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Comparison of ultrasonography-guided percutaneous microwave ablation for subcapsular and nonsubcapsular hepatocellular carcinoma
Accepted Manuscript Title: Comparison of ultrasonography-guided percutaneous microwave ablation for subcapsular and nonsubcapsular hepatocellular carcinoma Authors: Fangyi Liu, Xiaoling Yu, Zhigang Cheng, Zhiyu Han, Ya Sun, Ping Liang, Fubo Zhou PII: DOI: Reference:
S0720-048X(17)30146-8 http://dx.doi.org/doi:10.1016/j.ejrad.2017.04.002 EURR 7791
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
23-10-2016 28-3-2017 3-4-2017
Please cite this article as: Liu Fangyi, Yu Xiaoling, Cheng Zhigang, Han Zhiyu, Sun Ya, Liang Ping, Zhou Fubo.Comparison of ultrasonography-guided percutaneous microwave ablation for subcapsular and nonsubcapsular hepatocellular carcinoma.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Comparison of ultrasonography-guided percutaneous microwave ablation
for
subcapsular
and
nonsubcapsular
hepatocellular
carcinoma
Fangyi Liu, MD, Xiaoling Yu, MD, Zhigang Cheng, MD, Zhiyu Han, MD, Ya Sun, MD, Ping Liang, MD, Fubo Zhou, MD,
All authors: Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
Corresponding author: Liang Ping, MD, Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China. Tel.: +86 10 66939530. Fax: +86 10 68161218. E-mail address: [email protected] E-mail address can be published.
This study was supported by the National Scientific Foundation Committee of China (81201167) and Beijing Nova Program (xx2013108). Type of manuscript: Original research Word count:2914
Purpose: To compare the prognosis of subcapsular and nonsubcapsular hepatocellular
carcinoma(HCC)
after
ultrasonography(US)-guided
percutaneous microwave ablation (MWA). Materials and Methods: From January 2012 to December 2015, 463
enrollment patients(382 men, 81 women; age range, 24-95 years) with a single HCC underwent US-guided percutaneous MWA. The patients were divided into two groups according to tumor location: subcapsular (n = 224) and nonsubcapsular (n = 239). Therapeutic efficacy was assessed by contrast enhanced imaging after MWA. The technique effectiveness rate, the local tumor progression(LTP) rate, overall survival(OS) rate and complication were compared between two groups. Results: There were no significant differences in the mean treatment sessions (p =0.105) and the mean number of antenna insertions (p=0.065) between two groups. No significant difference in the technique effectiveness rate was found between subcapsular and nonsubcapsular tumors(95.5% vs 98.3%, p = 0.089). The respective 1-,2-,3-,and 4-year cumulative LTP rates were 5.0%, 5.5 %, 5.5% and 5.5% in subcapsular group and 6.4%, 6.4%, 6.4% and 6.4% in nonsubcapsular group, respectively(p=0.861). The 1-,2-,3-,and 4-year OS rates were estimated to be 95.7%, 90.1%, 82.9%, and 71.1% in subcapsular group and 98.5%, 92.8%,
83.2%,
and
73.6%
in
nonsubcapsular
group,
respectively(p=0.426). There was no significant difference in major complication
rates
between
the
subcapsular
group(2.2%)
and
nonsubcapsular group(1.3%) (p=0.653). There was higher postoperative pain rate in subcapsular group(13.4%) than nonsubcapsular group(7.1%) (p=0.025).
Conclusions: There were no significant differences in the technique effectiveness rate, cumulative LTP rate, OS rate and major complication rate between subcapsular and nonsubcapsular group after MWA for HCC.
KEYWORDS: subcapsular; microwave ablation; hepatocellular carcinoma
INTRODUCTION Thermal ablation therapies such as radiofrequency (RF) and microwave ablation (MWA) has been most widely used for the treatment of hepatocellular carcinoma (HCC), achieving good results in local tumor control and low morbidity and mortality[1-3]. Nonetheless, ablation of exophytic and subcapsular liver tumors is a controversial issue because it may increase risks of tumor seeding , hemorrhage and thermal injury to the adjacent structure[4-6]. Some studies show that a subcapsular location is a risk factor for local tumor progression (LTP) because of the difficulty of placing an electrode and not being able to obtain enough ablation margin along the hepatic capsule[7-9]. Several technical methods have been developed to prevent complications, including different approaches, e.g., percutaneous, laparoscopic, or open laparotomy, artificial ascites or pleural effusion, different guiding techniques, and no-touch wedge ablation technique[10-13]. Investigators in a retrospective study reported
a low risk of seeding in a nonselect group of patients[14], and a prospective study showed comparable morbidity after RF ablation between subcapsular and nonsubcapsular tumors[15]. A propensity score matched study showed that the differences in LTP, overall survival (OS), and major complication rates of RF ablation for HCC were not significant between subcapsular and nonsubcapsular groups[16]. MWA has higher thermal effectiveness and less heat-sink effect than RF ablation [17], however, to our knowledge, limited data are available on the outcomes of US-guided percutaneous MWA in treating subcapsular hepatocellular carcinoma. The purpose of this study was to compare the prognosis of subcapsular and nonsubcapsular hepatocellular carcinoma after US-guided percutaneous MWA.
MATERIALS AND METHODS PATIENTS From January 2012 to December 2015, 463 enrollment patients(382 men, 81 women; age range, 24-95 years) with a single HCC less than 5cm in diameter underwent US-guided percutaneous MWA. The patients were divided into two groups according to tumor location: subcapsular (n=224) and nonsubcapsular (n = 239). Subcapsular group included those patients with one subcapsular nodule near the stomach, bowel, liver dome, diaphragm, or abdominal wall. Subcapsular HCC was defined as an index
tumor located within 0.1 cm of the liver capsule. Nonsubcapsular HCC was defined as an index tumor located more than 1 cm of the liver capsule and hepatic hilum and large vessels. There was no extrahepatic metastasis and vascular invasion for all patients. There was no significant difference in clinical backgrounds between the two groups except for the age (Table1). Diagnosis of HCC was based on American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL) and Asian Pacific Association for the Study of the Liver (APASL) imaging guidelines. Routine coagulation tests were performed prior to the procedure, which included prothrombin time (as measured by percentage of activity), partial thromboplastin time, and platelet count. An INR of <1.5, and a platelet count >40,000/mm3 were viewed as the minimum threshold for safety in performing MWA. This investigation was approved by our Institutional Ethics Committee. Written informed consent was obtained from all patients.
