To assess the utility of Sonazoid contrast-enhanced ultrasound (CEUS) for guiding percutaneous microwave ablation (MWA) for colorectal liver metastases (CRLMs). The medical records of patients who had undergone ultrasound (US)-guided percutaneous MWA between July 2020 and June 2022, were reviewed. Propensity score matching (PSM) with a ratio of 1:1 was used to balance the potential bias between the grayscale US-guided and Sonazoid CEUS-guided groups. Local tumor progression (LTP), intrahepatic recurrence (IR), and complication rates were compared between the two groups. Of 252 patients enrolled, 247 achieved complete ablation, and the technical effectiveness was 98.0% (247/252). Of these 247 patients, 158 were in the grayscale US-guided group and 89 in the Sonazoid CEUS-guided group. The median follow-up period was 14.6 months. After PSM, there were no significant differences in LTP, IR, or complication rates between the two groups (p = 0.100, p = 0.511, p > 0.99, respectively). Multivariate analysis identified tumor size ≥ 3 cm (hazard ratio [HR], 7.945; 95% CI, 2.591-24.370; p < 0.001), perivascular (HR, 2.331; 95% CI, 1.068-5.087; p = 0.034), and tumor depth > 8 cm (HR, 3.194; 95% CI, 1.439-7.091; p = 0.004) as significant factors associated with LTP. For tumors with poor vision on grayscale US, Sonazoid CEUS-guided ablation achieved a better LTP rate than grayscale US-guided ablation (3.7% vs.14.8%, p = 0.032). For tumors with poor vision on grayscale US, Sonazoid CEUS guidance is recommended for better local tumor control.
Keywords: Colorectal liver metastases; sonazoid; ablation; local tumor progression; contrast-enhanced ultrasound
Colorectal cancer (CRC) is the second most common cancer and the third leading cause of cancer-related death worldwide [[
Computed tomography (CT) and ultrasound (US) are the most widely used imaging modalities for guiding ablation. Compared to CT, US has the advantages of facilitation, occurring in real-time, being radiation-free, and flexibility [[
The Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University approved this retrospective study (approval protocol number: 2021ZSLYEC-340) and informed consent for the treatment was obtained from all patients. The requirement for informed consent to publish these results was waived because of the retrospective nature of this study. Patients diagnosed with CRLM who underwent percutaneous US-guided microwave liver ablation between July 2020 and June 2022 were included. The inclusion criteria were [[
Graph: Figure 1. Study design. CRLM: colorectal liver metastases; PSM: propensity score matching; LTP: local tumor progression; IR: intrahepatic recurrence; US: ultrasound; CEUS: contrast-enhanced ultrasound.
A 2450-MHz microwave ablation system (KY2000; Nanjing Kangyou Biological Energy Co., Ltd., Nanjing, China) was employed. This system consisted of a microwave generator with an output power range of 1–100 W, a flexible coaxial cable, and a cooled-shaft antenna (KY-2450-b; Nanjing Kangyou Biological Energy Co., Ltd., Nanjing, China). The antenna was 18 cm long and 1.9 mm in diameter (15 G), and the temperature was maintained below 40 °C by adjusting the flow of the cold water. Based on the number, size, and visualization of the tumor on grayscale US, the radiologist decided to perform the procedure under the guidance of grayscale US or Sonazoid CEUS. Before puncture, 2% lidocaine was administered into the liver capsule using a 24-G needle 10 cm in length to provide local anesthesia. The key MWA parameters, including the number of antennas, number of insertions, ablation time, and output energy, were determined according to the tumor size, shape, location, and adjoining structures and organs. Generally, 1–2 antennas and 1–2 insertions are used for tumors <3.0 cm in diameter, and two antennas and multiple insertions are used for tumors ≥ 3.0 cm. After the antenna was inserted into the center of the tumor under the guidance of grayscale US or Sonazoid CEUS, an energy output of 40–60 W was applied for 3–10 min. A radiologist with more than 20 years of experience in liver tumor ablation performed all the procedures.
