operation time, operative blood loss, treatment related morbidity, as well as the length of postoperative hospital stay were similar between two groups (Table 3). Long-term outcomes after ablations The complete ablation rates in the MWA and RFA groups were 95.7% and 97.8% respectively (p > 0.99). On first CT scans performed 1 month after ablation, residual disease was noted in 2 patients in the MWA group and 1 patient in the RFA group. These patients were subsequently treated with repeat ablation (n = 1) and TACE (n = 2) (Table 4). With a median follow up of more than 30 months in both groups, the 1-year, 3-year, 5-year overall survival rates of MWA and RFA were 97.9%, 67.1%, 42.8% and 93.5%, 72.7% and 56.7% respectively (p = 0.899) (Fig. 2a). The 1-year, 3-year disease-free survival rates of MWA and RFA were 51.1%, 24.1% and 58.7%, 22.7% respectively (p = 0.912) (Fig. 2b).
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Please cite this article as: Chong CCN et al., Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial), HPB, https://doi.org/10.1016/j.hpb.2020.01.008
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Figure 1 CONSORT diagram
Table 2 Baseline demographics of patients in microwave and radi-
Table 3 Perioperative outcomes of patients in microwave and
ofrequency ablation groups
radiofrequency ablation groups
MWA (N [ 47)
RFA (N [ 46)
p-value
MWA (n [ 47) RFA (n [ 46)
p-value
2 (1–5)
2 (1–6)
0.868
Age
63.0 (50.0–80.0) 64.5 (42.0–85.0) 0.726
Number of cycles
Male gender
30 (63.8%)
0.041*
Ablation time (min)
12 (6–30)
24 (12–72)
<0.001*
>0.999
Operative time (min)
100 (0–195)
105 (0–220)
0.850
10 (1–600)
0.415
38 (82.6%)
Child’s grading A
39 (83.0%)
40 (87.0%)
Operative blood loss (ml) 10 (1–726)
B
7 (14.9%)
6 (13.0%)
Complication rate
C
1 (2.1%)
0 (0.0%)
1 (2.1%) Ileus (n = 1)
1 (2.2%) >0.999 Ascites (n = 1)
38 (80.9%)
34 (73.9%)
30-days mortality
0 (0.0%)
0 (0.0%)
>0.999
Length of post-operative 4 (1–10) hospital stay (Days)
4 (1–13)
0.543
Hepatitis B infection
2.8 (2.0–5.5)
0.424
Tumor size (cm)
3.1 (2.0–4.5)
Solitary lesion
43 (91.5%)
39 (84.8%)
0.317
Juxta-vascular location 24 (51.1%)
18 (39.1%)
0.248
Approach
0.154
MWA, microwave ablation; RFA, radiofrequency ablation. * p < 0.05.
0.512
Percutaneous
11 (23.4%)
13 (28.3%)
Laparoscopic
21 (44.7%)
18 (39.1%)
Open
15 (31.9%)
15 (32.6%)
difference in complete ablation rate and survival analysis between MWA and RFA (Supplementary Table 2).
MWA, microwave ablation; RFA, radiofrequency ablation. * p < 0.05.
Discussion
Long-term outcomes among different subgroups The median tumor sizes in this study were around 3 cm in both groups. For tumors larger than 3 cm, MWA was associated with significantly less operative blood loss when compared with RFA (7.5 ml vs 50 ml, p = 0.008). There was no significant difference in complete ablation rate and survival analysis (Supplementary Table 1). We performed a subgroup analysis on tumor sizes with various cutoffs in the current study. There was no significant difference in complete ablation rate and survival analysis between MWA and RFA. Similarly, short-term and long-term outcomes for patients with juxta-vascular tumors treated with both modalities were compared. There was no significant
Our study has shown that MWA is no different to RFA with respect to completeness of ablation. With a significantly shorter ablation time, MWA provided a similar complete ablation rate and comparable long-term survival as RFA. It is equally safe and effective as RFA in treating HCC. Local ablation is now regarded as one of the curative treatments for early HCC.6 MWA and RFA are the two most commonly used modalities of local ablation with thermal energy. Microwaves generate heat by oscillation of dipole water molecules within tissues. Currently, MWA generators only allow 915 MHz and 2.45 GHz frequency spectrums. In this study, the 2.45 GHz system was used. It can create a 4 × 6 cm ablation zone in 4 min and 5 × 7 cm ablation zone in 8 min.17 Unlike in case of
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Table 4 Long-term outcomes after ablations
MWA (n [ 47) RFA (n [ 46)
p-value
Follow-up period (months) 38.3 (2.3–78.0) 33.9 (4.9–72.7) 0.272 Complete ablation
45 (95.7%)
45 (97.8%)
>0.999
Residual disease at 1-month
2 (4.3%)
1 (2.2%)
>0.999
- Repeat ablation
1 (2.1%)
0 (0.0%)
>0.999
- TACE
1 (2.1%)
1 (2.2%)
Treatment:
Overall survival
>0.999 0.899
1-year survival
97.9%
93.5%
3-year survival
67.1%
72.7%
5-year survival
42.8%
56.7%
Disease-free survival
0.912
1-year survival
51.1%
58.7%
3-year survival
24.1%
22.7%
5-year survival
19.3%
0.0%
MWA, microwave ablation; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.
