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1
==Summary==
2
3
====Objective====
4
5
To compare the effectiveness of early termination (ET) and standard termination (ST) of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) using internally cooled electrodes.
6
7
====Methods====
8
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Eighty-three treatment naïve patients with HCC with 101 index tumor underwent RFA. ET was defined as termination of ablation if after 6 minutes the power emission was < 10 seconds for three times per minute under maximal power. Standard termination was defined as termination of ablation according to manufactures’ algorithms of 12 minutes’ procedure. Primary end point was complete ablation of index tumor after 4 weeks of RFA.
10
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====Results====
12
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Nineteen patients (22.9%) underwent ET and 64 patients (77.1%) underwent ST. The mean size of the index tumor was 2.2 + 0.9 cm. Patient had complete ablation of the index tumor at 92.0% for the ET and 88.2% for the ST (''p''  = 0.593). Eight of 25 (32.0%) for the ET and 18 of 73 (24.7%) for the ST group had local tumor progression on last follow-up (''p''  = 0.473). After a median follow-up of 23 weeks (range, 9–33 weeks), the 24 weeks cumulative probability of local tumor progression was not different between ET (46.2%) and ST (25.6%; ''p''  = 0.387). Complete ablation at 4 weeks was the only independent factor associated with local tumor progression (adjusted hazard ratio 0.04, 95% confidence interval 0.01–0.16, ''p''  < 0.001).          
14
15
====Conclusion====
16
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Using ET in RFA is as effective as the ST in achieving complete ablation and local tumor progression.
18
19
==Keywords==
20
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Hepatocellular carcinoma ; Internally cooled electrode ; Local tumor progression ; Radiofrequency ablation ; Standard termination ; Termination of ablation
22
23
==Introduction==
24
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Hepatic resection and transplantation are the potential curative therapy for hepatocellular carcinoma (HCC). Unfortunately, only 20–30% of those patients presenting with HCC are eligible candidates [[#bib1|[1]]]  ;  [[#bib2|[2]]] . With the introduction of radiofrequency ablation (RFA) in 1983, it has become one of the modalities that have been gaining acceptance in treating small inoperable HCC [[#bib3|[3]]] ; [[#bib4|[4]]] ; [[#bib5|[5]]] ; [[#bib6|[6]]] ; [[#bib7|[7]]] ; [[#bib8|[8]]] ; [[#bib9|[9]]] ; [[#bib10|[10]]] ; [[#bib11|[11]]]  ;  [[#bib12|[12]]] . RFA have been shown in several studies to have a high complete ablation rate of 85–96% in the management of HCC < 5 cm in diameter [[#bib4|[4]]] ; [[#bib5|[5]]] ; [[#bib6|[6]]] ; [[#bib7|[7]]] ; [[#bib8|[8]]] ; [[#bib9|[9]]] ; [[#bib10|[10]]]  ;  [[#bib11|[11]]] .      
26
27
The mechanism behind RFA is based on adequate conversion of electrical energy to thermal energy to produce tissue heating. The heat has coagulation and direct cytotoxic effects on the tumor leading to tumor destruction [[#bib12|[12]]] . Several electrodes are available commercially and the internally cooled electrode is among the commonly used electrode because of its ease of use and proven efficacy [[#bib3|[3]]] ; [[#bib4|[4]]] ; [[#bib5|[5]]] ; [[#bib6|[6]]] ; [[#bib7|[7]]] ; [[#bib8|[8]]] ; [[#bib9|[9]]] ; [[#bib10|[10]]] ; [[#bib11|[11]]] ; [[#bib12|[12]]] ; [[#bib13|[13]]] ; [[#bib14|[14]]] ; [[#bib15|[15]]]  ;  [[#bib16|[16]]] . Its tip is internally cooled to prevent tissue charring leading to a significant increase in energy delivery and lesion size [[#bib13|[13]]] ; [[#bib14|[14]]] ; [[#bib15|[15]]]  ;  [[#bib16|[16]]] . Previous studies showed that increasing the power or prolonged ablation procedure would produce larger coagulation area however a power > 130 watts would induce a frequent increase in impedance and multiple automatic reduction in current that might consequently diminish the total treated time [[#bib14|[14]]] ; [[#bib15|[15]]] ; [[#bib16|[16]]] ; [[#bib17|[17]]]  ;  [[#bib18|[18]]] . A rising impedance may be due to irreversible dehydration and charring [[#bib19|[19]]]  ;  [[#bib20|[20]]]  or due to reversible formation of electrically insulating gas between the electrode and the tissue due to boiling and evaporation of tissue fluid [[#bib21|[21]]] .      