Technical success, local tumor progression (LTP), intrahepatic recurrence (IR), and complications were evaluated according to terminology standardization guidelines [[
Graph
The location of each tumor was classified as perivascular or subcapsular. A perivascular tumor was defined as a tumor margin less than 1 cm from the first- or second-degree branch of a portal or hepatic vein with a diameter greater than 3 mm [[
Using propensity score matching (PSM) to balance the potential bias of baseline information between the two groups before analysis, the propensity score was calculated using a logistic regression model. Patients in the two groups were matched using the 1:1 nearest-neighbor matching method with a match tolerance of 0.1. An absolute standard difference lower than 0.2 were used to assess the balance of variables used for matching. The variables included in the propensity score model were as follows: age, sex, comorbidities, body mass index (BMI), carcinoembryonic antigen (CEA) levels, primary tumor location, T and N categories, extrahepatic metastasis, prior chemotherapy, after chemotherapy, therapeutic purpose, synchronous or metachronous liver metastases, disease-free interval (DFI), number and maximal size of metastases, and tumor burden score (TBS).
Continuous variables satisfying a normal distribution were expressed as mean ± standard deviation (SD) and variables that did not satisfy a normal distribution were expressed as median (range). Continuous variables were compared using the Student's t-test or Mann-Whitney U test, and categorical variables were compared using the chi-square test. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank test. Cox univariate and multivariate regression analyses were used to analyze the significant factors for LTP and IR. Factors with p < 0.05 in univariable analysis were further entered into multivariable Cox regression. Subgroup analysis used Cox regression and was performed on matched patients after PSM. All statistical analyses were performed using SPSS (version 25.0) and MedCalc (version 11.2; 2011 MedCalc Software bvba, Mariakerke, Belgium) software. All statistical tests were two-sided, and p < 0.05 indicated statistical significance.
In total, 252 patients with 558 CRLMs were included in the (Figure 1). Technical success was achieved in 100% (558/558) of the tumors, according to CEUS performed 30 min and 24 h after ablation. Incomplete ablation occurred in 6 CRLMs of 5 patients on contrast-enhanced imaging acquired 1 month after ablation, and technical effectiveness was achieved in 98.9% (552/558) of tumors and 98.0% (247/252) of patients. The technical effectiveness in patients in the grayscale US-guided and Sonazoid CEUS-guided groups was 98.1% (158/161) and 97.8% (89/91), respectively (p = 1.000). After excluding 5 patients with incomplete ablation tumors, 247 patients were included in the analysis of LTP, IR, and complications.
A total of 247 patients (167 males and 80 females; mean age, 55.5 ± 10.9 years; range, 25-79 years) were included for the analysis of LTP, IR, and complications. Ablation was performed in 158 patients in the grayscale US-guided group and 89 patients in the Sonazoid CEUS-guided group. The median follow-up period was 14.6 months (range, 1.8-31.3 months). Before PSM, the mean number of ablated tumors in the grayscale US-guided group and Sonazoid CEUS-guided group per patient was 1.96 ± 0.11 and 2.70 ± 0.15, respectively. The median number of ablated tumors was 1 (range, 1-8) and 1 (range, 1–7) in the grayscale US-guided and Sonazoid CEUS-guided groups, respectively. Patients in the Sonazoid CEUS-guided group had more CRLMs than those in the gray scale US-guided group (p < 0.001). Additionally, the number of liver metastases, TBS, extrahepatic metastases, and therapeutic purposes differed between the two groups. After PSM, 144 patients were matched and baseline information showed no significant differences between the two groups. The median number of ablated tumors was 2 (range, 1-8) and 2 (range, 1-6) in the grayscale US-guided and Sonazoid CEUS-guided groups, respectively. Baseline information before and after PSM is summarized in Table 1.
Table 1. Baseline information of patients before and after PSM (N = 247).