RFA, earth plate placement is not required. Therefore, the potential early plate burn injury can be completely avoided. The heat-sink effect in MWA is supposed to be less evident and can be used in treating juxta-vascular lesions. In our series, around 51.1% of lesions in MWA group and 39.1% of lesions in RFA group were in juxta-vascular location. Subgroup analysis was performed in patients with juxta-vascular lesions. No significant difference was noted in the complete ablation rate, disease-free and overall survival between two groups. It could be
a false negative given the small sample size, especially after subgroup analysis. A larger study focusing on juxta-vascular lesions may be needed to confirm this advantage of MWA over RFA. Our group had previously reported the long-term outcomes of MWA vs RFA for HCC in a retrospective comparative study.18 MWA provided similar treatment outcomes as compared with RFA for HCC. However, limited by the retrospective nature, the results were not convincing enough and therefore we carried out the current study to verify the findings in a prospective randomized control study. The current study confirmed that MWA is as safe and as effective as RFA in treating small HCC and the performance of RFA has improved when compared with previous retrospective cohort. Potential selection bias was eliminated by the study design. The two groups were comparable in baseline demographics including tumor size and background liver function. Concerning the short-term perioperative outcomes, the treatment-related complication rate was similar between two groups. Only one patient in each group developed a postoperative complication. One patient in the MWA group developed post-operative ileus requiring a short-course of parental nutritional support and another patient in the RFA group developed ascites which was successfully managed with conservative treatment. The overall and disease survival rates of patients treated with both modalities were also comparable. Our study showed that MWA could provide similar survivals and adverse events rate when compared with RFA. This is compatible with the findings in the recent meta-analyses.28–30 The two meta-analyses by Huo et al. and Chinnaratha et al. both demonstrated that the overall survival and major adverse events rate were similar between the two ablative modalities.28,29
Figure 2 Log-rank test showed no difference between the two groups in overall and disease-free survival. (a) Overall survival; Log-rank test:
p = 0.899. (b) Disease-free survival; Log-rank test: p = 0.912. MWA, microwave ablation; RFA, radiofrequency ablation
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On the other hand, Glassberg et al. analyzed 28 randomized and observational studies on the same topic and found that the local tumor progression was significantly reduced by 30% with MWA versus RFA when all included studies were analyzed.30 If only randomized studies were analyzed, the local tumor progression was reduced by 45% with MWA versus RFA. The authors hence concluded that MWA is at least as safe and effective as RFA for treating liver cancer and significantly reduced local tumor progression rate. They also suggested future studies should assess time and costs associated with these two treatment modalities. When compared with RFA, microwave can create a larger ablation zone with a shorter ablation time. In this study, there was no significantly difference in terms of overall procedure time between two modalities but MWA was associated with a significantly shorter ablation time (12 min vs 24 min). MWA could create a large ablation zone with single application while in case of RFA, multiple applications at overlapping sites is needed to create a similar area. This may affect the completeness of ablation for larger tumor as the artefacts on ultrasound after ablation will hinder further evaluation. In our previous retrospective report, MWA was associated with a better overall survival when a subgroup analysis was performed for tumors >/ = 3.5 cm.18 In the current study, only 14 patients in MWA group and 10 patients in the RFA group had a tumor larger than 3.5 cm in size. Hence a small difference between MWA and RFA might be not shown. Chinnaratha et al. found that the local tumor progression rates were lower with MWA for treatment of larger tumors.29 One of the limitations of this study is that the estimate for ablation rate of RFA in the sample size calculation a bit low. With increasing experience, the performance of RFA in our center has improved significantly when compared with our earlier report. Moreover, the sample size calculation was based on the complete ablation rate for tumor with mean size of 3.7 cm based on our historical cohort.8 Since the same inclusion and exclusion criteria was applied in the current study, we assumed the tumor size were similar in the present study. However, the final mean tumor size was around 3 cm. A potential explanation to that was tumors were detected at earlier at a smaller size due to increased awareness and screening, and surveillance. The expected difference in complete ablation rate between MWA and RFA might be smaller for tumors around 3 cm and therefore a larger sample size might be needed. Evidence demonstrating the excellent results of RFA in treating single HCC <3 cm were strong.31 In order to study the true merits of MWA over RFA, studies focused on tumor with intermediate size or juxta-vascular lesions might be needed. Due to several advancements in the technology and the clinical applications, the use of MWA has increased dramatically over the past decade. Whether MWA is a better alternative to RFA in treating small HCC remains unknown but the results from this trial suggest that it is at least as effective as RFA. Detailed indications for each modality have not been defined clearly. Hopefully, results of this study can provide some insights into ablation modality selection.
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Conclusion MWA is not superior to RFA with respect to completeness of ablation and survivals. It is as safe and as effective as RFA in treating small HCC, with additional benefits of shorter ablation time and elimination of burn injury from earth plate. Acknowledgments We would like to thank the Shun Tak District Min Yuen Tong of Hong Kong for providing funding for the purchase of MWA applicators in this study. We would also like to thank Mr Philip Ip for his assistance in data processing and statistical analysis. Conflicts of interest None to declare. References 1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. 2. Howlader N, Mariotto AB, Woloshin S, Schwartz LM. (2014) Providing clinicians and patients with actual prognosis: cancer in the context of competing causes of death. J Natl Cancer Inst Monogr 2014: 255–264. 3. Mittal S, El-Serag HB. (2013) Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47(Suppl):S2–S6. 4. Curley SA, Izzo F, Ellis LM, Nicolas Vauthey J, Vallone P. (2000) Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 232:381–391. 5. Yokoyama T, Egami K, Miyamoto M, Watanabe H, Hasegawa H, Iida S et al. (2003) Percutaneous and laparoscopic approaches of radiofrequency ablation treatment for liver cancer. J Hepatobiliary Pancreat Surg 10:425–427. 6. Chong CC, Chan AW, Wong J, Chu CM, Chan SL, Lee KF et al. (2018) Albumin-bilirubin grade predicts the outcomes of liver resection versus radiofrequency ablation for very early/early stage of hepatocellular carcinoma. Surgeon 16:163–170. 7. Wong J, Lee KF, Yu SC, Lee PS, Cheung YS, Chong CN et al. (2013) Percutaneous radiofrequency ablation versus surgical radiofrequency ablation for malignant liver tumours: the long-term results. HPB 15: 595–601. 8. Wong J, Lee KF, Lee PS, Ho SS, Yu SC, Ng WW et al. (2009) Radiofrequency ablation for 110 malignant liver tumours: preliminary results on percutaneous and surgical approaches. Asian J Surg 32:13–20. 9. Liang P, Wang Y. (2007) Microwave ablation of hepatocellular carcinoma. Oncology 72(Suppl 1):124–131. 10. Ong SL, Gravante G, Metcalfe MS, Strickland AD, Dennison AR, Lloyd DM. (2009) Efficacy and safety of microwave ablation for primary and secondary liver malignancies: a systematic review. Eur J Gastroenterol Hepatol 21:599–605. 11. Thandassery RB, Goenka U, Goenka MK. (2014) Role of local ablative therapy for hepatocellular carcinoma. J Clin Exp Hepatol 4: S104–S111. 12. Wright AS, Lee FT, Jr., Mahvi DM. (2003) Hepatic microwave ablation with multiple antennae results in synergistically larger zones of coagulation necrosis. Ann Surg Oncol 10:275–283. 13. Iannitti DA, Martin RC, Simon CJ, Hope WW, Newcomb WL, McMasters KM et al. (2007) Hepatic tumor ablation with clustered microwave antennae: the US Phase II trial. HPB 9:120–124.