28
29
Modification of treatment strategies such as performing percutaneous saline-enhanced impedance controlled RFA to minimize potential carbonization to produce a larger tumor response rate has been studied; though promising, it is not often convenient and applicable to all operators [[#bib21|[21]]]  ;  [[#bib22|[22]]] . Hence seeking for newer techniques, constant modification or refinement of treatment strategies is of value.      
30
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This study aimed to determine whether there is any difference in using the early termination technique than the standard termination in terms of complete ablation of the index tumor, local tumor progression, and complication rates.
32
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==Methods==
34
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===Patients===
36
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Consecutively registered patients with HCC who underwent RFA using internally cooled electrode from May 2010 to April 2011 at Chang Gung Memorial Hospital (Linkou Branch), Taipei, Taiwan were screened. The study included patients with treatment-naïve HCC with less than three index tumors and < 4 cm in size. Excluded patients were those with Child-Pugh Class C cirrhosis, with macroscopic vascular invasion or extrahepatic metastases and those with malignancy other than HCC.
38
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The diagnosis of HCC was through cytologic or histopathologic findings or the presence of a hypervascular liver mass in the arterial phase of a dynamic imaging study (computed tomography or magnetic resonance imaging) with contrast washout during the portal or delayed phase plus angiographic confirmation of a hypervascular mass or an α-fetoprotein concentration > 200 ng/mL. Patient demographics, hematology, biochemistry, size, and number of index tumor were recorded. Etiological factors of hepatitis B virus or hepatitis C virus were examined by serological assays. Patients included in the study gave informed written consent for RFA.
40
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===Radiofrequency ablation technique===
42
43
This study was limited to patients treated with an internally cooled electrode with a 3-cm uninsulated tip (Cool-tip radiofrequency system, Valleylab Inc., Boulder, CO, USA) in all tumors. Cluster-type electrodes were not used in this study. All RFA were performed by three gastroenterologists with at least 10 years’ experience with sonographic-guided interventions. Multiple overlapping ablations were performed as needed to cover the whole tumor plus a 5- to 10-mm ablative margin around the tumor, when feasible [[#bib3|[3]]] ; [[#bib12|[12]]] ; [[#bib17|[17]]]  ;  [[#bib18|[18]]] . Electrode track thermocoagulation was routinely performed with a temperature over 70°C on withdrawal [[#bib3|[3]]] ; [[#bib12|[12]]] ; [[#bib17|[17]]] ; [[#bib18|[18]]]  ;  [[#bib23|[23]]] .      
44
45
A standard protocol for conscious sedation consisting of 30 mg meperidine and 3 mg midazolam were administered intravenously prior to ablation. These doses were then titrated to achieve an adequate comfort level throughout the procedure. Continuous monitoring of vital signs and oxygen saturation during the procedure was performed. Local anesthesia with 1% lidocaine hydrochloride was applied along the planned puncture site. The electrode was introduced percutaneously through the tumor for at least 0.5 cm beyond its deep margin under real-time sonographic guidance (Aplio SSA-700A, Toshiba, Tokyo, Japan). The radiofrequency generator contains an internal program that automatically runs a 12-min pulsed energy ablation cycle and adjusts the power output relative to tissue impedance to optimize the diameter of ablated tissue.