Before PSM After PSM Variable Grayscale US-guided ( Sonazoid CEUS-guided ( ASD Grayscale US-guided ( Sonazoid CEUS-guided ( ASD Age 0.481 −0.094 0.609 0.000 ≤ 60 94 (59.5%) 57 (64.0%) 42 (58.3%) 45 (62.5%) > 60 64 (40.5%) 32 (36.0%) 30 (41.7%) 27 (37.5%) Sex 0.815 −0.031 0.863 −0.100 Male 106 (67.1%) 61 (68.5%) 45 (62.5%) 46 (63.9%) Female 52 (32.9%) 28 (31.5%) 27 (37.5%) 26 (36.1%) Comorbidity 0.691 0.051 0.386 −0.040 No 131 (82.9%) 72 (80.9%) 61 (84.7%) 57 (79.2%) Yes 27 (17.1%) 17 (19.1%) 11 (15.3%) 15 (20.8%) BMI (kg/m2) 0.441 0.105 > 0.99 0.070 < 24 108 (68.4%) 65 (73.0%) 51 (70.8%) 51 (70.8%) ≥ 24 50 (31.6%) 25 (27.0%) 21 (29.2%) 21 (29.2%) CEA (ug/ml) 0.252 0.152 0.613 0.000 < 5 75 (47.5%) 49 (55.1%) 43 (59.7%) 40 (55.6%) ≥ 5 83 (52.5%) 40 (44.9%) 29 (40.3%) 32 (44.4%) Primary tumor location 0.189 −0.171 0.499 −0.031 Colon 97 (61.4%) 47(52.8%) 44 (61.1%) 40 (55.6%) Rectum 61 (38.6%) 42(47.2%) 28 (38.9%) 32 (44.4%) Primary tumor invasion 0.910 0.015 > 0.99 0.000 T1-3 134 (84.8%) 75 (84.3%) 63 (87.5%) 63 (87.5%) T4 24 (15.2%) 14 (15.7%) 9 (12.5%) 9 (12.5%) Nodal status of primary tumor 0.052 −0.275 0.585 0.175 Negative 62 (39.2%) 24 (27.0%) 23 (31.9%) 20 (27.8%) Positive 96 (73.3%) 65 (73.0%) 49 (68.1%) 52 (72.2%) EHD 0.010* 0.310 0.441 −0.131 No 128 (81.0%) 59 (66.3%) 56 (77.8%) 52 (72.2%) Yes 30 (19.0%) 30 (33.7%) 16 (22.2%) 20 (27.8%) Prior chemotherapy 0.122 −0.253 0.857 −0.119 No 54 (34.2%) 22 (24.7%) 23 (31.9%) 22 (30.6%) Yes 104 (65.8%) 67 (75.3%) 49 (68.1%) 50 (69.4%) After chemotherapy 0.220 −0.181 0.509 <0.001 No 29 (19.4%) 11 (12.4%) 14 (19.4%) 11 (15.3%) Yes 129 (81.6%) 78 (87.6%) 58 (80.6%) 61(84.7%) Therapeutic purpose <0.001* 0.560 0.394 0.000 Initial treatment 119 (75.3%) 42 (47.2%) 46 (63.9%) 41 (56.9%) Recurrence 39 (24.7%) 47 (52.8%) 26 (36.1%) 31 (43.1%) Liver metastases 0.221 −0.173 0.843 −0.039 Synchronous 115 (72.8%) 71 (79.8%) 55 (76.4%) 56 (77.8%) Metachronous 43 (27.2%) 18 (20.2%) 17 (23.6%) 16 (22.2%) DFI 0.223 −0.195 > 0.99 −0.067 < 12 142 (89.9%) 84 (94.4%) 69 (95.8%) 68 (94.4%) ≥ 12 16 (10.1%) 5 (5.6%) 3 (4.2%) 4 (5.6%) TBS 0.001* −0.492 0.939 0.094 Median (range) 2.4 (range, 1.0-8.1) 3.1 (range, 1.1-7.2) 3.0 (range, 1.1-8.1) 3.0 (range, 1.2-6.4) Maximal tumor size 0.458 −0.189 0.404 0.000 < 3 cm 150 (94.9%) 87 (97.8%) 68 (94.4%) 70 (97.2%) ≥ 3 cm 8 (5.1%) 2 (2.2%) 4 (5.6%) 2 (2.8%) Tumor number <0.001* −0.726 0.710 −0.152 Median (range) 1 (range, 1-8) 1 (range, 1-7) 2 (range, 1-8) 2 (range, 1-6) Single 81 (51.3%) 19 (21.3%) 21 (29.2%) 19 (26.4%) Multiple 77 (48.7%) 70 (78.7%) 51 (70.8%) 53 (73.6%)
1 PSM: propensity score matching; ASD: absolute standard difference; US: ultrasound; CEUS: contrast-enhanced ultrasound; BMI: body mass index; CEA: carcinoembryonic antigen; EDH: extrahepatic diseases; DFI: disease-free interval; TBS: tumor burden score.
2 *p < 0.05 was considered a significant difference.