Microwave equipment and ablation technique All treatments were performed in our institution and were carried out under US guidance with the patients under unconscious intravenous anesthesia (Propofol, 6-12mg/kg/h; Ketamine, 1-2mg/kg) in the operating room. Additionally, when the tumors were not well visualized with conventional B-mode US, a contrast-enhanced ultrasound(CEUS)-guided
ablation with SonoVue (Bracco, Milan, Italy) was performed. The microwave unit (KY-2000, Kangyou Medical, Nanjing, China) consists of three independent microwave generators, three flexible coaxial cables and three water-pumping machines, which can drive three cool-tip needle antennas. The generator is capable of producing 1~100 W of power at 2450 MHz. The antenna is 15 gauges in diameter with cool-shaft. All therapy was performed by two experienced radiologists according to the preoperative planning. During the therapy, we monitored the hyperechoic area of ablation using gray-scale sonography and thermal monitoring to decide the endpoint of treatment. Within 3 days after ablation, every patient received CEUS to evaluate ablation area. If residual tumor or unablated therapeutic margin was detected, additional MWA treatment was performed. When withdrawing the antennae, the needle tracks were routinely cauterized to avoid tumor seeding and bleeding.
Ablation technique for subcapsular tumors The key points of the ablation technique used for tumors located subcapsular were as follows:(1) In cases of small tumor ablation, the tumors were punctured through the normal hepatic parenchyma rather than via direct puncture when possible. (2) In cases of larger or exophytic tumor ablation, traversing normal hepatic parenchyma was not always possible due to tumor position and the available angles of entry, and
tumor-feeding artery was ablated firstly, then a direct puncture of the tumor was performed without passing through normal liver parenchyma. Color Doppler US or CEUS was performed to determine the location of the target tumor-feeding artery. (3) Hydrodissection technique and thermal monitoring technique were applied for subcapsular tumors abutting vital structures to avoid thermal damage.
Hydrodissection technique After administering a local anesthetic comprising 1% lidocaine, a 16-gauge intravenous catheter (BD Angiocath; Sandy, UT) was punctured into the peritoneal cavity between the edge of the liver and the abutting gastrointestinal tract(GIT) under US guidance. A sufficient amount of normal saline was delivered until a separation of more than 0.5 cm between the target lesion and the adjacent GIT was achieved. Drip infusion was continued during the MWA procedure to maintain a distance of more than 0.5 cm.
Thermal monitoring procedure A thermal monitoring system attached to the microwave unit was used during treatment for the study group. With US guidance, one or two 21G thermal monitoring needles (Kangyou Medical, Nanjing, China) were placed into marginal tissue of tumor or liver proximal to the
surrounding tissues or organs for real-time temperature monitoring during the ablation to protect the surrounding tissues or organs from thermal mediated injury. Based on our experimental evidence and clinical experience, the temperature cut off of ablation therapy was set at 60°C in the patients. If the measured temperature reached 60°C, emission of microwave antenna was stopped immediately and was activated again after the temperature decreased to 50°C.
Therapeutic efficacy assessment and follow-up Therapeutic efficacy assessment and follow-up was assessed by contrast enhanced imaging after the treatment. The technique effectiveness was defined as the ‘complete ablation’ of the macroscopic tumor proved by imaging 1 month after ablation. Local tumor progression (LTP) was defined as incompletely treated viable tumor continuing to grow or a new tumor (‘daughter’ or ‘satellite’ tumors) growing at the original site during follow-up. The number of antenna insertions was defined as the total number of antenna placements for each tumor until this tumor was ablated completely. The follow-up period was calculated starting from the beginning of MW ablation in all patients. CEUS and contrast-enhanced CT or MRI were repeated at 1 month and at 3-months intervals within 1 year and then at 6-month intervals after MWA. If abnormal peripheral nodular enhancement of the ablation area was found
during follow-up and it was presumed to be LTP, further MWA was performed. Median follow-up time was 22 months (range, 3–52 months) in the subcapsular group and 27 months (range, 6–48 months) in the nonsubcapsular group.
Statistical analysis Data analysis was performed using SPSS11.0 for windows (SPSS Inc,Chicago,IL,USA) and the continuous data were expressed as means±standard deviations(SD). Independent samples t-test was used to compare the means between two groups. The technique effectiveness rate, the LTP rate, OS rate and other ratio were compared between subcapsular tumors and nonsubcapsular tumors group using the chi-square test. Cumulative incidence rates for LTP and OS rates by using the Kaplan-Meier method were estimated. The level of statistical significance was set at P-value less than 0.05.
RESULTS All patients were performed MWA successfully. The mean number of treatment sessions was 1.2 ± 0.8 for the subcapsular tumors and 1.1 ± 0.5 for the nonsubcapsular tumors. The subcapsular tumors and nonsubcapsular tumors showed no statistically significant difference (p=0.105). The mean number of antenna insertions was 2.3 ± 2.3 for the
subcapsular tumors and 2.1 ± 2.1 for the nonsubcapsular tumors. There was no significant difference in the mean number of antenna insertions between the subcapsular tumors group and nonsubcapsular tumors group (p=0.065).(Table2) Hydrodissection with saline solution was performed successfully on 40 patients. The average amount of solution for hydrodissection was 858.5±354mL (range, 120-1600mL). No patients had abnormal vital signs until the day after the procedure. The injected solution was completely absorbed in all patients at the 1-month follow-up CT or MRI. No
delayed
complications
related
to
hydrodissection
such
as
hemoperitoneum or peritonitis developed during the 1-month follow-up. Among the 463 tumors, 214 of the 224 that were subcapsular and 235 of the 239 that were nonsubcapsular showed complete tumor ablation on the 1-month follow-up contrast enhanced imaging(Figure 1, Figure2). Thus, the overall technique effectiveness rate was 97.0%. The technique effectiveness rates for subcapsular and nonsubcapsular tumors were 95.5%
and
98.3%,
respectively.