46
47
For the early termination group (ET) maximum power setting was done and if after 6 minutes the power emission was < 10 seconds for three times per minute the ablation was terminated after 9 minutes. As for the standard termination (ST) the modified automated algorithm as previously described was used [[#bib18|[18]]] . Briefly, the ablation begins by activating the impedance control mode with a gradual increase in power output over the 1<sup>st</sup>  minute to reach 120 W. The power is maintained at this level until tissue impedance rises to 20 Ω above the baseline impedance. The power output is automatically reduced to zero for 15 seconds once the 20 Ω of threshold is exceeded. The power is then returned to the initial peak power setting until the tissue impedance rises again. Successive cycles are continued for 12 minutes to complete a single ablation. The discretion to perform either technique was left to the decision of the operator.      
48
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===Follow-up protocol===
50
51
Four weeks after the ablation, a dynamic imaging study [computed tomography (CT) or magnetic resonance imaging (MRI)] was performed to assess the completeness of ablation. A completely ablated tumor was defined as an area of low attenuation on CT or low signal intensity on T2-weighted MRI that encompassed the area of the index tumor with no nodular peripheral enhancement on dynamic studies [[#bib23|[23]]] . Any nodular enhancement seen in the treated tumor was considered to be a residual viable tumor. In cases of incomplete ablation, additional sessions using the same algorithm or percutaneous ethanol injection or transarterial chemoembolization (TACE) were performed. Treatment for each tumor is limited to three sessions within 3 months. An immediate follow-up dynamic study was carried out to confirm the absence of a residual tumor after the additional treatments. After complete ablation, monitoring for local recurrence with dynamic imaging studies, liver function tests, and α-fetoprotein measurement were done every 3–6 months.      
52
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===Study endpoints===
54
55
The primary endpoint of this study was complete ablation of the index tumor after one RFA session. Secondary end points were primary effectiveness defined as complete ablation of the index tumor after more than one RFA session and local tumor progression. Local tumor progression was defined as the appearance of nodular enhancement contiguous with the ablated tumor on dynamic study or an increase in the size of the ablated area on follow-up imaging of a tumor that was previously completely ablated [[#bib23|[23]]] . Major complications were defined as those requiring therapy with hospitalization or involving permanent adverse sequelae. These endpoints were based on the guidelines set by the International Working Group on Image-Guided Tumor Ablation [[#bib23|[23]]] .      
56
57
===Statistical analysis===
58
59
Statistical analysis was performed using IBM SPSS statistics for Windows version 19.0 (Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation or median (interquartile range), and compared using unpaired ''t''  test or Mann–Whitney ''U''  test as appropriate. Categorical variables were presented as frequency (percentage) and compared using the Chi-square test or Fisher’s exact test as appropriate. Cumulative probability local tumor progression was estimated with Kaplan–Meier curve. Multiple logistic regression analysis was used to determine independent predictors of complete ablation and Cox regression analysis with forward logistic regression was used to model independent predictors of local tumor progression. Covariates with ''p''  < 0.05 from univariate analysis were included in multivariate analysis. All statistical tests were two sided and a ''p''  < 0.05 was considered statistically significant. Survival analysis was not performed due to the short-term follow-up of the study population.      
60
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==Results==
62
63
===Patients characteristics===
64
65
A total of 115 patients underwent first-time RFA using internally cooled electrode during the study period. Twenty-nine patients were excluded due to history of previous treatment (''n''  = 18), Child-Pugh class C (''n''  = 1), index tumor number of more than three (''n''  = 6) and tumor size of more than four (''n''  = 4). Eighty-three patients were eventually included in the final analysis, with 19 patients belonging to the ET group and 64 patients to the ST group ( [[#fig1|Figure 1]] ). The mean age of patients was 67.0 + 9.2 with a median follow-up of 23 weeks (range, 9–33 weeks). The mean size of the index tumor was 2.2 + 0.9 cm. More cirrhotic patients (89.1%) were included in the ST group than ET group (68.4%, ''p''  = 0.030;  [[#tbl1|Table 1]] ).
