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Percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: A long-term follow-up
European Journal of Radiology 83 (2014) 552–558
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: A long-term follow-up Shijia Huang a,1,2 , Jie Yu a,1,2 , Ping Liang a,∗ , Xiaoling Yu a,2 , Zhigang Cheng a,2 , Zhiyu Han a,2 , Qinying Li b,3 a b
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China No. 135, Shengli East Road, Huanglong District, Puyang City, Henan Province 475000, China
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Article history: Received 9 August 2013 Received in revised form 5 December 2013 Accepted 12 December 2013 Keywords: Hepatocellular carcinoma Microwave ablation Large vessels Ultrasound Radiofrequency Percutaneous ethanol injection
a b s t r a c t Purpose: To retrospectively evaluate the effectiveness and safety of ultrasound (US)-guided percutaneous microwave ablation (MWA) in the treatment of hepatocellular carcinoma (HCC) adjacent to large vessels. Materials and methods: From February 2006 to February 2013, 452 patients with 605 HCC nodules were treated with US-guided percutaneous MWA. Into large vessels group (Group L), 139 patients with 163 lesions (diameter, 1.0–7.0 cm; mean, 2.5 ± 1.1 cm) located less than 5 mm away from large vessels were enrolled. And 313 patients with 442 lesions (diameter, 1.0–8.0 cm; mean, 2.5 ± 1.2 cm) located more than 5 mm away from hepatic surface, large vessels, gallbladder and gastrointestinal tract were included in control group (Group C). During the ablation, the temperature of marginal ablation tissues was monitored and controlled. Results: The median follow-up time was 24.5 months (range 2.1–87.7 months) in Group L, and 25.7 months (range 1.6–93.9 months) in Group C. Technical effectiveness was achieved in 157 of 163 (96.3%) tumors in Group L and 429 of 442 (97.1%) tumors in Group C, respectively (p > 0.05). The 1-, 3- and 5-year local tumor progression rates and the 1-, 3- and 5-year accumulative survival rates in the two groups have no significantly statistical differences. In addition, no immediate or periprocedural major complications, no delayed complication of vessels or bile ducts injury were found in both of the two groups. Conclusions: With strict temperature monitoring, US-guided percutaneous MWA is an efficient and safe technology in treating hepatocellular carcinoma adjacent to large vessels. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hepatocellular carcinoma (HCC) is the fifth frequently diagnosed cancer worldwide and is the second main cause in the cancer-related deaths [1]. It was reported that 695,900 cancer deaths occurred all over the world in 2008, and half of these deaths were estimated to occur in China [1,2]. Improvement in abdominal imaging has made early diagnosis of HCC more easily [3]. Traditionally, hepatic resection is the first-line treatment option for patients who are with solitary tumors and well-preserved liver function [3–5]. However, resection also has limitations if it is used to treat HCC patients with unfavorable tumor locations. As report
∗ Corresponding author. Tel.: +86 10 66939530; fax: +86 10 68161218. E-mail addresses: [email protected] (S. Huang), [email protected] (J. Yu), [email protected] (P. Liang), [email protected] (X. Yu), [email protected] (Z. Cheng), [email protected] (Z. Han), [email protected] (Q. Li). 1 These authors contributed equally to the manuscript. 2 Tel.: +86 10 66937982. 3 Tel.: +86 10 13939364234. 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.12.015
goes, resections for malignant zones close to main hepatic veins or the vena cava are sometimes practicable[6,7], but they are always associated with increased risks [8]. The emergence of local thermal ablation provides a feasible choice for these patients [9–13]. Minimally invasive percutaneous local ablation techniques, such as radiofrequency ablation (RFA), cryoablation and microwave ablation (MWA), have already been suggested as alternatives for the treatment of HCC [3]. And these techniques referred before, in treating small HCC, were turned out to be promising in clinical results [9–11]. However, an important inherent effect of heat-sink on thermal ablation may influence the treatment result for the tumors adjacent to large vessels (≥3 mm) [14]. At present, some researchers have already put RFA into practice of treating liver tumors adjacent to large vessels. And the result is satisfying [15–17]. However, as another kind of thermal ablation techniques, MWA has its special features. It destroys the tumors via high temperature produced by rotating adjacent polar water molecules in the targeted pathologic tissues through electromagnetic energy, which would lead to protein denaturation, cell membrane disruption, and finally coagulation necrosis with
S. Huang et al. / European Journal of Radiology 83 (2014) 552–558 Table 1 The location distribution of tumors in Group L.
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2.2. Preprocedure evaluation
The vessels adjacent to tumors
No. of tumors
Inferior vena cava Right hepatic vein Middle hepatic vein Left hepatic vein Main portal vein Right portal vein Anterior branch of right portal vein Posterior branch of right portal vein Left portal vein Left portal venous bifurcation External branch of left portal vein Internal branch of left portal vein Inferior vena cava and Main portal vein
19 12 9 2 12 41 13 22 3 8 18 2 2
cellular death. Under the condition of giving 4–6 min treatment for patients with temperature being greater than 50 ◦ C or reaching 60 ◦ C immediately, the changes described before would appear [18,19]. MWA has several theoretical advantages over RFA. First, it would produce consistently higher intratumoral temperatures, larger ablation zones, less ablation time and less dependence on the electrical conductivities of tissue. Second, energy delivery is less limited by the exponentially rising electrical impedance of tumor tissue [19–22]. These advantages may make MWA treatment less affected by heat-sink [21]. Although MWA has been widely used in liver cancer therapy [10], there are no authoritative clinical achievements but only some foundational reports on the effects of treating the tumors adjacent to large vessels [23]. This study aims to assess the effectiveness, safety and clinical outcomes of US-guided MWA in treating patients with HCC adjacent to large vessels.