© 2020 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Chong CCN et al., Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial), HPB, https://doi.org/10.1016/j.hpb.2020.01.008
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7
14. Jagad RB, Koshariya M, Kawamoto J, Papastratis P, Kefalourous H,
24. Poulou LS, Botsa E, Thanou I, Ziakas PD, Thanos L. (2015)
Patris V et al. (2008) Laparoscopic microwave ablation of liver tumors:
Percutaneous microwave ablation vs radiofrequency ablation in the
our experience. Hepatogastroenterology 55:27–32.
treatment
15. Bhardwaj N, Strickland AD, Ahmad F, El-Abassy M, Morgan B,
of
hepatocellular
carcinoma.
World
J
Hepatol
7:
1054 – 1063.
Robertson GS et al. (2010) Microwave ablation for unresectable hepatic
25. Santambrogio R, Chiang J, Barabino M, Meloni FM, Bertolini E,
tumours: clinical results using a novel microwave probe and generator.
Melchiorre F et al. (2017) Comparison of laparoscopic microwave to
Eur J Surg Oncol 36:264–268.
radiofrequency ablation of small hepatocellular carcinoma (
16. Martin RC, Scoggins CR, McMasters KM. (2010) Safety and efficacy of microwave ablation of hepatic tumors: a prospective review of a 5-year
Ann Surg Oncol 24:257–263. 26. Vietti Violi N, Duran R, Guiu B, Cercueil JP, Aube C, Digklia A et al. (2018) Efficacy of microwave ablation versus radiofrequency ablation for
experience. Ann Surg Oncol 17:171–178. 17. Lee KF, Hui JW, Cheung YS, Wong JS, Chong CN, Wong J et al. (2012)
the treatment of hepatocellular carcinoma in patients with chronic liver
Surgical ablation of hepatocellular carcinoma with 2.45-GHz microwave:
disease: a randomised controlled phase 2 trial. Lancet Gastroenterol
a critical appraisal of treatment outcomes. Hong Kong Med J 18:85–91.
Hepatol 3:317–325.
18. Lee KF, Wong J, Hui JW, Cheung YS, Chong CC, Fong AK et al. (2017)
27. Huang S, Yu J, Liang P, Yu X, Cheng Z, Han Z et al. (2014) Percuta-
Long-term outcomes of microwave versus radiofrequency ablation for
neous microwave ablation for hepatocellular carcinoma adjacent to
hepatocellular carcinoma by surgical approach: a retrospective
large vessels: a long-term follow-up. Eur J Radiol 83:552–558. 28. Huo YR, Eslick GD. (2015) Microwave ablation compared to radio-
comparative study. Asian J Surg 40:301–308. 19. Dong B, Liang P, Yu X, Su L, Yu D, Cheng Z et al. (2003) Percutaneous sonographically guided microwave coagulation therapy for hepatocellular carcinoma: results in 234 patients. AJR Am J Roentgenol 180:
frequency ablation for hepatic lesions: a meta-analysis. J Vasc Intervent Radiol 26:1139–11346 e2. 29. Chinnaratha MA, Chuang MY, Fraser RJ, Woodman RJ, Wigg AJ. (2016) Percutaneous thermal ablation for primary hepatocellular carcinoma: a
1547–1555. 20. Shibata T, Iimuro Y, Yamamoto Y, Maetani Y, Ametani F, Itoh K et al. (2002) Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology
systematic review and meta-analysis. J Gastroenterol Hepatol 31: 294–301. 30. Glassberg MB, Ghosh S, Clymer JW, Qadeer RA, Ferko NC, Sadeghirad B et al. (2019) Microwave ablation compared with radio-
223:331–337. 21. Xu HX, Xie XY, Lu MD, Chen JW, Yin XY, Xu ZF et al. (2004) Ultrasound-
frequency ablation for treatment of hepatocellular carcinoma and liver
guided percutaneous thermal ablation of hepatocellular carcinoma
metastases: a systematic review and meta-analysis. Onco Targets Ther
using microwave and radiofrequency ablation. Clin Radiol 59:53–61.
12:6407–6438.
22. Ding J, Jing X, Liu J, Wang Y, Wang F, Wang Y et al. (2013) Comparison
31. Cheung TT, Kwok PC, Chan S, Cheung CC, Lee AS, Lee V et al. (2018)
of two different thermal techniques for the treatment of hepatocellular
Hong Kong consensus statements for the management of unresectable
carcinoma. Eur J Radiol 82:1379–1384.
hepatocellular carcinoma. Liver Cancer 7:40–54.
23. Ohmoto K, Yoshioka N, Tomiyama Y, Shibata N, Kawase T, Yoshida K et al. (2009) Comparison of therapeutic effects between radiofrequency
Appendix A. Supplementary data
ablation and percutaneous microwave coagulation therapy for small
Supplementary data to this article can be found online at https://doi.org/10.
hepatocellular carcinomas. J Gastroenterol Hepatol 24:223–227.