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<span id='fig1'></span>
68
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{| style="text-align: center; border: 1px solid #BBB; margin: 1em auto; max-width: 100%;" 
70
|-
71
|
72
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74
[[Image:draft_Content_597895113-1-s2.0-S2351979715001000-gr1.jpg|center|371px|Flowchart of patient distribution. TACE = transarterial chemoembolization.]]
75
76
77
|-
78
| <span style="text-align: center; font-size: 75%;">
79
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Figure 1.
81
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Flowchart of patient distribution. TACE = transarterial chemoembolization.
83
84
</span>
85
|}
86
87
<span id='tbl1'></span>
88
89
{| class="wikitable" style="min-width: 60%;margin-left: auto; margin-right: auto;"
90
|+
91
92
Table 1.
93
94
Clinical characteristics of patients and outcome management of hepatocellular carcinoma for patient groups.
95
96
|-
97
98
! Characteristics
99
! All (''n''  = 83)                                                    
100
! Early Termination (''n''  = 19)                                                    
101
! Standard Termination (''n''  = 64)                                                    
102
! ''p''
103
|-
104
105
| Age (y)
106
| 67.0 + 9.2
107
| 66.7 + 9.9
108
| 67.1 + 9.1
109
| 0.896
110
|-
111
112
| Male (%)
113
| 55 (66.3)
114
| 15 (78.9)
115
| 40 (62.5)
116
| 0.183
117
|-
118
119
| Etiologic factor
120
| 
121
| 
122
| 
123
| rowspan="4" | 0.560
124
|-
125
126
| Hepatitis B virus
127
| 25 (30.1)
128
| 4 (21.1)
129
| 21 (32.8)
130
|-
131
132
| Hepatitis C virus
133
| 40 (48.2)
134
| 11 (57.8)
135
| 29 (45.3)
136
|-
137
138
| Others[[#tbl1fna|<sup>a</sup>]]
139
| 18 (21.7)
140
| 4 (21.1)
141
| 14 (21.9)
142
|-
143
144
| Cirrhosis
145
| 70 (84.3)
146
| 13 (68.4)
147
| 57(89.1)
148
| 0.030
149
|-
150
151
| Child-Pugh class (''n''  = 70)                                                    
152
| 
153
| 
154
| 
155
| rowspan="3" | 0.627
156
|-
157
158
| A
159
| 50 (71.4)
160
| 10 (76.9)
161
| 40 (70.2)
162
|-
163
164
| B
165
| 20 (28.6)
166
| 3 (23.1)
167
| 17 (29.8)
168
|-
169
170
| α-fetoprotein (ng/mL)
171
| 9.7 (4.8–36.7)
172
| 12.3 (5.7–39.6)
173
| 8.1 (4.2–36.0)
174
| 0.319
175
|-
176
177
| Total bilirubin (mg/dL)
178
| 0.9 + 0.6
179
| 1.0 + 0.6
180
| 0.9 + 0.6
181
| 0.428
182
|-
183
184
| Albumin (g/dL) (''n''  = 80)                                                    
185
| 3.6 + 0.6
186
| 3.7 + 0.7
187
| 3.6 + 0.6
188
| 0.439
189
|-
190
191
| Prothrombin time (international normalized ratio)
192
| 1.2 + 0.1
193
| 1.2 + 0.2
194
| 1.2 + 0.1
195
| 0.342
196
|-
197
198
| Platelet count (×10<sup>9</sup> /L)                                                    
199
| 115.6 + 53.6
200
| 112.0 + 55.6
201
| 116.6 + 53.4
202
| 0.743
203
|-
204
205