2. Materials and methods 2.1. Patients This retrospective study was approved by the institutional review board of Chinese PLA General Hospital. Written informed consent for this procedure was obtained from all the enrolled patients. From February 2006 to February 2013, 452 consecutive patients (605 lesions) with HCC were enrolled and underwent percutaneous MWA treatment at this department. Among the 452 patients, 139 patients with 163 HCC lesions, located less than 5 mm from large vessels (large vessels were defined as the first or second branch of the portal vein, the base of hepatic veins, or the inferior vena cava of which diameters being equal or bigger than 3 mm) shown by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), were enrolled into large vessels group (Group L). And 313 patients with 442 lesions located in safe site (more than 5 mm from hepatic surface, large vessels, gallbladder and gastrointestinal tract) were included in control group (Group C). All the enrolled HCC patients are treated by MWA, and they were closely followed up until May 2013. There were 109 males and 30 females in Group L with a median follow-up time 24.5 months (range 2.1–87.7 months), and 247 males and 66 females in Group C with a median follow-up time 25.7 months (range 1.6–93.9 months). No statistical differences of median follow-up time exist between the both groups (p = 0.998). The average ages were 59.5 ± 10.6 (range 33–86) years in Group L, and 58.4 ± 10.5(range 28–92) years in Group C, respectively (p > 0.05). The numbers of the lesions adjacent to different large vessels in Group L are list in Table 1.
All patients enrolled in this study had to meet the following criteria: the percutaneous approach was accessible to the tumors; the size of single nodular HCC lesions was less than or equal to 8 cm; each multiple nodular hepatic lesions, three or fewer, was with a maximum dimension of 4 cm or less; there was no portal vein embolus nor extrahepatic metastases; the prothrombin time was less than 25 s; the prothrombin time activity percentage was higher than 40%; the platelet count was higher than 40 cells × 109 /L. In the pre-operation, the number of tumors and the absence of portal vein thrombosis were evaluated by contrastenhanced US (CEUS), CT or MRI. The maximum diameter of nodules was measured by arterial phase of CEUS. The absence of extrahepatic metastases was determined by means of a thorough clinical assessment, chest radiography, abdominal US, and abdominal CT or MRI or position-emission tomography (PET). HCC diagnosis was largely made through an intraoperative tumor biopsy before ablation with US guidance. 2.3. MWA system The microwave ablation system (KY-2000; Kangyou Medical Instruments, Nanjing, China) consists of two MW generators, two flexible coaxial cables and two cooled shaft antennae. The machine is capable of producing 2450 MHz and 1–100 W [24]. The cooled shaft antenna (diameter: 1.9 mm, 15 gauge; length: 18 cm; pinpoint size: 5 mm or 11 cm) which is coated with polytetrafluoroethylene to prevent conglutination can be easily observed by ultrasound (US). Inside antenna shaft are dual channels, through which distilled water is circulated by a peristaltic pump continuously cooling the shaft and preventing overheating. 2.4. MWA procedure First, after giving the patients local anesthesia with 1% lidocaine, US-guided biopsy was performed by an automatic biopsy gun with an 18-gauge cutting needle and 2 or 3 separate punctures were performed then. Second, under US guidance, the antennae were percutaneously inserted into the tumors. At each insertion, the tip of the needle was placed in the deepest part of the tumor. For tumors less than 2.0 cm, one antenna was inserted; for tumors measuring 2.0 cm or greater, two antennae were inserted with an interantenna distance of no more than 2.5 cm. Third, after all insertions, intravenous anesthesia, via the peripheral vein, was administered by a combination of propofol (Diprivan; Zeneca Pharmaceuticals, Wilmington, Del) and ketamine (Shuanghe Pharmaceuticals, Beijing, China) during standard hemodynamic monitoring. Fourth, MWA emission started, and the region of ablation was monitored by US. During the MWA process, the output of power is 40–60 W for 5–10 min in a session. Multiple thermal lesions are created along the major axis of the needle antenna by simply withdrawing the needle from the preceding thermal lesion, and reactivating the MW generator. If necessary, due to tumor size, multiple overlapping ablations are usually needed to envelope the entire tumor with a safety margin. If the heat-generated hyperechoic water vapor did not completely encompass the entire tumor, a prolonged microwave emission would be applied until the desired temperature was reached. Finally, when the antenna was withdrawn, the applicator track was heated with sufficient microwave energy by quitting the cooling-shaft water dump. 2.5. Thermal monitoring during the procedure To continuously measure temperature in real time during the ablation, the microwave machine is also equipped with a thermal
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Fig. 1. Contrast-enhanced MRIs of a 57-year-old man with a 1.9 cm × 1.9 cm nodule of HCC adjacent to right portal vein treated by MWA. (a) Preablation image shows one neoplasm (arrows) adjacent to right portal vein. (b) On the arterial phase image obtained in the first year after treatment, no enhancement is seen in the ablation zone (arrows). (c) Transverse and (d) coronal images obtained in the third year after treatment show that the nonenhancing ablation zone gradually shrinks (arrows). And (e) Transverse and (f) coronal images show that there remains no enhancement of the ablation zone (arrows) in the fifth year after treatment.
monitoring system. A 20-gauge thermocouple was inserted at the site of 5 mm away from the tumor margin. If the measured temperature reached 60 ◦ C or 54 ◦ C lasting for over three minutes, it can be considered that the tumors are necrotic thoroughly. This condition will continue until the entire tumor was completely covered by the hyperechoic micro-bubbles under gray-scale US. 2.6. Adjuvant therapy with small dose of ethanol injection For the 94 of 163 lesions in Group L adjacent to both large vessels and bile ducts, one to two 21-G PTC needles (Hakko, Japan)
were placed into marginal tissue of tumor proximal to the large vessels with US guidance. Every needle was inserted in one site for the purpose of precision. At the time of microwave emission, dehydrated sterile 99.5% ethanol (Changhai Hospital of Shanghai, China) was slowly injected into the margin of tumors (about 1 ml/min). And, the quotas of ethanol injected were determined by the size and location of the tumor empirically. For the tumors less than 3 cm, no more than 5 ml ethanol was injected; for the tumors larger than 3 cm, 5–10 ml ethanol was injected. The mean ethanol dose was 4.77 ml (range 1.5–10 ml). All ethanol injections were planned before the ablation procedure.