1016/j.hpb.2020.01.008.
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https://doi.org/10.1016/j.hpb.2020.01.008
ORIGINAL ARTICLE
Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial) Charing C.N. Chong1, Kit F. Lee1, Sunny Y.S. Cheung1, Clement C.M. Chu2, Anthony K.W. Fong1, John Wong1, Joyce W.Y. Hui2, Andrew K.Y. Fung1, Hon T. Lok1, Eugene Y.J. Lo1, Stephen L. Chan3, Simon C.H. Yu2, Kelvin K.C. Ng1 & Paul B.S. Lai1 1
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, 2Department of Imaging & Interventional Radiology, and 3Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong
Abstract Background: Microwave (MWA) and radiofrequency ablation are the commonly used local ablation for hepatocellular carcinoma (HCC). Studies comparing both techniques are scarce. The aim of this study was to compare the efficacy of MWA versus RFA as a treatment for HCC. Methods: Patients with HCC who were suitable for local ablation were randomized into MWA or RFA. All patients were followed up regularly with contrast-enhanced computed tomography (CT) performed at 1, 3, 6 and 12 months after ablation. Both patients and the radiologists who interpreted the postprocedure CT scans were blinded to the treatment allocation. Treatment-related morbidity, overall and disease-free survivals were analyzed. Results: A total of 93 patients were recruited. Among them, 47 and 46 patients were randomized to MWA and RFA respectively. Patients in two groups were comparable in baseline demographics and tumor characteristics. With a median follow-up of around 30 months, there were no significant difference in the treatment-related morbidity, overall and disease-free survivals. MWA had a significantly shorter overall ablation time when compared with RFA (12 min vs 24 min, p < 0.001). Conclusions: MWA is no different to RFA with respect to completeness of ablation and survivals. It is, however, as safe and effective as RFA in treating small HCC. Received 5 November 2019; accepted 20 January 2020
Correspondence Charing C.N. Chong, Department of Surgery, 4/F Clinical Science Building, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. Tel: +852 3505 1496. E-mail: [email protected]
Introduction Liver cancer is the fifth most common cancer and second most common cause of cancer death in men worldwide, with an increasing annual incidence in both developing and developed countries.1 The majority (70%–90%) of primary liver cancers occurring worldwide are hepatocellular carcinoma (HCC). In the United States, the age-adjusted incidence rates of liver cancer have tripled from 1975 to 2011.2 This increase may be
Source of support: Donation from medical fund from Shun Tak District Min Yuen Tong of Hong Kong for the purchase of microwave applicators.
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attributable to the increases in chronic HCV infection or possibly increases in the prevalence of obesity and diabetes mellitus.3 Only around 10–20% of patients with HCC are suitable for curative liver resection. Many of the inoperable patients undergo palliative treatments or supportive care. Background liver cirrhosis is one the major factors that limits resectability. Local ablation therapy is a form of local treatment for HCC. It involves the introduction of chemicals like alcohol or heat energy like laser, radiofrequency and microwave into tumors to cause necrosis of the tumor. It can preserve more non-tumor liver parenchyma and is regarded as a curative treatment especially for small size HCC in patients with liver cirrhosis.
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Radiofrequency ablation (RFA) is the most commonly used local ablation therapy for HCC.4–7 It involves the placement of a RFA needle into the tumor by either the percutaneous route, laparoscopic route or during open operation. The heat energy generated causes coagulative necrosis of tumor according to the size of needle used and the duration of treatment applied. The procedure is usually well tolerated with mortality less than 1% and morbidity less than 10%. Our previous experience showed that complete ablation was achieved in 82.3% of patients with a mean tumor size 2.4 cm.8 Microwave ablation (MWA) is another type of local ablation therapy that has been used for more than 20 years.9 It has received attention again in recent years because of the progress in microwave technology. Currently, frequencies of 915 and 2450 MHz are being used for microwave tissue ablation. The advantage of microwave as compared with RFA is that heating by microwave is primarily active and the transmission of microwaves in the living tissue is not limited by tissue desiccation and charring.9,10 The heat-sink effect has been shown to be reduced with MWA.11,12 Furthermore, there is no need to apply earth plates on body of patient as in RFA. So it can avoid the potential complication of earth plate burn injury. The new generation of MWA system has been used in many centres in Europe, North America and Australia.13–16 We have applied MWA as a treatment of liver cancer since early 2009. Clinically it can create a larger zone of ablation in a shorter period of time. Complete ablation can be achieved in 95.8% of patients with a mean tumor size 3.7 cm.17 Whether microwave ablation is as safe and effective as, or even better than, RFA in treating HCC remains unclear. Several cohort studies have reported similar safety and efficacy outcomes when
Table 1 Inclusion and exclusion criteria for the current study
Inclusion criteria:
Exclusion criteria:
Age >18 years
Informed consent not available
Unresectable HCC and tumor amendable for local ablation
Pregnant female patients
Resectable HCC but patient opts for local ablation
Tumors unfavorable for local ablation (e.g. tumor close to porta hepatis)
Maximum diameter of tumor 5 cm
HCC with history of rupture
Maximum number of tumor nodules 3
Concomitant hepatectomy
Absence of extrahepatic metastasis
Patients with chronic renal failure
Absence of radiology evidence of major vascular or bile duct invasion Child’s A or B liver function Karnofsky performance status 70%
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compared with RFA.18–25 The only prospective randomized controlled study on this topic was focused on percutaneous ablation only.26 We, therefore, conducted this randomized control trial in patients with HCC who need local ablation therapy in order to compare the efficacy of MWA with RFA.