| Size of index tumor (cm) (''n''  = 101)                                                    
206
| 2.2 + 0.9
207
| 2.1 + 0.8
208
| 2.3 + 1.0
209
| 0.271
210
|-
211
212
| Single tumor
213
| 65 (78.3)
214
| 13 (20)
215
| 52 (80)
216
| 0.216
217
|-
218
219
| No. of index tumor
220
| 1.2 + 0.4
221
| 1.3 + 0.5
222
| 1.2 + 0.4
223
| 0.239
224
|-
225
226
| Patients with tumors in difficult-to-treat location
227
| 24 (28.9)
228
| 6 (31.5)
229
| 18 (28.1)
230
| 0.538
231
|-
232
233
| Cool down temperature (°C) (''n''  = 81)                                                    
234
| 65.3 + 7.6
235
| 62.4 + 7.8
236
| 66.2 + 7.4
237
| 0.057
238
|-
239
240
| Complete ablation at 4 wk (''n''  = 101)                                                    
241
| 90 (89.1)
242
| 23/25 (92)
243
| 67/76 (88.2)
244
| 0.593
245
|-
246
247
| Primary technique effectiveness (''n''  = 101)                                                    
248
| 98 (97)
249
| 25/25 (100)
250
| 73/76 (96.1)
251
| 0.313
252
|-
253
254
| Local progression (''n''  = 98)[[#tbl1fnb|<sup>b</sup>]]
255
| 21 (21.4)
256
| 6/25 (24)
257
| 15/73 (20.5)
258
| 0.717
259
|-
260
261
| New HCC on follow-up (''n''  = 98)[[#tbl1fnb|<sup>b</sup>]]
262
| 5 (5.1)
263
| 2/25(8)
264
| 3/73 (4.1)
265
| 0.445
266
|}
267
268
Data are presented as ''n''  (%), mean + standard deviation, or median (interquartile range) as appropriate.      
269
270
a. Alcoholic liver disease (''n''  = 6), idiopathic (''n''  = 5), hepatitis B and C coinfection (''n''  = 3), Wilsons disease (''n''  = 1), primary biliary cirrhosis (''n''  = 1), hepatitis B and alcoholic liver disease (''n''  = 2).                                      
271
272
b. Not included in analysis because dynamic images after complete ablation unavailable (''n''  = 2) and complete ablation was not achieved (''n''  = 1).              
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===Complete ablation===
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A total of 101 index tumors were included in the analysis for complete ablation after 4 weeks of RFA with 25 tumors for the ET group and 76 tumors for the ST group. There was no significant difference between the 92% of the ET group and 88.2% of the ST group in achieving complete ablation after 4 weeks of RFA (''p''  = 0.593). There was also no significant independent factor, including a tumor in a difficult-to-treat location, that would predict complete ablation after 4 weeks of RFA from our study ( [[#tbl2|Table 2]] ).
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<span id='tbl2'></span>
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{| class="wikitable" style="min-width: 60%;margin-left: auto; margin-right: auto;"
281
|+
282
283
Table 2.
284
285
Factors predicting complete ablation after 4 weeks of radiofrequency ablation among hepatocellular carcinoma patients: univariate analysis.