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Fig. 2. Contrast-enhanced images show a 3.4 cm × 3.0 cm HCC nodule adjacent to the right portal vein in the liver of a 56-year-old man treated with MWA. (a) preoperative CEUS and (b) preoperative MRI show that there is one HCC nodule (white arrows) is on post top of the right portal vein (black arrow); (c) After one session, the nodule (white arrows) which closes to the blood vessel (black arrows) was completely ablated; (d) On the arterial phase image obtained in the first year after treatment, no enhancement is seen in the ablation zone (arrows); And (e) Transverse and (f) coronal images show that there remains no enhancement of the ablation zone (arrows) in the second year after treatment.
2.7. Follow-up To evaluate treatment effectiveness, contrast-enhanced imaging (US and CT or MRI) were performed in 1–3 days after the last ablation. Technique effectiveness, namely complete ablation, is defined as the absence of enhancement in any areas of the mass on enhanced images obtained at the 1 month follow-up after MWA. The routine CEUS, CT, or MRI should be performed to monitor recurrence or metastasis in the later three months after MWA and should be repeated every six months if complete ablation was achieved (Figs. 1 and 2). Local tumor progression is defined as irregular
peripheral enhancement in scattered, nodular, or eccentric pattern occurring at the original sites which were previously considered to be completely ablated during the follow-up period. In terms of complications, they can be defined as major or minor and can be detected by US and CT or MRI. 2.8. Statistical methods Data analysis was performed by SPSS (version 16.0.01 for Windows, SPSS, 6 Chicago, IL, USA). The ages of patients and the sizes of tumors were presented by the mean ± SD, and the time of
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Table 2 Clinical features of patients and tumors. Variable Patient information No. of patients Male/Femalea Mean age (y)b Tumor information No. of tumors Mean tumor diameter (cm)b Ablation time (min)b Ablation power (W)c Ablation sessionsd Ablation insertionsd Median follow-up (mo.)d a b c d
Group L
Group C
p-Value
139 109 (78.4)/30 (21.6) 59.5 ± 10.6 (33–86)
313 247 (78.9)/66 (21.1) 58.4 ± 10.5 (28–92)
– – p > 0.05
163 2.5 ± 1.1 (1–7) 10.4 ± 5.4 (3–31) 49.4 ± 2.8 1 (1–3) 2 (1–4) 24.5 (2.1–87.7)
442 2.5 ± 1.2 (1–8) 8.9 ± 4.8 (2.5–29.3) 50 ± 1.9 1 (1–3) 2 (1–4) 25.4 (1.6–93.9)
p > 0.05 p < 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05
Data in parentheses are percentages. Data are means ± standard deviation; data in parentheses are ranges. Data are means ± standard deviation. Data are medians; data in parentheses are ranges.
follow-up was expressed as the median. The accumulative survival rates and local tumor progression rates were calculated by using the Kaplan–Meier method. Differences in the survival rates and local tumor progression rates between the two groups were examined by the log-rank test. Continuous variables of the two groups were analyzed by using Student’s t-test or Wilcoxon rank sum test. 2 test was applied to compare categorical variables of the two groups. Differences with p values less than 0.05 were considered statistically significant.
3. Results 3.1. Pretreatment clinical parameters US-guided MWA was performed for 605 HCC nodules in 452 patients. Of 139 patients with 163 lesions closed to large vessels, 104 patients were infected with Hepatitis B and 24 patients with Hepatitis C. In the control group, 252 patients were infected with Hepatitis B and 46 patients with Hepatitis C. The size of lesions ranged from 1 to 7 cm (mean maximum diameter 2.5 ± 1.1 cm) in Group L and 1 to 8 cm (mean maximum diameter 2.5 ± 1.2 cm) in Group C (p > 0.05). The clinical features of patients and tumors were summarized in Table 2.
time of local tumor progression is 9.3 ± 8.7 months; in Group C, the numbers are 2.7 ± 1.4 cm and 6.4 ± 6.7months (p1 = 0.20, p2 = 0.25). There were 30 patients in Group L and 74 patients in Group C died during the follow-up. In Group L, the death causes were as follows: progression of HCC in 15 patients, variceal bleeding in 6 patients, liver failure in 5 patients, myocardial infarction in 2 patients, and cerebral hemorrhage in 2 patients. And in Group C, several death causes were concluded as below: progression of HCC in 36 patients, variceal bleeding in 14 patients, liver failure in 16 patients, myocardial infarction in 3 patients, cerebral hemorrhage in 2 patients, intestinal obstruction in one patient, heart failure in one patient, and acute pulmonary embolism in one patient. The 1-, 3- and 5-year accumulative survival rates were 94.0%, 72.0% and 64.0% in Group L, and 93.0%, 79.0% and 57.0% in Group C, respectively. What’s more, no significantly statistical difference was found (p = 0.95, Fig. 4). 3.3. Complications and side effects There was no immediate nor periprocedural major complications in both of the two groups. Twenty of 139 (14.4%) patients of Group L and 43/313 (13.7%) patients of Group C complained of mild pain after the ablation. No significant difference was found (p > 0.05). Thrombosis was found by CEUS in the right portal vein and the central part of the left portal vein (lengths of
3.2. Clinical outcomes In this study, of all the patients, pathology was proven by biopsy in 420 cases and by clinical and imaging features in 32 cases which had refused the biopsy (Table 3). The clinical and imaging diagnostic criteria for HCC included hepatitis B or C cirrhosis, serum AFP levels and at least two kinds of contrast-enhanced imaging (US, CT or MRI). All 605 lesions were given 721 MWA sessions. The median MWA sessions of the two groups were both 1 (range 1–3). Ablation times were 10.4 ± 5.4 (3–31) minutes in Group L and 8.9 ± 4.8 (2.5–29.3) minutes in Group C, respectively (p < 0.05). And 157 of 163 (96.3%) lesions in Group L and 429 of 442 (97.1%) lesions in Group C achieved complete ablation. No significantly statistical difference in the rates of technical effectiveness was found between the two groups (p > 0.05). Local tumor progression was detected in 22 of 163 tumors (13.5%) in Group L, 42 of 442 tumors (9.5%) in Group C in the follow-up 7 years, respectively (p > 0.05). And the 1, 3- and 5-year local tumor progression rates were 10.7%, 17.3% and 17.3% in Group L, and 6.9%, 12.7% and 12.7% in Group C, respectively (p = 0.27, Fig. 3), which revealed no statistical difference between the two groups. In the local tumor progression cases of Group L, the mean largest tumor diameter is 2.3 ± 0.6 cm, and the mean
Fig. 3. The graph is a comparison of 5-year local tumor progression rates of the patients between Group L (L) and Group C (C) after undergoing percutaneous microwave ablation. There are no significant differences between the local tumor progression rates of two groups.