Method This was a prospective randomized study conducted in a tertiary referral teaching hospital with a specialized hepatobiliary surgery and interventional radiology team. The team had experience of more than 300 local ablations for liver cancers. Patients with the diagnosis of HCC based on histology or the typical imaging appearance and raised alpha-fetal protein (AFP) were screened for eligibility. Selection of patients for recruitment into this study was performed by the principal investigator or co-investigators within the team according to the following inclusion and exclusion criteria stated in Table 1. This study is registered at ClinicalTrials.gov, number NCT01340105. Randomization was made by a computer generated random number list. Cases were stratified into two groups: percutaneous ablation and surgical ablation (laparoscopic and open ablation). Eligible patients were randomized to either MWA or RFA after thorough workup and informed consent was obtained. Treatment procedures Percutaneous RFA and MWA were performed by an interventional radiologist under local anesthesia in the Department of Imaging & Interventional Radiology under ultrasound or CT guidance. For RFA, cool-tip RFA needles (Covidien, Boulder, CO, USA) of various sizes were used depending on the tumor size. Cluster cool-tip needles tended to be used for treatment of larger tumors. The choice of needle was determined by the interventional radiologist performing the procedure. For MWA, percutaneous microwave needle (Microsulis Medical Ltd, Denmead, UK) was used for tumor ablation with various power and duration setting depending on tumor size. For both RFA and MWA, the ablation zone was planned to include a 1 cm ablation margin around tumor. For tumors that were not suitable for percutaneous ablations (e.g. tumors next to adjacent viscera) or tumors that were not accessible by a percutaneous route (e.g. tumor at dome of liver), surgical ablation was be performed. The procedure was undertaken by surgeons with intra-operative ultrasound guidance in the operation theatre under general anesthesia. A laparoscopic approach was used if possible, otherwise laparotomy and open ablation were performed. The same models of needles described above for percutaneous RFA and MWA were used in surgical ablation. Concomitant procedures like lysis of adhesions and cholecystectomy were sometimes performed to facilitate the ablation of tumors. Again, the aim was to obtain a 1 cm ablation margin around the tumors.
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Post-ablation management Patients were closely monitored after ablation treatment and any complications were documented. Serial blood tests, especially liver function tests, were performed. Patients were discharged once they were fully mobilized and tolerated oral diet, with evidence of improvement of liver function. Any in-hospital or 30day mortality after local ablation was documented. Long-term assessment All patients were followed up regularly by the investigators in the outpatient clinic. A triphasic contrast enhanced CT scan were performed at 1, 3, 6, 12 months after ablation to determine the completeness of ablation therapy and to document any local-regional recurrence. The radiologists who interpreted the post-procedure CT scans were blinded to the type of ablation. Chest X-Ray was performed 3 monthly for the first year after ablation to exclude lung metastasis. Serum AFP and liver function test were checked at 1, 3, 6, 12 months after ablation to monitor disease progress and liver function status. Patients with incomplete ablation or recurrent diseases were treated accordingly, which included repeat local ablation, transarterial therapy or systemic therapy. After the first year, patients were followed-up 4-monthly and then every 6 months after the second year. Outcome measures The primary outcome measure was the completeness of ablation as revealed by post-ablation CT scans at 1 month, with reference to AFP level. Other secondary outcomes included treatmentrelated mortality, morbidity, hospital stay, recurrent disease as documented by subsequent CT and AFP level, overall and disease-free survival. A juxta-vascular lesion was defined as a lesion located within 5 mm from a blood vessel of diameter 3 mm or more.27 Adherence with protocol was assessed by review of the operation records and clinical case notes. Sample size calculation We determined the sample size by comparing the complete ablation rate between microwave and RFA at 1-month as the primary endpoint. According to our previous experience, microwave ablation could achieve 95.8% complete ablation for tumors with mean size of 3.7 cm.17 Since the same inclusion and exclusion criteria were used in this study, we assumed the mean tumor size of 3.7 cm and that the complete ablation rate for RFA would be 75%. Using a two-sided test with a power of 80% at an alpha value of 0.05, 42 patients were needed in each arm to detect an improvement of complete ablation rate from 75% to 95% by microwave ablation. Considering a potential drop-out rate of 10% post-randomization 46 patients needed to be recruited in each treatment arm.
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Statistical analysis All data were prospectively collected by a research assistant and registered in a computer database. Comparison between treatment arms was based on an intention-to-treat analysis. Statistical analysis was performed by Chi-square test or Fisher’s exact test to compare discrete variables and Mann–Whitney U test for continuous variables. Survival was calculated from the time of procedure using Kaplan–Meier method. Survival analysis was performed using the Log-rank test and Cox-regression in univariate and multivariate analysis. A p-value < 0.05 was considered significant.
Results Fig. 1 shows the CONSORT diagram of the study flow. From April 2011 to March 2017, 152 patients fulfilled the inclusion and exclusion criteria. Among them, 56 patients refused to participate and a total of 93 patients was recruited and randomized. Three patients in the RFA group had tumors which were found to be smaller than 2 cm on operative ultrasound and hence were excluded. Finally, 47 patients in MWA group and 46 patients in RFA group were analyzed. Patients’ baseline demographics were shown in Table 2. Patients in two groups were comparable in terms of age, etiology and child’s grading. The mean size of the tumor in MWA group and RFA group were 3.1 cm and 2.8 cm respectively (p = 0.154). Juxta-vascular lesions were found in 24/ 47 (51.1%) patients in MWA group and 18/46 (39.1%) patients in RFA group (p = 0.248). Perioperative outcomes Concerning the perioperative outcomes, the median numbers of ablation cycles were 2 in both groups. MWA was associated with a significantly shorter ablation time when compared with RFA (12 min vs 24 min, p < 0.001). Nevertheless, the total operation time, operative blood loss, treatment related morbidity, as well as the length of postoperative hospital stay were similar between two groups (Table 3). Long-term outcomes after ablations The complete ablation rates in the MWA and RFA groups were 95.7% and 97.8% respectively (p > 0.99). On first CT scans performed 1 month after ablation, residual disease was noted in 2 patients in the MWA group and 1 patient in the RFA group. These patients were subsequently treated with repeat ablation (n = 1) and TACE (n = 2) (Table 4). With a median follow up of more than 30 months in both groups, the 1-year, 3-year, 5-year overall survival rates of MWA and RFA were 97.9%, 67.1%, 42.8% and 93.5%, 72.7% and 56.7% respectively (p = 0.899) (Fig. 2a). The 1-year, 3-year disease-free survival rates of MWA and RFA were 51.1%, 24.1% and 58.7%, 22.7% respectively (p = 0.912) (Fig. 2b).