286
287
|-
288
289
! colspan="2" | Variable
290
! HR (95% CI)
291
! ''p''
292
|-
293
294
| Cirrhosis
295
| Yes (''n''  = 70)                                                    
296
| 0.41 (0.1–1.8)
297
| 0.231
298
|-
299
300
| 
301
| No (''n''  = 13)                                                    
302
| 1.0
303
| 
304
|-
305
306
| Child-Pugh class
307
| B (''n''  = 20)                                                    
308
| 0.38 (0.1–2.6)
309
| 0.326
310
|-
311
312
| 
313
| A (''n''  = 50)                                                    
314
| 1.0
315
| 
316
|-
317
318
| Cool-down temperature (°C)
319
| ≤ 70 (''n''  = 8)                                                    
320
| 0.98 (0.9–1.1)
321
| 0.722
322
|-
323
324
| 
325
| > 70 (''n''  = 75)                                                    
326
| 1.0
327
| 
328
|-
329
330
| Early termination
331
| No (''n''  = 64)                                                    
332
| 0.65 (0.1–3.2)
333
| 0.595
334
|-
335
336
| 
337
| Yes (''n''  = 19)                                                    
338
| 1.0
339
| 
340
|-
341
342
| Number of needle passes
343
| 2–3(''n''  = 62)                                                    
344
| 1.07 (0.6–1.8)
345
| 0.803
346
|-
347
348
| 
349
| 1 (''n''  = 21)                                                    
350
| 1.0
351
| 
352
|-
353
354
| Size of index tumor
355
| ≤ 2 cm (''n''  = 78)                                                    
356
| 1.00 (0.5–2.0)
357
| 0.996
358
|-
359
360
| 
361
| > 2 cm (''n''  = 23)                                                    
362
| 1.0
363
| 
364
|-
365
366
| Patients with tumors in difficult-to-treat location
367
| Yes (''n''  = 24)                                                    
368
| 1.56 (0.78–3.84)
369
| 0.443
370
|-
371
372
| 
373
| No (''n''  = 59)                                                    
374
| 1.0
375
| 
376
|}
377
378
CI = confidence interval; HR = hazard ratio.
379
380
===Primary technique effectiveness===
381
382
Among the 11 tumors not completely ablated after one RFA session, eight were managed with further RFA session to achieve complete ablation. Of the remaining three tumors with incomplete ablation, two underwent transarterial chemoembolization and one underwent ethanol injection that was determined by patient’s preference. All patients in the ET group and 73 in the ST group (96.1%) achieved primary technique effectiveness (''p''  = 0.313).      
383
384
===Local tumor progression===
385
386
Out of the 101 tumors, only 98 tumors were included in the final analysis for local tumor progression because dynamic images after complete ablation were unavailable for two tumors and complete ablation was not achieved in one tumor. The follow up duration was 20.1 + 14.8 weeks (20.2 + 13.1 weeks for the ET group and 20.0 + 15.4 weeks for the ST group; ''p''  = 0.966). Twenty-one tumors had local recurrence and five tumors were new recurrences. Local tumor progression for the ET group and ST group were not significantly different (32% and 24.7% respectively, ''p''  = 0.473). Both cirrhosis and complete ablation after 4 weeks of RFA were significant in univariate analysis for predicting local tumor progression, however, on multivariate analysis only complete ablation after 4 weeks of RFA is the independent predictive factor for local tumor progression ( [[#tbl3|Table 3]] ). The cumulative local tumor progression rate of patients in the ET group was not significantly different to those in the ST group (''p''  = 0.387,  [[#fig2|Figure 2]] ). The 24 weeks cumulative probability of local tumor progression was not different among those with ET group [46.2%; 95% confidence interval (CI) 0.191–0.733] and those with ST group (25.6%; 95% CI 0.119–0.393).
387
388
<span id='tbl3'></span>
389
390
{| class="wikitable" style="min-width: 60%;margin-left: auto; margin-right: auto;"
391
|+
392
393
Table 3.
394
395
Factors predicting local recurrence on last follow-up by Cox proportional hazard model.