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Table 3 Diagnostic investigations of HCC before and after the treatment. Diagnostic methods before the treatment
No. of the HCC diagnosed before the treatment
Histodiagnosis
No. of the HCC diagnosed after the treatment
≥ two kinds of contrast-enhanced imaging Biopsy
32 420
– HCC
32 420
thrombosis: 3 mm, 2.5 mm) of one patient in Group L (0.7%) in the second month after treatment, which disappeared 3 months later without any management. Two cases of tumor seeding were found in Group L (2/139, 1.4%; at abdominal wall: diameter 2.2 cm at 9 months; at hepatic surface: diameter 1.3 cm at 12 months) and Group C (2/313, 0.6%; at abdominal wall: diameter 1.4 cm at 7 months; at hepatic surface: diameter 1.7 cm at 13 months), respectively. Two disseminated tumors detected at abdominal wall were seeding from the lesions in the segment IV of the Group L and the segment VIII of the Group C, respectively; while the other two at hepatic surface were seeding from the lesions in the segment VI of the Group L and the segment V of the Group C, the distance from the surface of the liver to the lesion were 4.1 cm and 2.5 cm, respectively. All seeding tumors received MWA and achieved complete ablation. No delayed complication of vessels or bile ducts injury was detected in this study. 4. Discussion RF ablation remains to be the most widely used ablative technique worldwide for liver tumors and it achieved optimistic effectiveness in treating the tumors adjacent to large vessels. Compared with RFA, MWA may provide larger ablation zones and higher intratumoral temperatures. In addition, MWA is also less affected by the heat-sink effect [21]. Therefore, theoretically speaking, the advantages of MWA in dealing with that kind of tumors could get an ideal therapeutic effect. This study aimed to provide clinical evidence for this choice of intervention therapy in HCC nodules adjacent to large vessels. The treatment effectiveness in this study was very encouraging. Ablation sessions, local tumor progression and survival in large vessels group do not have any significant differences with those in control group. These results illustrate that heat-sink effect is unable to affect MWA treatment of HCC nodules adjacent to large vessels markedly. Also, the technical effectiveness rate is higher and the local tumor progression rate is lower than those in other reports
[25–27]. That may be attributable to the following reasons: (1) MWA has theoretical merits in producing consistently higher intratumoral temperatures, larger ablation zones, less ablation time and less dependence on the electrical conductivities of tissue. Also, the energy delivery is less controlled by the exponentially rising electrical impedance of tumor tissue. (2) Long-duration ablation may cause gradual ablation of the tumors adjacent to large vessels and compensate the defect from heat-sink effect in the large vessels. (3) CEUS should be reviewed timely in the subsequent three days after the first procedure to check whether any residual cancer still exist, from which a second session is needed or not can be decided to achieve complete ablation. (4) PEI was performed simultaneously with MWA emission for the tumors adjacent to both large vessels and bile ducts. The aim was to kill the tumor tissue adjacent to biliary duct and blood vessel, and to prevent the overheating injury to these vital tissues by increasing thermal conduction and diffusivity through previously coagulated tissue [28]. (5) Real-time peritumoral temperature monitoring was used as an indicator for complete MWA. (6) Lots of experience in detailed treatment protocol, accurate image guiding and proper placement of antennae was another essential factor for the success of treatment. There were no major complications discovered, even in patients with the tumors adjacent to large vessels. Thrombosis was found once in the second month after the treatment, which may be caused by blood coagulation effected by heat. Takuma Teratani et al. performed RFA for liver tumors adjacent to large vessels and bile ducts injury was observed in 6 (7.6%) of 79 cases [16]. Lu, David S.K. et al. also adopted RFA for that kind of tumors. Two major complications, abscess and perihepatic hematoma, were detected in 2 of 31 patients [15]. And Meloni M.F. et al. reported that 3 of 21 (14%) showed diffuse endothelial damage of portal vein after MWA in an in vivo porcine model [29]. As shown above, the percutaneous MWA approach which has exciting therapeutic effects is applicable to nodules adjacent to large vessels. This study had some limitations. First, the data were obtained from a single center with extensive experience in microwave ablation procedures, which may lead to higher complete ablation rates and lower local tumor progression rates. A multicenter study with a larger number of patients is required. Second, the nature of the retrospective study decides that the uniform approach to follow-up cannot be attained, which might have influenced the evaluation of clinical outcomes. Last, the sample size also needs to be enlarged further, and MWA treatment used in this study still needs to be compared with other techniques. 5. Conclusion With strict temperature monitoring, US-guided percutaneous microwave ablation in treating hepatocellular carcinoma adjacent to large vessels is safe and effective. Conflict of interest None.
Fig. 4. The graph is a comparison of 5-year accumulative survival rates of the patients between Group L (L) and Group C (C) after undergoing percutaneous microwave ablation. There are no significant differences between the survival rates of two groups.