The
subcapsular
tumors
and
nonsubcapsular tumors showed no statistically significant differences (p = 0.089). LTP was detected in 12 of 224 patients (5.4%) in the subcapsular group and 15 of 239 patients (6.3%) in the nonsubcapsular group during the follow-up periods. The subcapsular tumors and nonsubcapsular
tumors showed no statistically significant difference (p=0.673) in LTP rate. The respective 1-,2-, 3-,and 4-year cumulative LTP rates were 5.0%,5.5 %, 5.5%, and 5.5% in the subcapsular group and 6.4%, 6.4%, 6.4%, and 6.4% in the nonsubcapsular group, respectively. The median time to LTP was 6 months (range, 3–14 months) in subcapsular tumors group and 6 months (range,3–15 months) in nonsubcapsular tumors group. No significant difference in cumulative LTP rates was observed between the subcapsular tumors group and nonsubcapsular tumors group (p=0.861) (Figure 3). During follow-up, the overall data showed the death of 33 of 224patients (14.7%) in the subcapsular group and 25 of 239 patients (10.4%) in the nonsubcapsular group. The 1-,2-, 3-,and 4-year OS rates were estimated to be 95.7%, 90.1%, 82.9%, and 71.1% in the subcapsular group and 98.5%, 92.8%, 83.2%, and 73.6% in the nonsubcapsular group, respectively. No procedure-related mortality occurred. There was no significant difference in OS rates between the subcapsular tumors group and nonsubcapsular tumors group (p=0.426) (Figure 4). The major complication rate associated with MWA was 1.7% (8 of 463 patients) in the overall data. 4 cases in subcapsular tumors group and 2 cases in nossubcapsular tumors group had a large amount of pleural fluid requiring aspiration. One case of peritoneal seeding in the subcapsular group and one case of abdominal wall seeding in
nonsubcapsular group occurred. There was no significant difference in the major complication rate between the subcapsular tumors group(2.2%) and nonsubcapsular tumors group(1.3%) (p=0.653). No patients in either group had immediate major complications associated with collateral thermal injury to the perihepatic structures. 30 cases in subcapsular tumors group and 17 cases in nonsubcapsular tumors group had moderate right upper quadrant pain (grade 2) requiring oral analgesics (oxycodone) and the symptoms gradually disappeared one week later. There was higher incidence rate of postoperative pain in subcapsular
tumors
group(13.4%)
than
nonsubcapsular
tumors
group(7.1%) (p=0.025).
DISCUSSION RF ablation of exophytic and subcapsular liver tumors was a controversial issue because it may have a high rate of LTP and increase risk of complications[7,8]. MWA results in active heating of the tissue and has higher thermal efficacy and less heat-sink effect than RF ablation, however, MWA of subcapsular HCC is also a controversial issue. In our study, there was no significant difference in technique effectiveness rate, LTP rate, OS rate, and major complication rate between the subcapsular tumors group and nonsubcapsular tumors group. Our results were similar to the results of comparison studies about RF ablation for subcapsular
versus nonsubcapsular HCC[16,18]. Investigators in previous studies suggested that the subcapsular location of a tumor was a risk factor for LTP after RF ablation because of the inability to achieve a 0.5–1.0-cm tumor-free margin [8,9]. However, subcapsular location should not be considered a risk factor for recurrence after HCC resection and there is no definite evidence that the absence of a margin on the capsular side increases the rate of local recurrence[15,19]. In our study, the subcapsular tumors and nonsubcapsular tumors showed no statistically significant differences in LTP rate (p=0.673) and cumulative LTP rates (p=0.861) after MWA. Kang et al. reported a multivariate analysis of risk factors for LTP showed that use of hydrodissection for tumor in a high-risk location (HR = 1.73; 95% CI: 1.07, 2.80; P = .026) and total ablation time (HR = 1.06; 95% CI: 1.01, 1.10; P = .009) were independent risk factors for LTP[16]. Kang et al. proposed that tumor size, poor liver function, and technical difficulty of RF ablation could influence the outcome of local tumor control in the subcapsular group, however, subcapsular location itself did not significantly influence local tumor control after RF ablation for HCC[16]. Previous studies reported that subcapsular HCCs had a higher incidence of hemorrhage and tumor seeding in respect to nonsubcapsular tumors [4,20]. However, investigators in a multicenter study reported a low rate of tumor seeding (12 [0.9%] seedings in 1314 treated patients) in
a large series of nonselect patients, and they did not identify subcapsular location as a risk factor for seeding [14]. Similarly, other studies on tumor seeding after RF ablation showed no significant relationship between tumor seeding and subcapsular tumor location[16,18]. Yu et al. reported another large retrospective case series of 1,462 patients performed microwave ablation, seeding was found in 0.75% of patients, and subcapsular location was not found be significantly associated with tumor seeding[21]. Avoiding capsular breach during ablation the no-touch wedge ablation technique may reduce the risk of tumor rupture and consequent hemorrhage and tumor seeding[13]. In our study, although we did not use the no-touch wedge ablation technique, no hemorrhage occurred, and only two cases of tumor seeding occurred. Our results showed no significant difference in two groups for tumor seeding as major complications. Two technique points used to prevent hemorrhage and tumor seeding in our study: First, for small tumor ablation, the tumors were punctured through the normal hepatic parenchyma rather than via direct puncture when possible, while for larger or exophytic tumor ablation, traversing normal hepatic parenchyma was not possible, and tumor-feeding artery was ablated firstly, then a direct puncture of the tumor was performed; Second, when withdrawing the antennae, the needle tracks were routinely cauterized to avoid tumor seeding and bleeding.