396
397
|-
398
399
! colspan="2" rowspan="2" | Variable
400
! colspan="2" | Univariate analysis
401
! colspan="2" | Multivariate analysis
402
|-
403
404
! HR (95% CI)
405
! ''p''
406
! HR (95% CI)
407
! ''p''
408
|-
409
410
| Cirrhosis
411
| Yes (''n''  = 70)                                                    
412
| 0.32 (0.13–0.77)
413
| 0.011
414
| 0.56 (0.20–1.52)
415
| 0.251
416
|-
417
418
| 
419
| No (''n''  = 13)                                                    
420
| 1.0
421
| 
422
| 1.0
423
| 
424
|-
425
426
| Child-Pugh class
427
| B (''n''  = 20)                                                    
428
| 0.4 6(0.17–1.29)
429
| 0.142
430
| 
431
| 
432
|-
433
434
| 
435
| A (''n''  = 50)                                                    
436
| 1.0
437
| 
438
| 
439
| 
440
|-
441
442
| Tumor size
443
| ≤ 2 cm (''n''  = 78)                                                    
444
| 0.75 (0.44–1.28)
445
| 0.285
446
| 
447
| 
448
|-
449
450
| 
451
| > 2 cm (''n''  = 23)                                                    
452
| 1.0
453
| 
454
| 
455
| 
456
|-
457
458
| Patients with tumors in difficult-to-treat location
459
| Yes (''n''  = 24)                                                    
460
| 1.89 (0.94–3.18)
461
| 0.562
462
| 
463
| 
464
|-
465
466
| 
467
| No (''n''  = 59)                                                    
468
| 1.0
469
| 
470
| 
471
| 
472
|-
473
474
| Early termination
475
| No (''n''  = 64)                                                    
476
| 1.44 (0.62–3.32)
477
| 0.394
478
| 
479
| 
480
|-
481
482
| 
483
| Yes (''n''  = 19)                                                    
484
| 1.0
485
| 
486
| 
487
| 
488
|-
489
490
| Number of needle passes
491
| 2–3 (''n''  = 62)                                                    
492
| 0.62 (0.36–1.09)
493
| 0.096
494
| 
495
| 
496
|-
497
498
| 
499
| 1 (''n''  = 21)                                                    
500
| 1.0
501
| 
502
| 
503
| 
504
|-
505
506
| Complete ablation of HCC after 4 w
507
| Yes (''n''  = 90)                                                    
508
| 0.01 (0.01–0.11)
509
| < 0.001
510
| 0.04 (0.01–0.16)
511
| < 0.001
512
|-
513
514
| 
515
| No (''n''  = 11)                                                    
516
| 1.0
517
| 
518
| 1.0
519
| 
520
|}
521
522
CI = confidence interval; HCC = hepatocellular carcinoma; HR = hazard ratio.
523
524
<span id='fig2'></span>
525
526
{| style="text-align: center; border: 1px solid #BBB; margin: 1em auto; max-width: 100%;" 
527
|-
528
|
529
530
531
[[Image:draft_Content_597895113-1-s2.0-S2351979715001000-gr2.jpg|center|373px|Cumulative proportion of local recurrence among patients with hepatocellular ...]]
532
533
534
|-
535
| <span style="text-align: center; font-size: 75%;">
536
537
Figure 2.
538
539
Cumulative proportion of local recurrence among patients with hepatocellular carcinoma treated with early termination (ET) radiofrequency ablation versus standard termination (ST). Cumulative local tumor progression rate of those patients with hepatocellular carcinoma treated with ET was not significantly different to those treated with ST of radiofrequency ablation (''p''  = 0.387). ''n''  indicates the number of remaining patients who were not lost to follow-up and still had nonviable tumor.                  
540
541
</span>
542
|}
543
544
===Complications===
545
546
All patients tolerated the procedure well. No major complications occurred in both groups. Side effects seen were not significant in both groups (''p''  = 0.612). One patient had post-ablation syndrome (fever, general malaise) and one patient had minimal asymptomatic perihepatic or renal fluid for the ET group. Although five patients of the ST group had asymptomatic pleural effusion, four had asymptomatic pleural effusion plus ascites, two had postablation syndrome, another two had minimal asymptomatic perihepatic or renal fluid, and one had minimal pain. During the follow-up period, no patients died but two patients were lost to follow-up.      
547
548
==Discussion==
549
550
In this study, performing percutaneous RFA using the ET technique is not different from the ST technique in terms of achieving complete ablation. Local tumor progression and side effects were also comparable between the groups. To our knowledge, this study is the first of its kind in using such a technique in performing RFA.