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: A long-term follow-up Shijia Huang a,1,2 , Jie Yu a,1,2 , Ping Liang a,∗ , Xiaoling Yu a,2 , Zhigang Cheng a,2 , Zhiyu Han a,2 , Qinying Li b,3 a b
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China No. 135, Shengli East Road, Huanglong District, Puyang City, Henan Province 475000, China
a r t i c l e
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Article history: Received 9 August 2013 Received in revised form 5 December 2013 Accepted 12 December 2013 Keywords: Hepatocellular carcinoma Microwave ablation Large vessels Ultrasound Radiofrequency Percutaneous ethanol injection
a b s t r a c t Purpose: To retrospectively evaluate the effectiveness and safety of ultrasound (US)-guided percutaneous microwave ablation (MWA) in the treatment of hepatocellular carcinoma (HCC) adjacent to large vessels. Materials and methods: From February 2006 to February 2013, 452 patients with 605 HCC nodules were treated with US-guided percutaneous MWA. Into large vessels group (Group L), 139 patients with 163 lesions (diameter, 1.0–7.0 cm; mean, 2.5 ± 1.1 cm) located less than 5 mm away from large vessels were enrolled. And 313 patients with 442 lesions (diameter, 1.0–8.0 cm; mean, 2.5 ± 1.2 cm) located more than 5 mm away from hepatic surface, large vessels, gallbladder and gastrointestinal tract were included in control group (Group C). During the ablation, the temperature of marginal ablation tissues was monitored and controlled. Results: The median follow-up time was 24.5 months (range 2.1–87.7 months) in Group L, and 25.7 months (range 1.6–93.9 months) in Group C. Technical effectiveness was achieved in 157 of 163 (96.3%) tumors in Group L and 429 of 442 (97.1%) tumors in Group C, respectively (p > 0.05). The 1-, 3- and 5-year local tumor progression rates and the 1-, 3- and 5-year accumulative survival rates in the two groups have no significantly statistical differences. In addition, no immediate or periprocedural major complications, no delayed complication of vessels or bile ducts injury were found in both of the two groups. Conclusions: With strict temperature monitoring, US-guided percutaneous MWA is an efficient and safe technology in treating hepatocellular carcinoma adjacent to large vessels. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hepatocellular carcinoma (HCC) is the fifth frequently diagnosed cancer worldwide and is the second main cause in the cancer-related deaths [1]. It was reported that 695,900 cancer deaths occurred all over the world in 2008, and half of these deaths were estimated to occur in China [1,2]. Improvement in abdominal imaging has made early diagnosis of HCC more easily [3]. Traditionally, hepatic resection is the first-line treatment option for patients who are with solitary tumors and well-preserved liver function [3–5]. However, resection also has limitations if it is used to treat HCC patients with unfavorable tumor locations. As report
∗ Corresponding author. Tel.: +86 10 66939530; fax: +86 10 68161218. E-mail addresses: [email protected] (S. Huang), [email protected] (J. Yu), [email protected] (P. Liang), [email protected] (X. Yu), [email protected] (Z. Cheng), [email protected] (Z. Han), [email protected] (Q. Li). 1 These authors contributed equally to the manuscript. 2 Tel.: +86 10 66937982. 3 Tel.: +86 10 13939364234. 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.12.015
goes, resections for malignant zones close to main hepatic veins or the vena cava are sometimes practicable[6,7], but they are always associated with increased risks [8]. The emergence of local thermal ablation provides a feasible choice for these patients [9–13]. Minimally invasive percutaneous local ablation techniques, such as radiofrequency ablation (RFA), cryoablation and microwave ablation (MWA), have already been suggested as alternatives for the treatment of HCC [3]. And these techniques referred before, in treating small HCC, were turned out to be promising in clinical results [9–11]. However, an important inherent effect of heat-sink on thermal ablation may influence the treatment result for the tumors adjacent to large vessels (≥3 mm) [14]. At present, some researchers have already put RFA into practice of treating liver tumors adjacent to large vessels. And the result is satisfying [15–17]. However, as another kind of thermal ablation techniques, MWA has its special features. It destroys the tumors via high temperature produced by rotating adjacent polar water molecules in the targeted pathologic tissues through electromagnetic energy, which would lead to protein denaturation, cell membrane disruption, and finally coagulation necrosis with
S. Huang et al. / European Journal of Radiology 83 (2014) 552–558 Table 1 The location distribution of tumors in Group L.
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2.2. Preprocedure evaluation
The vessels adjacent to tumors
No. of tumors
Inferior vena cava Right hepatic vein Middle hepatic vein Left hepatic vein Main portal vein Right portal vein Anterior branch of right portal vein Posterior branch of right portal vein Left portal vein Left portal venous bifurcation External branch of left portal vein Internal branch of left portal vein Inferior vena cava and Main portal vein
19 12 9 2 12 41 13 22 3 8 18 2 2
cellular death. Under the condition of giving 4–6 min treatment for patients with temperature being greater than 50 ◦ C or reaching 60 ◦ C immediately, the changes described before would appear [18,19]. MWA has several theoretical advantages over RFA. First, it would produce consistently higher intratumoral temperatures, larger ablation zones, less ablation time and less dependence on the electrical conductivities of tissue. Second, energy delivery is less limited by the exponentially rising electrical impedance of tumor tissue [19–22]. These advantages may make MWA treatment less affected by heat-sink [21]. Although MWA has been widely used in liver cancer therapy [10], there are no authoritative clinical achievements but only some foundational reports on the effects of treating the tumors adjacent to large vessels [23]. This study aims to assess the effectiveness, safety and clinical outcomes of US-guided MWA in treating patients with HCC adjacent to large vessels.