Thermal damage to adjacent structures was another possible major complication for thermal ablation of subcapsular HCC[4,14]. Studies showed that hydrodissection was technically feasible and effective in improving protection of the adjacent structures by separating them away from the liver capsule[11,22,23]. Hydrodissection was applied in 40 cases of subcapsular HCC in our study. No thermal damage to adjacent perihepatic structures occurred in our study. Song et al. reported that potential complications related to hydrodissection were bleeding, peritonitis,
and
tumor
seeding[23].
Our
study
showed
that
hydrodissection was a safe technique without complication. The other reason of reducing the incidence of thermal damage to perihepatic structures in our study was the application of thermal monitoring technique. About the minor complications in our study, there was higher incidence rate of postoperative pain in subcapsular tumors group(13.4%) than nonsubcapsular tumors group(7.1%) (p=0.025). After ablation, the local exudation of the hepatic capsule can lead to the adhesion of the liver and the abdominal wall or surrounding structures, which may be the main cause of postoperative pain of subcapsular HCC. In addition to postoperative pain medicine, patients getting out of bed as early as possible can prevent adhesion and reduce the incidence of pain. Despite these promising results, this study may have some
limitations. First, these data were obtained at a single centre with significant experience with MWA for liver tumors, and a multi-center study would be more convincing. Second, the follow-up period was not over 52 months, and a longer follow-up period may be needed.
CONCLUSIONS There were no significant differences in the technique effectiveness rate, cumulative LTP rate, OS rate and major complication rate between the subcapsular and nonsubcapsular tumors group after US-guided percutaneous MWA for HCC.
Conflict of Interest This study was supported by the National Scientific Foundation Committee of China (grant numbers 81201167) and Beijing Nova Program (xx2013108). The authors alone are responsible for the correct and writing of the paper. There was no conflict of interest about the study.
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7.Hori T, Nagata K, Hasuike S, Onaga M, Motoda M, Moriuchi A, et al. Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation. J Gastroenterol 2003;38(10):977–981. 8. Komorizono Y, Oketani M, Sako K, Yamasaki N, Shibatou T, Maeda M, et al. Risk factors for local recurrence of small hepatocellular carcinoma tumors after a single session, single application of percutaneous radiofrequency ablation. Cancer 2003;97(5):1253–1262 9. Yang B, Zou J, Xia J, Ren Z, Gan Y, Wang Y, et al. Risk factors for recurrence of small hepatocellular carcinoma after long-term follow-up of percutaneous radiofrequency ablation. Eur J Radiol 2011;79(2):196–200. 10. Machi J, Uchida S, Sumida K, Limm WM, Hundahl SA, Oishi AJ, et al. Ultrasound-guided radiofrequency thermal ablation of liver tumors: percutaneous, laparoscopic, and open surgical approaches. J Gastrointest Surg 2001;5:477-89. 11. Rhim H, Lim HK, Kim YS, Choi D. Percutaneous radiofrequency ablation with artificial ascites for hepatocellular carcinoma in the hepatic dome: initial experience. AJR 2008;190:91-8. 12. Uehara T, Hirooka M, Ishida K, Hiraoka A, Kumaqi T, Kisaka Y, et al. Percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinoma with artificially induced pleural effusion and ascites. J Gastroenterol 2007;42:306-11.
13.Patel PA, Ingram L, Wilson ID, Breen DJ. No-touch wedge ablation technique of microwave ablation for the treatment of subcapsular tumors in the liver. J Vasc Interv Radiol.2013;24:1257–62 14. Livraghi T, Lazzaroni S, Meloni F, Solbiati L. Risk of tumour seeding after percutaneous radiofrequency ablation for hepatocellular carcinoma. Br J Surg 2005;92(7):856–858. 15. Poon RT, Ng KK, Lam CM, Ai V, Yuen J, Fan ST. Radiofrequency ablation for subcapsular hepatocellular carcinoma. Ann Surg Oncol 2004;11(3):281–289. 16. Kang TW, Lim HK, Lee MW, Kim YS, Rhim H, Lee WJ, et al. Long-term therapeutic outcomes of radiofrequency ablation for subcapsular
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20. Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radiofrequency ablation: complications encountered in a multicenter study. Radiology 2003; 226:441–451. 21. Yu J, Liang P, Yu XL, Cheng ZG, Han ZY, Dong BW. Needle track seeding after percutaneous microwave ablation of malignant liver tumors under ultrasound guidance: analysis of 14-year experience with1462 patients at a single center. Eur J Radiol 2012;81:2495–2499. 22. Zhang M, Liang P, Cheng ZG, Yu XL, Han ZY, Yu J. Efficacy and safety of artificial ascites in assisting percutaneous microwave ablation of hepatic tumours adjacent to the gastrointestinal tract. Int J Hyperthermia. 2014 Mar;30(2):134-41. 23. Song I, Rhim H, Lim HK, Kim YS, Choi D. Percutaneous radiofrequency ablation of hepatocellular carcinoma abutting the diaphragm and gastrointestinal tracts with the use of artificial ascites: safety
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Figure legends: Figure1. Images in a 68-year-old-man who underwent MWA for subcapsular HCC. (a) Preoperative CEUS showed the subcapsular tumor was hyperenhanced in arterial phase and abutting the colon and right kidney (arrow). (b) The injection of normal saline(arrow) to separate the tumor and the colon. (c) Colour Doppler ultrasonography depicts feeding arteries entering the tumor on the right side (arrow). (d) The antenna was inserted to ablate the feeding arteries(arrow). (e) US image showed the MWA antennae placed in the tumor (arrow). (f) Postoperative CEUS showed complete necrosis of the tumor a month after MWA(arrow). Figure2. Images in a 62-year-old-woman who underwent MWA for subcapsular HCC. (a,b) Preoperative contrast-enhanced MRI showed the subcapsular exophytic tumor abutting the colon (arrow). (c) The injection of normal saline(arrow) to separate the tumor and the colon. (d) US image showed the MWA antenna (arrow) placed in the tumor. (e,f) Postoperative contrast-enhanced MRI showed complete necrosis of the tumor a month after MWA(arrow). Figure3. 1-,2-, 3-,and 4-year cumulative LTP rates in subcapsular tumors group and nonsubcapsular tumors group. Figure4. 1-,2-, 3-,and 4-year OS rates in subcapsular tumors group and nonsubcapsular tumors group.