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Figure 1 CONSORT diagram
Table 2 Baseline demographics of patients in microwave and radi-
Table 3 Perioperative outcomes of patients in microwave and
ofrequency ablation groups
radiofrequency ablation groups
MWA (N [ 47)
RFA (N [ 46)
p-value
MWA (n [ 47) RFA (n [ 46)
p-value
2 (1–5)
2 (1–6)
0.868
Age
63.0 (50.0–80.0) 64.5 (42.0–85.0) 0.726
Number of cycles
Male gender
30 (63.8%)
0.041*
Ablation time (min)
12 (6–30)
24 (12–72)
<0.001*
>0.999
Operative time (min)
100 (0–195)
105 (0–220)
0.850
10 (1–600)
0.415
38 (82.6%)
Child’s grading A
39 (83.0%)
40 (87.0%)
Operative blood loss (ml) 10 (1–726)
B
7 (14.9%)
6 (13.0%)
Complication rate
C
1 (2.1%)
0 (0.0%)
1 (2.1%) Ileus (n = 1)
1 (2.2%) >0.999 Ascites (n = 1)
38 (80.9%)
34 (73.9%)
30-days mortality
0 (0.0%)
0 (0.0%)
>0.999
Length of post-operative 4 (1–10) hospital stay (Days)
4 (1–13)
0.543
Hepatitis B infection
2.8 (2.0–5.5)
0.424
Tumor size (cm)
3.1 (2.0–4.5)
Solitary lesion
43 (91.5%)
39 (84.8%)
0.317
Juxta-vascular location 24 (51.1%)
18 (39.1%)
0.248
Approach
0.154
MWA, microwave ablation; RFA, radiofrequency ablation. * p < 0.05.
0.512
Percutaneous
11 (23.4%)
13 (28.3%)
Laparoscopic
21 (44.7%)
18 (39.1%)
Open
15 (31.9%)
15 (32.6%)
difference in complete ablation rate and survival analysis between MWA and RFA (Supplementary Table 2).
MWA, microwave ablation; RFA, radiofrequency ablation. * p < 0.05.
Discussion
Long-term outcomes among different subgroups The median tumor sizes in this study were around 3 cm in both groups. For tumors larger than 3 cm, MWA was associated with significantly less operative blood loss when compared with RFA (7.5 ml vs 50 ml, p = 0.008). There was no significant difference in complete ablation rate and survival analysis (Supplementary Table 1). We performed a subgroup analysis on tumor sizes with various cutoffs in the current study. There was no significant difference in complete ablation rate and survival analysis between MWA and RFA. Similarly, short-term and long-term outcomes for patients with juxta-vascular tumors treated with both modalities were compared. There was no significant
Our study has shown that MWA is no different to RFA with respect to completeness of ablation. With a significantly shorter ablation time, MWA provided a similar complete ablation rate and comparable long-term survival as RFA. It is equally safe and effective as RFA in treating HCC. Local ablation is now regarded as one of the curative treatments for early HCC.6 MWA and RFA are the two most commonly used modalities of local ablation with thermal energy. Microwaves generate heat by oscillation of dipole water molecules within tissues. Currently, MWA generators only allow 915 MHz and 2.45 GHz frequency spectrums. In this study, the 2.45 GHz system was used. It can create a 4 × 6 cm ablation zone in 4 min and 5 × 7 cm ablation zone in 8 min.17 Unlike in case of
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Table 4 Long-term outcomes after ablations
MWA (n [ 47) RFA (n [ 46)
p-value
Follow-up period (months) 38.3 (2.3–78.0) 33.9 (4.9–72.7) 0.272 Complete ablation
45 (95.7%)
45 (97.8%)
>0.999
Residual disease at 1-month
2 (4.3%)
1 (2.2%)
>0.999
- Repeat ablation
1 (2.1%)
0 (0.0%)
>0.999
- TACE
1 (2.1%)
1 (2.2%)
Treatment:
Overall survival
>0.999 0.899
1-year survival
97.9%
93.5%
3-year survival
67.1%
72.7%
5-year survival
42.8%
56.7%
Disease-free survival
0.912
1-year survival
51.1%
58.7%
3-year survival
24.1%
22.7%
5-year survival
19.3%
0.0%
MWA, microwave ablation; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.