2. Materials and methods 2.1. Patients This retrospective study was approved by the institutional review board of Chinese PLA General Hospital. Written informed consent for this procedure was obtained from all the enrolled patients. From February 2006 to February 2013, 452 consecutive patients (605 lesions) with HCC were enrolled and underwent percutaneous MWA treatment at this department. Among the 452 patients, 139 patients with 163 HCC lesions, located less than 5 mm from large vessels (large vessels were defined as the first or second branch of the portal vein, the base of hepatic veins, or the inferior vena cava of which diameters being equal or bigger than 3 mm) shown by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), were enrolled into large vessels group (Group L). And 313 patients with 442 lesions located in safe site (more than 5 mm from hepatic surface, large vessels, gallbladder and gastrointestinal tract) were included in control group (Group C). All the enrolled HCC patients are treated by MWA, and they were closely followed up until May 2013. There were 109 males and 30 females in Group L with a median follow-up time 24.5 months (range 2.1–87.7 months), and 247 males and 66 females in Group C with a median follow-up time 25.7 months (range 1.6–93.9 months). No statistical differences of median follow-up time exist between the both groups (p = 0.998). The average ages were 59.5 ± 10.6 (range 33–86) years in Group L, and 58.4 ± 10.5(range 28–92) years in Group C, respectively (p > 0.05). The numbers of the lesions adjacent to different large vessels in Group L are list in Table 1.
All patients enrolled in this study had to meet the following criteria: the percutaneous approach was accessible to the tumors; the size of single nodular HCC lesions was less than or equal to 8 cm; each multiple nodular hepatic lesions, three or fewer, was with a maximum dimension of 4 cm or less; there was no portal vein embolus nor extrahepatic metastases; the prothrombin time was less than 25 s; the prothrombin time activity percentage was higher than 40%; the platelet count was higher than 40 cells × 109 /L. In the pre-operation, the number of tumors and the absence of portal vein thrombosis were evaluated by contrastenhanced US (CEUS), CT or MRI. The maximum diameter of nodules was measured by arterial phase of CEUS. The absence of extrahepatic metastases was determined by means of a thorough clinical assessment, chest radiography, abdominal US, and abdominal CT or MRI or position-emission tomography (PET). HCC diagnosis was largely made through an intraoperative tumor biopsy before ablation with US guidance. 2.3. MWA system The microwave ablation system (KY-2000; Kangyou Medical Instruments, Nanjing, China) consists of two MW generators, two flexible coaxial cables and two cooled shaft antennae. The machine is capable of producing 2450 MHz and 1–100 W [24]. The cooled shaft antenna (diameter: 1.9 mm, 15 gauge; length: 18 cm; pinpoint size: 5 mm or 11 cm) which is coated with polytetrafluoroethylene to prevent conglutination can be easily observed by ultrasound (US). Inside antenna shaft are dual channels, through which distilled water is circulated by a peristaltic pump continuously cooling the shaft and preventing overheating. 2.4. MWA procedure First, after giving the patients local anesthesia with 1% lidocaine, US-guided biopsy was performed by an automatic biopsy gun with an 18-gauge cutting needle and 2 or 3 separate punctures were performed then. Second, under US guidance, the antennae were percutaneously inserted into the tumors. At each insertion, the tip of the needle was placed in the deepest part of the tumor. For tumors less than 2.0 cm, one antenna was inserted; for tumors measuring 2.0 cm or greater, two antennae were inserted with an interantenna distance of no more than 2.5 cm. Third, after all insertions, intravenous anesthesia, via the peripheral vein, was administered by a combination of propofol (Diprivan; Zeneca Pharmaceuticals, Wilmington, Del) and ketamine (Shuanghe Pharmaceuticals, Beijing, China) during standard hemodynamic monitoring. Fourth, MWA emission started, and the region of ablation was monitored by US. During the MWA process, the output of power is 40–60 W for 5–10 min in a session. Multiple thermal lesions are created along the major axis of the needle antenna by simply withdrawing the needle from the preceding thermal lesion, and reactivating the MW generator. If necessary, due to tumor size, multiple overlapping ablations are usually needed to envelope the entire tumor with a safety margin. If the heat-generated hyperechoic water vapor did not completely encompass the entire tumor, a prolonged microwave emission would be applied until the desired temperature was reached. Finally, when the antenna was withdrawn, the applicator track was heated with sufficient microwave energy by quitting the cooling-shaft water dump. 2.5. Thermal monitoring during the procedure To continuously measure temperature in real time during the ablation, the microwave machine is also equipped with a thermal
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Fig. 1. Contrast-enhanced MRIs of a 57-year-old man with a 1.9 cm × 1.9 cm nodule of HCC adjacent to right portal vein treated by MWA. (a) Preablation image shows one neoplasm (arrows) adjacent to right portal vein. (b) On the arterial phase image obtained in the first year after treatment, no enhancement is seen in the ablation zone (arrows). (c) Transverse and (d) coronal images obtained in the third year after treatment show that the nonenhancing ablation zone gradually shrinks (arrows). And (e) Transverse and (f) coronal images show that there remains no enhancement of the ablation zone (arrows) in the fifth year after treatment.
monitoring system. A 20-gauge thermocouple was inserted at the site of 5 mm away from the tumor margin. If the measured temperature reached 60 ◦ C or 54 ◦ C lasting for over three minutes, it can be considered that the tumors are necrotic thoroughly. This condition will continue until the entire tumor was completely covered by the hyperechoic micro-bubbles under gray-scale US. 2.6. Adjuvant therapy with small dose of ethanol injection For the 94 of 163 lesions in Group L adjacent to both large vessels and bile ducts, one to two 21-G PTC needles (Hakko, Japan)
were placed into marginal tissue of tumor proximal to the large vessels with US guidance. Every needle was inserted in one site for the purpose of precision. At the time of microwave emission, dehydrated sterile 99.5% ethanol (Changhai Hospital of Shanghai, China) was slowly injected into the margin of tumors (about 1 ml/min). And, the quotas of ethanol injected were determined by the size and location of the tumor empirically. For the tumors less than 3 cm, no more than 5 ml ethanol was injected; for the tumors larger than 3 cm, 5–10 ml ethanol was injected. The mean ethanol dose was 4.77 ml (range 1.5–10 ml). All ethanol injections were planned before the ablation procedure.