Figure: 1a
Figure: 1b
Figure: 1c
Figure: 1d
Figure: 1e
Figure: 1f
Figure: 2a
Figure: 2b
Figure: 2c
Figure: 2d
Figure: 2e
Figure: 2f
Figure: 3
Figure: 4
Table 1. Clinical backgrounds in subcapsular and nonsubcapsular tumors groups. Variable
Nonsubcapsular （n=239） 58.6±10.4
Subcapsular （n=224） 56.4±9.9
P value
41/198
40/184
0.842
2.35±0.8
2.51±1.0
0.071
Class A
238
221
0.285
Class B
1
3
Age at enrollment (y) Sex( women/men) Tumor size (cm)
0.024
Child-Pugh class
Table 2.Comparison of results between subcapsular and nonsubcapsular tumors groups. Variable
Nonsubcapsular （n=239） 462.1±196.6
Subcapsular （n=224） 488±251.5
P value
No. of sessions
1.1±0.5
1.2±0.8
0.105
No. of antenna insertions
2.1±2.1
2.3±2.3
0.065
Hydrodissection(ml)
0
858.5±354（120-1600）*
NS
Complications Postoperative pain Major complication
17 3
30 5
0.025 0.653
Technique effectiveness
235
214
0.089
LTP * n=40
15
12
0.673
Total ablation time (min)
0.215
S0720-048X(17)30146-8 http://dx.doi.org/doi:10.1016/j.ejrad.2017.04.002 EURR 7791
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
23-10-2016 28-3-2017 3-4-2017
Please cite this article as: Liu Fangyi, Yu Xiaoling, Cheng Zhigang, Han Zhiyu, Sun Ya, Liang Ping, Zhou Fubo.Comparison of ultrasonography-guided percutaneous microwave ablation for subcapsular and nonsubcapsular hepatocellular carcinoma.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.04.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Comparison of ultrasonography-guided percutaneous microwave ablation
for
subcapsular
and
nonsubcapsular
hepatocellular
carcinoma
Fangyi Liu, MD, Xiaoling Yu, MD, Zhigang Cheng, MD, Zhiyu Han, MD, Ya Sun, MD, Ping Liang, MD, Fubo Zhou, MD,
All authors: Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
Corresponding author: Liang Ping, MD, Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China. Tel.: +86 10 66939530. Fax: +86 10 68161218. E-mail address: [email protected] E-mail address can be published.
This study was supported by the National Scientific Foundation Committee of China (81201167) and Beijing Nova Program (xx2013108). Type of manuscript: Original research Word count:2914
Purpose: To compare the prognosis of subcapsular and nonsubcapsular hepatocellular
carcinoma(HCC)
after
ultrasonography(US)-guided
percutaneous microwave ablation (MWA). Materials and Methods: From January 2012 to December 2015, 463
enrollment patients(382 men, 81 women; age range, 24-95 years) with a single HCC underwent US-guided percutaneous MWA. The patients were divided into two groups according to tumor location: subcapsular (n = 224) and nonsubcapsular (n = 239). Therapeutic efficacy was assessed by contrast enhanced imaging after MWA. The technique effectiveness rate, the local tumor progression(LTP) rate, overall survival(OS) rate and complication were compared between two groups. Results: There were no significant differences in the mean treatment sessions (p =0.105) and the mean number of antenna insertions (p=0.065) between two groups. No significant difference in the technique effectiveness rate was found between subcapsular and nonsubcapsular tumors(95.5% vs 98.3%, p = 0.089). The respective 1-,2-,3-,and 4-year cumulative LTP rates were 5.0%, 5.5 %, 5.5% and 5.5% in subcapsular group and 6.4%, 6.4%, 6.4% and 6.4% in nonsubcapsular group, respectively(p=0.861). The 1-,2-,3-,and 4-year OS rates were estimated to be 95.7%, 90.1%, 82.9%, and 71.1% in subcapsular group and 98.5%, 92.8%,
83.2%,
and
73.6%
in
nonsubcapsular
group,
respectively(p=0.426). There was no significant difference in major complication
rates
between
the
subcapsular
group(2.2%)
and
nonsubcapsular group(1.3%) (p=0.653). There was higher postoperative pain rate in subcapsular group(13.4%) than nonsubcapsular group(7.1%) (p=0.025).
Conclusions: There were no significant differences in the technique effectiveness rate, cumulative LTP rate, OS rate and major complication rate between subcapsular and nonsubcapsular group after MWA for HCC.
KEYWORDS: subcapsular; microwave ablation; hepatocellular carcinoma
INTRODUCTION Thermal ablation therapies such as radiofrequency (RF) and microwave ablation (MWA) has been most widely used for the treatment of hepatocellular carcinoma (HCC), achieving good results in local tumor control and low morbidity and mortality[1-3]. Nonetheless, ablation of exophytic and subcapsular liver tumors is a controversial issue because it may increase risks of tumor seeding , hemorrhage and thermal injury to the adjacent structure[4-6]. Some studies show that a subcapsular location is a risk factor for local tumor progression (LTP) because of the difficulty of placing an electrode and not being able to obtain enough ablation margin along the hepatic capsule[7-9]. Several technical methods have been developed to prevent complications, including different approaches, e.g., percutaneous, laparoscopic, or open laparotomy, artificial ascites or pleural effusion, different guiding techniques, and no-touch wedge ablation technique[10-13]. Investigators in a retrospective study reported
a low risk of seeding in a nonselect group of patients[14], and a prospective study showed comparable morbidity after RF ablation between subcapsular and nonsubcapsular tumors[15]. A propensity score matched study showed that the differences in LTP, overall survival (OS), and major complication rates of RF ablation for HCC were not significant between subcapsular and nonsubcapsular groups[16]. MWA has higher thermal effectiveness and less heat-sink effect than RF ablation [17], however, to our knowledge, limited data are available on the outcomes of US-guided percutaneous MWA in treating subcapsular hepatocellular carcinoma. The purpose of this study was to compare the prognosis of subcapsular and nonsubcapsular hepatocellular carcinoma after US-guided percutaneous MWA.