551
552
RFA has gained important role in ablation of small HCC for its high rate of complete ablation and minimal invasiveness [[#bib4|[4]]] ; [[#bib5|[5]]] ; [[#bib6|[6]]] ; [[#bib7|[7]]] ; [[#bib8|[8]]] ; [[#bib9|[9]]] ; [[#bib10|[10]]]  ;  [[#bib11|[11]]] . The determinants of complete ablation of RFA include tumor factors including size, location, conspicuousness, and heat sink effect, and ablation procedure factors including technical success and complications [[#bib12|[12]]] ; [[#bib13|[13]]]  ;  [[#bib20|[20]]] . The technical success was also dependent on the distribution of heat emission within the tumor [[#bib12|[12]]] . To our knowledge, there is no universal ablation algorithm for RFA procedure [[#bib20|[20]]]  ;  [[#bib23|[23]]] . However, if the heat emission was interrupted by the abnormally high temperature related carbonization and charring tissue, the ablation effect and zone would be incomplete [[#bib20|[20]]]  ;  [[#bib24|[24]]] . A manufacture algorithm of radio-frequency was used an internal program that automatically runs a 12-min pulsed energy ablation cycle and adjusts the power output relative to tissue impedance to optimize the diameter of ablated tissue [[#bib3|[3]]] ; [[#bib4|[4]]] ; [[#bib12|[12]]] ; [[#bib13|[13]]] ; [[#bib16|[16]]] ; [[#bib18|[18]]] ; [[#bib20|[20]]]  ;  [[#bib23|[23]]] . Nevertheless, frequent rising of impedance between very short intervals was observed and it subsequently might hinder heat further emission due to more charring formation during frequent high impedance [[#bib17|[17]]] ; [[#bib18|[18]]] ; [[#bib24|[24]]]  ;  [[#bib25|[25]]] . Our finding in the current study showed a similar rate of complications and local tumor progression between standard and early termination of ablation procedures. The benefit of early termination may include shorter ablation time, less discomfort, and probably more useful for ablation of larger tumor that requires overlapping ablation.      
553
554
Furthermore, to our knowledge, there is no definition of early termination procedure. However, based on the mechanism of radiofrequency emission, the power is maintained at the setting level until tissue impedance rises to 20 Ω above the baseline impedance [[#bib18|[18]]] . The power output is automatically reduced to zero for 15 seconds (time of power temporary off) once the 20 Ω of threshold is exceeded. The power is then returned to the initial peak power setting until the tissue impedance rises again. Therefore, if the power emission is < 15 seconds of power temporary off, it may indicate that sufficient impedance will interrupt further power emission, particularly, as the ablation procedure is up to 9 minutes as compared with 12 minutes of standard ablation. Therefore, we defined the ET group if a maximum power setting was done and if after 6 minutes the power emission was < 10 seconds for three times per minute, the ablation was terminated after 9 minutes.      
555
556
Although saline-linked RFA or using a novel needle perfusion technique currently can reduce the charring effects and enhance efficacy [[#bib15|[15]]] ; [[#bib21|[21]]] ; [[#bib22|[22]]] ; [[#bib24|[24]]]  ;  [[#bib25|[25]]] , these devices are slightly cumbersome and not so popular in most institutes. Therefore, the current algorithm using ET might be an option to reduce charring effects and achieve comparable efficacy as the standard termination of RFA procedures.      
557
558
The limitation of this study is its small sample size. Despite the small sample size, our study still showed that ET of the ablation procedure would achieve comparable complete ablation and local tumor progression compared with ST of the RF procedure. Further randomized study or a cohort study with larger sample size and longer follow-up may be needed to confirm our findings.
559
560
In conclusion, using ET in RFA is as effective as the ST in achieving complete ablation. It is also not associated with an increased risk of local tumor progression, and side effects between the two groups are comparable.
561
562
==Conflicts of interest==
563
564
All authors declared no conflicts of interest.
565
566
==References==
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