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Fig. 2. Contrast-enhanced images show a 3.4 cm × 3.0 cm HCC nodule adjacent to the right portal vein in the liver of a 56-year-old man treated with MWA. (a) preoperative CEUS and (b) preoperative MRI show that there is one HCC nodule (white arrows) is on post top of the right portal vein (black arrow); (c) After one session, the nodule (white arrows) which closes to the blood vessel (black arrows) was completely ablated; (d) On the arterial phase image obtained in the first year after treatment, no enhancement is seen in the ablation zone (arrows); And (e) Transverse and (f) coronal images show that there remains no enhancement of the ablation zone (arrows) in the second year after treatment.
2.7. Follow-up To evaluate treatment effectiveness, contrast-enhanced imaging (US and CT or MRI) were performed in 1–3 days after the last ablation. Technique effectiveness, namely complete ablation, is defined as the absence of enhancement in any areas of the mass on enhanced images obtained at the 1 month follow-up after MWA. The routine CEUS, CT, or MRI should be performed to monitor recurrence or metastasis in the later three months after MWA and should be repeated every six months if complete ablation was achieved (Figs. 1 and 2). Local tumor progression is defined as irregular
peripheral enhancement in scattered, nodular, or eccentric pattern occurring at the original sites which were previously considered to be completely ablated during the follow-up period. In terms of complications, they can be defined as major or minor and can be detected by US and CT or MRI. 2.8. Statistical methods Data analysis was performed by SPSS (version 16.0.01 for Windows, SPSS, 6 Chicago, IL, USA). The ages of patients and the sizes of tumors were presented by the mean ± SD, and the time of
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Table 2 Clinical features of patients and tumors. Variable Patient information No. of patients Male/Femalea Mean age (y)b Tumor information No. of tumors Mean tumor diameter (cm)b Ablation time (min)b Ablation power (W)c Ablation sessionsd Ablation insertionsd Median follow-up (mo.)d a b c d
Group L
Group C
p-Value
139 109 (78.4)/30 (21.6) 59.5 ± 10.6 (33–86)
313 247 (78.9)/66 (21.1) 58.4 ± 10.5 (28–92)
– – p > 0.05
163 2.5 ± 1.1 (1–7) 10.4 ± 5.4 (3–31) 49.4 ± 2.8 1 (1–3) 2 (1–4) 24.5 (2.1–87.7)
442 2.5 ± 1.2 (1–8) 8.9 ± 4.8 (2.5–29.3) 50 ± 1.9 1 (1–3) 2 (1–4) 25.4 (1.6–93.9)
p > 0.05 p < 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05
Data in parentheses are percentages. Data are means ± standard deviation; data in parentheses are ranges. Data are means ± standard deviation. Data are medians; data in parentheses are ranges.
follow-up was expressed as the median. The accumulative survival rates and local tumor progression rates were calculated by using the Kaplan–Meier method. Differences in the survival rates and local tumor progression rates between the two groups were examined by the log-rank test. Continuous variables of the two groups were analyzed by using Student’s t-test or Wilcoxon rank sum test. 2 test was applied to compare categorical variables of the two groups. Differences with p values less than 0.05 were considered statistically significant.
3. Results 3.1. Pretreatment clinical parameters US-guided MWA was performed for 605 HCC nodules in 452 patients. Of 139 patients with 163 lesions closed to large vessels, 104 patients were infected with Hepatitis B and 24 patients with Hepatitis C. In the control group, 252 patients were infected with Hepatitis B and 46 patients with Hepatitis C. The size of lesions ranged from 1 to 7 cm (mean maximum diameter 2.5 ± 1.1 cm) in Group L and 1 to 8 cm (mean maximum diameter 2.5 ± 1.2 cm) in Group C (p > 0.05). The clinical features of patients and tumors were summarized in Table 2.
time of local tumor progression is 9.3 ± 8.7 months; in Group C, the numbers are 2.7 ± 1.4 cm and 6.4 ± 6.7months (p1 = 0.20, p2 = 0.25). There were 30 patients in Group L and 74 patients in Group C died during the follow-up. In Group L, the death causes were as follows: progression of HCC in 15 patients, variceal bleeding in 6 patients, liver failure in 5 patients, myocardial infarction in 2 patients, and cerebral hemorrhage in 2 patients. And in Group C, several death causes were concluded as below: progression of HCC in 36 patients, variceal bleeding in 14 patients, liver failure in 16 patients, myocardial infarction in 3 patients, cerebral hemorrhage in 2 patients, intestinal obstruction in one patient, heart failure in one patient, and acute pulmonary embolism in one patient. The 1-, 3- and 5-year accumulative survival rates were 94.0%, 72.0% and 64.0% in Group L, and 93.0%, 79.0% and 57.0% in Group C, respectively. What’s more, no significantly statistical difference was found (p = 0.95, Fig. 4). 3.3. Complications and side effects There was no immediate nor periprocedural major complications in both of the two groups. Twenty of 139 (14.4%) patients of Group L and 43/313 (13.7%) patients of Group C complained of mild pain after the ablation. No significant difference was found (p > 0.05). Thrombosis was found by CEUS in the right portal vein and the central part of the left portal vein (lengths of
3.2. Clinical outcomes In this study, of all the patients, pathology was proven by biopsy in 420 cases and by clinical and imaging features in 32 cases which had refused the biopsy (Table 3). The clinical and imaging diagnostic criteria for HCC included hepatitis B or C cirrhosis, serum AFP levels and at least two kinds of contrast-enhanced imaging (US, CT or MRI). All 605 lesions were given 721 MWA sessions. The median MWA sessions of the two groups were both 1 (range 1–3). Ablation times were 10.4 ± 5.4 (3–31) minutes in Group L and 8.9 ± 4.8 (2.5–29.3) minutes in Group C, respectively (p < 0.05). And 157 of 163 (96.3%) lesions in Group L and 429 of 442 (97.1%) lesions in Group C achieved complete ablation. No significantly statistical difference in the rates of technical effectiveness was found between the two groups (p > 0.05). Local tumor progression was detected in 22 of 163 tumors (13.5%) in Group L, 42 of 442 tumors (9.5%) in Group C in the follow-up 7 years, respectively (p > 0.05). And the 1, 3- and 5-year local tumor progression rates were 10.7%, 17.3% and 17.3% in Group L, and 6.9%, 12.7% and 12.7% in Group C, respectively (p = 0.27, Fig. 3), which revealed no statistical difference between the two groups. In the local tumor progression cases of Group L, the mean largest tumor diameter is 2.3 ± 0.6 cm, and the mean
Fig. 3. The graph is a comparison of 5-year local tumor progression rates of the patients between Group L (L) and Group C (C) after undergoing percutaneous microwave ablation. There are no significant differences between the local tumor progression rates of two groups.