MATERIALS AND METHODS PATIENTS From January 2012 to December 2015, 463 enrollment patients(382 men, 81 women; age range, 24-95 years) with a single HCC less than 5cm in diameter underwent US-guided percutaneous MWA. The patients were divided into two groups according to tumor location: subcapsular (n=224) and nonsubcapsular (n = 239). Subcapsular group included those patients with one subcapsular nodule near the stomach, bowel, liver dome, diaphragm, or abdominal wall. Subcapsular HCC was defined as an index
tumor located within 0.1 cm of the liver capsule. Nonsubcapsular HCC was defined as an index tumor located more than 1 cm of the liver capsule and hepatic hilum and large vessels. There was no extrahepatic metastasis and vascular invasion for all patients. There was no significant difference in clinical backgrounds between the two groups except for the age (Table1). Diagnosis of HCC was based on American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL) and Asian Pacific Association for the Study of the Liver (APASL) imaging guidelines. Routine coagulation tests were performed prior to the procedure, which included prothrombin time (as measured by percentage of activity), partial thromboplastin time, and platelet count. An INR of <1.5, and a platelet count >40,000/mm3 were viewed as the minimum threshold for safety in performing MWA. This investigation was approved by our Institutional Ethics Committee. Written informed consent was obtained from all patients.
Microwave equipment and ablation technique All treatments were performed in our institution and were carried out under US guidance with the patients under unconscious intravenous anesthesia (Propofol, 6-12mg/kg/h; Ketamine, 1-2mg/kg) in the operating room. Additionally, when the tumors were not well visualized with conventional B-mode US, a contrast-enhanced ultrasound(CEUS)-guided
ablation with SonoVue (Bracco, Milan, Italy) was performed. The microwave unit (KY-2000, Kangyou Medical, Nanjing, China) consists of three independent microwave generators, three flexible coaxial cables and three water-pumping machines, which can drive three cool-tip needle antennas. The generator is capable of producing 1~100 W of power at 2450 MHz. The antenna is 15 gauges in diameter with cool-shaft. All therapy was performed by two experienced radiologists according to the preoperative planning. During the therapy, we monitored the hyperechoic area of ablation using gray-scale sonography and thermal monitoring to decide the endpoint of treatment. Within 3 days after ablation, every patient received CEUS to evaluate ablation area. If residual tumor or unablated therapeutic margin was detected, additional MWA treatment was performed. When withdrawing the antennae, the needle tracks were routinely cauterized to avoid tumor seeding and bleeding.
Ablation technique for subcapsular tumors The key points of the ablation technique used for tumors located subcapsular were as follows:(1) In cases of small tumor ablation, the tumors were punctured through the normal hepatic parenchyma rather than via direct puncture when possible. (2) In cases of larger or exophytic tumor ablation, traversing normal hepatic parenchyma was not always possible due to tumor position and the available angles of entry, and
tumor-feeding artery was ablated firstly, then a direct puncture of the tumor was performed without passing through normal liver parenchyma. Color Doppler US or CEUS was performed to determine the location of the target tumor-feeding artery. (3) Hydrodissection technique and thermal monitoring technique were applied for subcapsular tumors abutting vital structures to avoid thermal damage.
Hydrodissection technique After administering a local anesthetic comprising 1% lidocaine, a 16-gauge intravenous catheter (BD Angiocath; Sandy, UT) was punctured into the peritoneal cavity between the edge of the liver and the abutting gastrointestinal tract(GIT) under US guidance. A sufficient amount of normal saline was delivered until a separation of more than 0.5 cm between the target lesion and the adjacent GIT was achieved. Drip infusion was continued during the MWA procedure to maintain a distance of more than 0.5 cm.
Thermal monitoring procedure A thermal monitoring system attached to the microwave unit was used during treatment for the study group. With US guidance, one or two 21G thermal monitoring needles (Kangyou Medical, Nanjing, China) were placed into marginal tissue of tumor or liver proximal to the
surrounding tissues or organs for real-time temperature monitoring during the ablation to protect the surrounding tissues or organs from thermal mediated injury. Based on our experimental evidence and clinical experience, the temperature cut off of ablation therapy was set at 60°C in the patients. If the measured temperature reached 60°C, emission of microwave antenna was stopped immediately and was activated again after the temperature decreased to 50°C.
Therapeutic efficacy assessment and follow-up Therapeutic efficacy assessment and follow-up was assessed by contrast enhanced imaging after the treatment. The technique effectiveness was defined as the ‘complete ablation’ of the macroscopic tumor proved by imaging 1 month after ablation. Local tumor progression (LTP) was defined as incompletely treated viable tumor continuing to grow or a new tumor (‘daughter’ or ‘satellite’ tumors) growing at the original site during follow-up. The number of antenna insertions was defined as the total number of antenna placements for each tumor until this tumor was ablated completely. The follow-up period was calculated starting from the beginning of MW ablation in all patients. CEUS and contrast-enhanced CT or MRI were repeated at 1 month and at 3-months intervals within 1 year and then at 6-month intervals after MWA. If abnormal peripheral nodular enhancement of the ablation area was found
during follow-up and it was presumed to be LTP, further MWA was performed. Median follow-up time was 22 months (range, 3–52 months) in the subcapsular group and 27 months (range, 6–48 months) in the nonsubcapsular group.