RFA, earth plate placement is not required. Therefore, the potential early plate burn injury can be completely avoided. The heat-sink effect in MWA is supposed to be less evident and can be used in treating juxta-vascular lesions. In our series, around 51.1% of lesions in MWA group and 39.1% of lesions in RFA group were in juxta-vascular location. Subgroup analysis was performed in patients with juxta-vascular lesions. No significant difference was noted in the complete ablation rate, disease-free and overall survival between two groups. It could be
a false negative given the small sample size, especially after subgroup analysis. A larger study focusing on juxta-vascular lesions may be needed to confirm this advantage of MWA over RFA. Our group had previously reported the long-term outcomes of MWA vs RFA for HCC in a retrospective comparative study.18 MWA provided similar treatment outcomes as compared with RFA for HCC. However, limited by the retrospective nature, the results were not convincing enough and therefore we carried out the current study to verify the findings in a prospective randomized control study. The current study confirmed that MWA is as safe and as effective as RFA in treating small HCC and the performance of RFA has improved when compared with previous retrospective cohort. Potential selection bias was eliminated by the study design. The two groups were comparable in baseline demographics including tumor size and background liver function. Concerning the short-term perioperative outcomes, the treatment-related complication rate was similar between two groups. Only one patient in each group developed a postoperative complication. One patient in the MWA group developed post-operative ileus requiring a short-course of parental nutritional support and another patient in the RFA group developed ascites which was successfully managed with conservative treatment. The overall and disease survival rates of patients treated with both modalities were also comparable. Our study showed that MWA could provide similar survivals and adverse events rate when compared with RFA. This is compatible with the findings in the recent meta-analyses.28–30 The two meta-analyses by Huo et al. and Chinnaratha et al. both demonstrated that the overall survival and major adverse events rate were similar between the two ablative modalities.28,29
Figure 2 Log-rank test showed no difference between the two groups in overall and disease-free survival. (a) Overall survival; Log-rank test:
p = 0.899. (b) Disease-free survival; Log-rank test: p = 0.912. MWA, microwave ablation; RFA, radiofrequency ablation
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On the other hand, Glassberg et al. analyzed 28 randomized and observational studies on the same topic and found that the local tumor progression was significantly reduced by 30% with MWA versus RFA when all included studies were analyzed.30 If only randomized studies were analyzed, the local tumor progression was reduced by 45% with MWA versus RFA. The authors hence concluded that MWA is at least as safe and effective as RFA for treating liver cancer and significantly reduced local tumor progression rate. They also suggested future studies should assess time and costs associated with these two treatment modalities. When compared with RFA, microwave can create a larger ablation zone with a shorter ablation time. In this study, there was no significantly difference in terms of overall procedure time between two modalities but MWA was associated with a significantly shorter ablation time (12 min vs 24 min). MWA could create a large ablation zone with single application while in case of RFA, multiple applications at overlapping sites is needed to create a similar area. This may affect the completeness of ablation for larger tumor as the artefacts on ultrasound after ablation will hinder further evaluation. In our previous retrospective report, MWA was associated with a better overall survival when a subgroup analysis was performed for tumors >/ = 3.5 cm.18 In the current study, only 14 patients in MWA group and 10 patients in the RFA group had a tumor larger than 3.5 cm in size. Hence a small difference between MWA and RFA might be not shown. Chinnaratha et al. found that the local tumor progression rates were lower with MWA for treatment of larger tumors.29 One of the limitations of this study is that the estimate for ablation rate of RFA in the sample size calculation a bit low. With increasing experience, the performance of RFA in our center has improved significantly when compared with our earlier report. Moreover, the sample size calculation was based on the complete ablation rate for tumor with mean size of 3.7 cm based on our historical cohort.8 Since the same inclusion and exclusion criteria was applied in the current study, we assumed the tumor size were similar in the present study. However, the final mean tumor size was around 3 cm. A potential explanation to that was tumors were detected at earlier at a smaller size due to increased awareness and screening, and surveillance. The expected difference in complete ablation rate between MWA and RFA might be smaller for tumors around 3 cm and therefore a larger sample size might be needed. Evidence demonstrating the excellent results of RFA in treating single HCC <3 cm were strong.31 In order to study the true merits of MWA over RFA, studies focused on tumor with intermediate size or juxta-vascular lesions might be needed. Due to several advancements in the technology and the clinical applications, the use of MWA has increased dramatically over the past decade. Whether MWA is a better alternative to RFA in treating small HCC remains unknown but the results from this trial suggest that it is at least as effective as RFA. Detailed indications for each modality have not been defined clearly. Hopefully, results of this study can provide some insights into ablation modality selection.
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Conclusion MWA is not superior to RFA with respect to completeness of ablation and survivals. It is as safe and as effective as RFA in treating small HCC, with additional benefits of shorter ablation time and elimination of burn injury from earth plate. Acknowledgments We would like to thank the Shun Tak District Min Yuen Tong of Hong Kong for providing funding for the purchase of MWA applicators in this study. We would also like to thank Mr Philip Ip for his assistance in data processing and statistical analysis. Conflicts of interest None to declare. References 1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. 2. Howlader N, Mariotto AB, Woloshin S, Schwartz LM. (2014) Providing clinicians and patients with actual prognosis: cancer in the context of competing causes of death. J Natl Cancer Inst Monogr 2014: 255–264. 3. Mittal S, El-Serag HB. (2013) Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47(Suppl):S2–S6. 4. Curley SA, Izzo F, Ellis LM, Nicolas Vauthey J, Vallone P. (2000) Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 232:381–391. 5. Yokoyama T, Egami K, Miyamoto M, Watanabe H, Hasegawa H, Iida S et al. (2003) Percutaneous and laparoscopic approaches of radiofrequency ablation treatment for liver cancer. J Hepatobiliary Pancreat Surg 10:425–427. 6. Chong CC, Chan AW, Wong J, Chu CM, Chan SL, Lee KF et al. (2018) Albumin-bilirubin grade predicts the outcomes of liver resection versus radiofrequency ablation for very early/early stage of hepatocellular carcinoma. Surgeon 16:163–170. 7. Wong J, Lee KF, Yu SC, Lee PS, Cheung YS, Chong CN et al. (2013) Percutaneous radiofrequency ablation versus surgical radiofrequency ablation for malignant liver tumours: the long-term results. HPB 15: 595–601. 8. Wong J, Lee KF, Lee PS, Ho SS, Yu SC, Ng WW et al. (2009) Radiofrequency ablation for 110 malignant liver tumours: preliminary results on percutaneous and surgical approaches. Asian J Surg 32:13–20. 9. Liang P, Wang Y. (2007) Microwave ablation of hepatocellular carcinoma. Oncology 72(Suppl 1):124–131. 10. Ong SL, Gravante G, Metcalfe MS, Strickland AD, Dennison AR, Lloyd DM. (2009) Efficacy and safety of microwave ablation for primary and secondary liver malignancies: a systematic review. Eur J Gastroenterol Hepatol 21:599–605. 11. Thandassery RB, Goenka U, Goenka MK. (2014) Role of local ablative therapy for hepatocellular carcinoma. J Clin Exp Hepatol 4: S104–S111. 12. Wright AS, Lee FT, Jr., Mahvi DM. (2003) Hepatic microwave ablation with multiple antennae results in synergistically larger zones of coagulation necrosis. Ann Surg Oncol 10:275–283. 13. Iannitti DA, Martin RC, Simon CJ, Hope WW, Newcomb WL, McMasters KM et al. (2007) Hepatic tumor ablation with clustered microwave antennae: the US Phase II trial. HPB 9:120–124.