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Table 3 Diagnostic investigations of HCC before and after the treatment. Diagnostic methods before the treatment
No. of the HCC diagnosed before the treatment
Histodiagnosis
No. of the HCC diagnosed after the treatment
≥ two kinds of contrast-enhanced imaging Biopsy
32 420
– HCC
32 420
thrombosis: 3 mm, 2.5 mm) of one patient in Group L (0.7%) in the second month after treatment, which disappeared 3 months later without any management. Two cases of tumor seeding were found in Group L (2/139, 1.4%; at abdominal wall: diameter 2.2 cm at 9 months; at hepatic surface: diameter 1.3 cm at 12 months) and Group C (2/313, 0.6%; at abdominal wall: diameter 1.4 cm at 7 months; at hepatic surface: diameter 1.7 cm at 13 months), respectively. Two disseminated tumors detected at abdominal wall were seeding from the lesions in the segment IV of the Group L and the segment VIII of the Group C, respectively; while the other two at hepatic surface were seeding from the lesions in the segment VI of the Group L and the segment V of the Group C, the distance from the surface of the liver to the lesion were 4.1 cm and 2.5 cm, respectively. All seeding tumors received MWA and achieved complete ablation. No delayed complication of vessels or bile ducts injury was detected in this study. 4. Discussion RF ablation remains to be the most widely used ablative technique worldwide for liver tumors and it achieved optimistic effectiveness in treating the tumors adjacent to large vessels. Compared with RFA, MWA may provide larger ablation zones and higher intratumoral temperatures. In addition, MWA is also less affected by the heat-sink effect [21]. Therefore, theoretically speaking, the advantages of MWA in dealing with that kind of tumors could get an ideal therapeutic effect. This study aimed to provide clinical evidence for this choice of intervention therapy in HCC nodules adjacent to large vessels. The treatment effectiveness in this study was very encouraging. Ablation sessions, local tumor progression and survival in large vessels group do not have any significant differences with those in control group. These results illustrate that heat-sink effect is unable to affect MWA treatment of HCC nodules adjacent to large vessels markedly. Also, the technical effectiveness rate is higher and the local tumor progression rate is lower than those in other reports
[25–27]. That may be attributable to the following reasons: (1) MWA has theoretical merits in producing consistently higher intratumoral temperatures, larger ablation zones, less ablation time and less dependence on the electrical conductivities of tissue. Also, the energy delivery is less controlled by the exponentially rising electrical impedance of tumor tissue. (2) Long-duration ablation may cause gradual ablation of the tumors adjacent to large vessels and compensate the defect from heat-sink effect in the large vessels. (3) CEUS should be reviewed timely in the subsequent three days after the first procedure to check whether any residual cancer still exist, from which a second session is needed or not can be decided to achieve complete ablation. (4) PEI was performed simultaneously with MWA emission for the tumors adjacent to both large vessels and bile ducts. The aim was to kill the tumor tissue adjacent to biliary duct and blood vessel, and to prevent the overheating injury to these vital tissues by increasing thermal conduction and diffusivity through previously coagulated tissue [28]. (5) Real-time peritumoral temperature monitoring was used as an indicator for complete MWA. (6) Lots of experience in detailed treatment protocol, accurate image guiding and proper placement of antennae was another essential factor for the success of treatment. There were no major complications discovered, even in patients with the tumors adjacent to large vessels. Thrombosis was found once in the second month after the treatment, which may be caused by blood coagulation effected by heat. Takuma Teratani et al. performed RFA for liver tumors adjacent to large vessels and bile ducts injury was observed in 6 (7.6%) of 79 cases [16]. Lu, David S.K. et al. also adopted RFA for that kind of tumors. Two major complications, abscess and perihepatic hematoma, were detected in 2 of 31 patients [15]. And Meloni M.F. et al. reported that 3 of 21 (14%) showed diffuse endothelial damage of portal vein after MWA in an in vivo porcine model [29]. As shown above, the percutaneous MWA approach which has exciting therapeutic effects is applicable to nodules adjacent to large vessels. This study had some limitations. First, the data were obtained from a single center with extensive experience in microwave ablation procedures, which may lead to higher complete ablation rates and lower local tumor progression rates. A multicenter study with a larger number of patients is required. Second, the nature of the retrospective study decides that the uniform approach to follow-up cannot be attained, which might have influenced the evaluation of clinical outcomes. Last, the sample size also needs to be enlarged further, and MWA treatment used in this study still needs to be compared with other techniques. 5. Conclusion With strict temperature monitoring, US-guided percutaneous microwave ablation in treating hepatocellular carcinoma adjacent to large vessels is safe and effective. Conflict of interest None.
Fig. 4. The graph is a comparison of 5-year accumulative survival rates of the patients between Group L (L) and Group C (C) after undergoing percutaneous microwave ablation. There are no significant differences between the survival rates of two groups.
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