Statistical analysis Data analysis was performed using SPSS11.0 for windows (SPSS Inc,Chicago,IL,USA) and the continuous data were expressed as means±standard deviations(SD). Independent samples t-test was used to compare the means between two groups. The technique effectiveness rate, the LTP rate, OS rate and other ratio were compared between subcapsular tumors and nonsubcapsular tumors group using the chi-square test. Cumulative incidence rates for LTP and OS rates by using the Kaplan-Meier method were estimated. The level of statistical significance was set at P-value less than 0.05.
RESULTS All patients were performed MWA successfully. The mean number of treatment sessions was 1.2 ± 0.8 for the subcapsular tumors and 1.1 ± 0.5 for the nonsubcapsular tumors. The subcapsular tumors and nonsubcapsular tumors showed no statistically significant difference (p=0.105). The mean number of antenna insertions was 2.3 ± 2.3 for the
subcapsular tumors and 2.1 ± 2.1 for the nonsubcapsular tumors. There was no significant difference in the mean number of antenna insertions between the subcapsular tumors group and nonsubcapsular tumors group (p=0.065).(Table2) Hydrodissection with saline solution was performed successfully on 40 patients. The average amount of solution for hydrodissection was 858.5±354mL (range, 120-1600mL). No patients had abnormal vital signs until the day after the procedure. The injected solution was completely absorbed in all patients at the 1-month follow-up CT or MRI. No
delayed
complications
related
to
hydrodissection
such
as
hemoperitoneum or peritonitis developed during the 1-month follow-up. Among the 463 tumors, 214 of the 224 that were subcapsular and 235 of the 239 that were nonsubcapsular showed complete tumor ablation on the 1-month follow-up contrast enhanced imaging(Figure 1, Figure2). Thus, the overall technique effectiveness rate was 97.0%. The technique effectiveness rates for subcapsular and nonsubcapsular tumors were 95.5%
and
98.3%,
respectively.
The
subcapsular
tumors
and
nonsubcapsular tumors showed no statistically significant differences (p = 0.089). LTP was detected in 12 of 224 patients (5.4%) in the subcapsular group and 15 of 239 patients (6.3%) in the nonsubcapsular group during the follow-up periods. The subcapsular tumors and nonsubcapsular
tumors showed no statistically significant difference (p=0.673) in LTP rate. The respective 1-,2-, 3-,and 4-year cumulative LTP rates were 5.0%,5.5 %, 5.5%, and 5.5% in the subcapsular group and 6.4%, 6.4%, 6.4%, and 6.4% in the nonsubcapsular group, respectively. The median time to LTP was 6 months (range, 3–14 months) in subcapsular tumors group and 6 months (range,3–15 months) in nonsubcapsular tumors group. No significant difference in cumulative LTP rates was observed between the subcapsular tumors group and nonsubcapsular tumors group (p=0.861) (Figure 3). During follow-up, the overall data showed the death of 33 of 224patients (14.7%) in the subcapsular group and 25 of 239 patients (10.4%) in the nonsubcapsular group. The 1-,2-, 3-,and 4-year OS rates were estimated to be 95.7%, 90.1%, 82.9%, and 71.1% in the subcapsular group and 98.5%, 92.8%, 83.2%, and 73.6% in the nonsubcapsular group, respectively. No procedure-related mortality occurred. There was no significant difference in OS rates between the subcapsular tumors group and nonsubcapsular tumors group (p=0.426) (Figure 4). The major complication rate associated with MWA was 1.7% (8 of 463 patients) in the overall data. 4 cases in subcapsular tumors group and 2 cases in nossubcapsular tumors group had a large amount of pleural fluid requiring aspiration. One case of peritoneal seeding in the subcapsular group and one case of abdominal wall seeding in
nonsubcapsular group occurred. There was no significant difference in the major complication rate between the subcapsular tumors group(2.2%) and nonsubcapsular tumors group(1.3%) (p=0.653). No patients in either group had immediate major complications associated with collateral thermal injury to the perihepatic structures. 30 cases in subcapsular tumors group and 17 cases in nonsubcapsular tumors group had moderate right upper quadrant pain (grade 2) requiring oral analgesics (oxycodone) and the symptoms gradually disappeared one week later. There was higher incidence rate of postoperative pain in subcapsular
tumors
group(13.4%)
than
nonsubcapsular
tumors
group(7.1%) (p=0.025).
DISCUSSION RF ablation of exophytic and subcapsular liver tumors was a controversial issue because it may have a high rate of LTP and increase risk of complications[7,8]. MWA results in active heating of the tissue and has higher thermal efficacy and less heat-sink effect than RF ablation, however, MWA of subcapsular HCC is also a controversial issue. In our study, there was no significant difference in technique effectiveness rate, LTP rate, OS rate, and major complication rate between the subcapsular tumors group and nonsubcapsular tumors group. Our results were similar to the results of comparison studies about RF ablation for subcapsular
versus nonsubcapsular HCC[16,18]. Investigators in previous studies suggested that the subcapsular location of a tumor was a risk factor for LTP after RF ablation because of the inability to achieve a 0.5–1.0-cm tumor-free margin [8,9]. However, subcapsular location should not be considered a risk factor for recurrence after HCC resection and there is no definite evidence that the absence of a margin on the capsular side increases the rate of local recurrence[15,19]. In our study, the subcapsular tumors and nonsubcapsular tumors showed no statistically significant differences in LTP rate (p=0.673) and cumulative LTP rates (p=0.861) after MWA. Kang et al. reported a multivariate analysis of risk factors for LTP showed that use of hydrodissection for tumor in a high-risk location (HR = 1.73; 95% CI: 1.07, 2.80; P = .026) and total ablation time (HR = 1.06; 95% CI: 1.01, 1.10; P = .009) were independent risk factors for LTP[16]. Kang et al. proposed that tumor size, poor liver function, and technical difficulty of RF ablation could influence the outcome of local tumor control in the subcapsular group, however, subcapsular location itself did not significantly influence local tumor control after RF ablation for HCC[16]. Previous studies reported that subcapsular HCCs had a higher incidence of hemorrhage and tumor seeding in respect to nonsubcapsular tumors [4,20]. However, investigators in a multicenter study reported a low rate of tumor seeding (12 [0.9%] seedings in 1314 treated patients) in
a large series of nonselect patients, and they did not identify subcapsular location as a risk factor for seeding [14]. Similarly, other studies on tumor seeding after RF ablation showed no significant relationship between tumor seeding and subcapsular tumor location[16,18]. Yu et al. reported another large retrospective case series of 1,462 patients performed microwave ablation, seeding was found in 0.75% of patients, and subcapsular location was not found be significantly associated with tumor seeding[21]. Avoiding capsular breach during ablation the no-touch wedge ablation technique may reduce the risk of tumor rupture and consequent hemorrhage and tumor seeding[13]. In our study, although we did not use the no-touch wedge ablation technique, no hemorrhage occurred, and only two cases of tumor seeding occurred. Our results showed no significant difference in two groups for tumor seeding as major complications. Two technique points used to prevent hemorrhage and tumor seeding in our study: First, for small tumor ablation, the tumors were punctured through the normal hepatic parenchyma rather than via direct puncture when possible, while for larger or exophytic tumor ablation, traversing normal hepatic parenchyma was not possible, and tumor-feeding artery was ablated firstly, then a direct puncture of the tumor was performed; Second, when withdrawing the antennae, the needle tracks were routinely cauterized to avoid tumor seeding and bleeding.