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Please cite this article as: Chong CCN et al., Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial), HPB, https://doi.org/10.1016/j.hpb.2020.01.008
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7
14. Jagad RB, Koshariya M, Kawamoto J, Papastratis P, Kefalourous H,
24. Poulou LS, Botsa E, Thanou I, Ziakas PD, Thanos L. (2015)
Patris V et al. (2008) Laparoscopic microwave ablation of liver tumors:
Percutaneous microwave ablation vs radiofrequency ablation in the
our experience. Hepatogastroenterology 55:27–32.
treatment
15. Bhardwaj N, Strickland AD, Ahmad F, El-Abassy M, Morgan B,
of
hepatocellular
carcinoma.
World
J
Hepatol
7:
1054 – 1063.
Robertson GS et al. (2010) Microwave ablation for unresectable hepatic
25. Santambrogio R, Chiang J, Barabino M, Meloni FM, Bertolini E,
tumours: clinical results using a novel microwave probe and generator.
Melchiorre F et al. (2017) Comparison of laparoscopic microwave to
Eur J Surg Oncol 36:264–268.
radiofrequency ablation of small hepatocellular carcinoma (
16. Martin RC, Scoggins CR, McMasters KM. (2010) Safety and efficacy of microwave ablation of hepatic tumors: a prospective review of a 5-year
Ann Surg Oncol 24:257–263. 26. Vietti Violi N, Duran R, Guiu B, Cercueil JP, Aube C, Digklia A et al. (2018) Efficacy of microwave ablation versus radiofrequency ablation for
experience. Ann Surg Oncol 17:171–178. 17. Lee KF, Hui JW, Cheung YS, Wong JS, Chong CN, Wong J et al. (2012)
the treatment of hepatocellular carcinoma in patients with chronic liver
Surgical ablation of hepatocellular carcinoma with 2.45-GHz microwave:
disease: a randomised controlled phase 2 trial. Lancet Gastroenterol
a critical appraisal of treatment outcomes. Hong Kong Med J 18:85–91.
Hepatol 3:317–325.
18. Lee KF, Wong J, Hui JW, Cheung YS, Chong CC, Fong AK et al. (2017)
27. Huang S, Yu J, Liang P, Yu X, Cheng Z, Han Z et al. (2014) Percuta-
Long-term outcomes of microwave versus radiofrequency ablation for
neous microwave ablation for hepatocellular carcinoma adjacent to
hepatocellular carcinoma by surgical approach: a retrospective
large vessels: a long-term follow-up. Eur J Radiol 83:552–558. 28. Huo YR, Eslick GD. (2015) Microwave ablation compared to radio-
comparative study. Asian J Surg 40:301–308. 19. Dong B, Liang P, Yu X, Su L, Yu D, Cheng Z et al. (2003) Percutaneous sonographically guided microwave coagulation therapy for hepatocellular carcinoma: results in 234 patients. AJR Am J Roentgenol 180:
frequency ablation for hepatic lesions: a meta-analysis. J Vasc Intervent Radiol 26:1139–11346 e2. 29. Chinnaratha MA, Chuang MY, Fraser RJ, Woodman RJ, Wigg AJ. (2016) Percutaneous thermal ablation for primary hepatocellular carcinoma: a
1547–1555. 20. Shibata T, Iimuro Y, Yamamoto Y, Maetani Y, Ametani F, Itoh K et al. (2002) Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology
systematic review and meta-analysis. J Gastroenterol Hepatol 31: 294–301. 30. Glassberg MB, Ghosh S, Clymer JW, Qadeer RA, Ferko NC, Sadeghirad B et al. (2019) Microwave ablation compared with radio-
223:331–337. 21. Xu HX, Xie XY, Lu MD, Chen JW, Yin XY, Xu ZF et al. (2004) Ultrasound-
frequency ablation for treatment of hepatocellular carcinoma and liver
guided percutaneous thermal ablation of hepatocellular carcinoma
metastases: a systematic review and meta-analysis. Onco Targets Ther
using microwave and radiofrequency ablation. Clin Radiol 59:53–61.
12:6407–6438.
22. Ding J, Jing X, Liu J, Wang Y, Wang F, Wang Y et al. (2013) Comparison
31. Cheung TT, Kwok PC, Chan S, Cheung CC, Lee AS, Lee V et al. (2018)
of two different thermal techniques for the treatment of hepatocellular
Hong Kong consensus statements for the management of unresectable
carcinoma. Eur J Radiol 82:1379–1384.
hepatocellular carcinoma. Liver Cancer 7:40–54.
23. Ohmoto K, Yoshioka N, Tomiyama Y, Shibata N, Kawase T, Yoshida K et al. (2009) Comparison of therapeutic effects between radiofrequency
Appendix A. Supplementary data
ablation and percutaneous microwave coagulation therapy for small
Supplementary data to this article can be found online at https://doi.org/10.
hepatocellular carcinomas. J Gastroenterol Hepatol 24:223–227.
1016/j.hpb.2020.01.008.
HPB xxxx, xxx, xxx
© 2020 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article as: Chong CCN et al., Prospective double-blinded randomized controlled trial of Microwave versus RadioFrequency Ablation for hepatocellular carcinoma (McRFA trial), HPB, https://doi.org/10.1016/j.hpb.2020.01.008