Thermal damage to adjacent structures was another possible major complication for thermal ablation of subcapsular HCC[4,14]. Studies showed that hydrodissection was technically feasible and effective in improving protection of the adjacent structures by separating them away from the liver capsule[11,22,23]. Hydrodissection was applied in 40 cases of subcapsular HCC in our study. No thermal damage to adjacent perihepatic structures occurred in our study. Song et al. reported that potential complications related to hydrodissection were bleeding, peritonitis,
and
tumor
seeding[23].
Our
study
showed
that
hydrodissection was a safe technique without complication. The other reason of reducing the incidence of thermal damage to perihepatic structures in our study was the application of thermal monitoring technique. About the minor complications in our study, there was higher incidence rate of postoperative pain in subcapsular tumors group(13.4%) than nonsubcapsular tumors group(7.1%) (p=0.025). After ablation, the local exudation of the hepatic capsule can lead to the adhesion of the liver and the abdominal wall or surrounding structures, which may be the main cause of postoperative pain of subcapsular HCC. In addition to postoperative pain medicine, patients getting out of bed as early as possible can prevent adhesion and reduce the incidence of pain. Despite these promising results, this study may have some
limitations. First, these data were obtained at a single centre with significant experience with MWA for liver tumors, and a multi-center study would be more convincing. Second, the follow-up period was not over 52 months, and a longer follow-up period may be needed.
CONCLUSIONS There were no significant differences in the technique effectiveness rate, cumulative LTP rate, OS rate and major complication rate between the subcapsular and nonsubcapsular tumors group after US-guided percutaneous MWA for HCC.
Conflict of Interest This study was supported by the National Scientific Foundation Committee of China (grant numbers 81201167) and Beijing Nova Program (xx2013108). The authors alone are responsible for the correct and writing of the paper. There was no conflict of interest about the study.
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Figure legends: Figure1. Images in a 68-year-old-man who underwent MWA for subcapsular HCC. (a) Preoperative CEUS showed the subcapsular tumor was hyperenhanced in arterial phase and abutting the colon and right kidney (arrow). (b) The injection of normal saline(arrow) to separate the tumor and the colon. (c) Colour Doppler ultrasonography depicts feeding arteries entering the tumor on the right side (arrow). (d) The antenna was inserted to ablate the feeding arteries(arrow). (e) US image showed the MWA antennae placed in the tumor (arrow). (f) Postoperative CEUS showed complete necrosis of the tumor a month after MWA(arrow). Figure2. Images in a 62-year-old-woman who underwent MWA for subcapsular HCC. (a,b) Preoperative contrast-enhanced MRI showed the subcapsular exophytic tumor abutting the colon (arrow). (c) The injection of normal saline(arrow) to separate the tumor and the colon. (d) US image showed the MWA antenna (arrow) placed in the tumor. (e,f) Postoperative contrast-enhanced MRI showed complete necrosis of the tumor a month after MWA(arrow). Figure3. 1-,2-, 3-,and 4-year cumulative LTP rates in subcapsular tumors group and nonsubcapsular tumors group. Figure4. 1-,2-, 3-,and 4-year OS rates in subcapsular tumors group and nonsubcapsular tumors group.
Figure: 1a
Figure: 1b
Figure: 1c
Figure: 1d
Figure: 1e
Figure: 1f
Figure: 2a
Figure: 2b
Figure: 2c
Figure: 2d
Figure: 2e
Figure: 2f
Figure: 3
Figure: 4
Table 1. Clinical backgrounds in subcapsular and nonsubcapsular tumors groups. Variable
Nonsubcapsular （n=239） 58.6±10.4
Subcapsular （n=224） 56.4±9.9
P value
41/198
40/184
0.842
2.35±0.8
2.51±1.0
0.071
Class A
238
221
0.285
Class B
1
3
Age at enrollment (y) Sex( women/men) Tumor size (cm)
0.024
Child-Pugh class
Table 2.Comparison of results between subcapsular and nonsubcapsular tumors groups. Variable
Nonsubcapsular （n=239） 462.1±196.6
Subcapsular （n=224） 488±251.5
P value
No. of sessions
1.1±0.5
1.2±0.8
0.105
No. of antenna insertions
2.1±2.1
2.3±2.3
0.065
Hydrodissection(ml)
0
858.5±354（120-1600）*
NS
Complications Postoperative pain Major complication
17 3
30 5
0.025 0.653
Technique effectiveness
235
214
0.089
LTP * n=40
15
12
0.673
Total ablation time (min)
0.215