The characteristics of the CRLMs in the grayscale US-guided and Sonazoid CEUS-guided groups are summarized in Table 2. Grayscale US vision and CRLM depth significantly differed between the two groups. Tumors with poor vision in US were usually ablated under the guidance of Sonazoid CEUS, and tumors with a depth > 8 cm were more often ablated under the guidance of grayscale US. There were no significant differences in other characteristics between the two groups (Table 2).
Table 2. The characteristics of CRLMs in the grayscale US-guided group and Sonazoid CEUS-guided group (N = 366).
Variable Grayscale US-guided ( Sonazoid CEUS-guided ( Segment 0.946 1/2/3/4 56(27.2%) 44(27.5%) 5/6/7/8 150(72.8%) 116(72.5%) Perivascular 0.491 No 160(77.7%) 129(80.6%) Yes 46(22.3%) 31(19.4%) Subcapsular 0.769 No 92(44.7%) 69(43.1%) Yes 114(55.3%) 91(56.9%) Maximal tumor size 0.919 < 3 cm 202(98.1%) 158(98.8%) ≥ 3 cm 4(1.9%) 2(1.3%) Depth 0.001* ≤ 8 cm 166(80.6%) 148(92.5%) > 8 cm 40(19.4%) 12(7.5%) US visualization <0.001* Poor vision 81(39.3%) 108(67.5%) Clear vision 125(60.7%) 52(32.5%) Prior chemotherapy 0.371 No 63(30.6%) 56(35.0%) Yes 143(69.4%) 104(65.0%) After chemotherapy 0.702 No 28(13.6%) 24(15.0%) Yes 178(86.4%) 136(85.0%)
- 3 CRLM: colorectal liver metastases; US: ultrasound; CEUS: contrast-enhanced ultrasound.
- 4 *p < 0.05 was considered a significant difference.
Before PSM, 27 of 158 (17.1%) and 13 of 89 (14.6%) patients developed LTP in the grayscale US-guided and Sonazoid CEUS-guided groups, respectively. After PSM, 16 of 72 (22.2%) and 11 of 72 (15.2%) patients developed LTP in the grayscale US-guided and Sonazoid CEUS-guided groups, respectively. There was no significant difference in the LTP rates before and after PSM between the two groups (Figure 2(A,B)).
PHOTO (COLOR): Figure 2. Kaplan–Meier curves for patients who underwent grayscale US-guided or Sonazoid CEUS-guided ablation before and after propensity score matching (PSM). (A) local tumor progression-free survival (LTPFS) curve before PSM. (B) LTPFS curve after PSM. (C) intrahepatic recurrence-free survival curve before PSM. (D) intrahepatic recurrence-free survival curve after PSM.
Univariate and multivariate Cox regression analyses to evaluate the factors associated with LTP are shown in Table 3. On multivariate analysis, tumor size ≥ 3 cm (hazard ratio [HR], 7.945; 95% CI, 2.591–24.370; p < 0.001), perivascular (HR, 2.331; 95% CI, 1.068–5.087; p = 0.034), and tumor depth > 8 cm (HR, 3.194; 95% CI, 1.439-7.091; p = 0.004) were identified as independent poor prognostic factors for LTP (Table 3). According to the univariate analyses, the method of guidance was not a significant factor associated with LTP (p = 0.964) (Table 3).
Table 3. Results of univariate and multivariate Cox regression analyses for evaluating factors associated with local tumor progression-free survival.
Variables HR (95% CI) HR (95% CI) Age ≤ 60 ( > 60 ( 0.65(1.40-3.02) 0.392 Sex Male ( Female ( 1.36(0.63-2.92) 0.435 Comorbidity No ( Yes ( 1.88(0.79-4.48) 0.153 BMI (kg/m2) < 24 ( ≥ 24 ( 1.78(0.83-)3.84 0.142 CEA (ug/ml) < 5 ( ≥ 5 ( 1.53(0.72-3.26) 0.271 Primary tumor Colon ( Rectum ( 1.39(0.65-2.97) 0.392 Primary tumor invasion T1-3 ( T4 ( 0.60(0.14-2.54) 0.487 Nodal status of primary tumor Negative ( Positive ( 1.75(0.70-4.37) 0.229 EHD No ( Yes ( 0.92(0.37-2.28) 0.855 Prior chemotherapy No ( Yes ( 2.44(0.84-7.08) 0.101 After chemotherapy No ( Yes ( 0.69(0.28-1.71) 0.424 Therapeutic purpose Initial treatment ( Recurrence ( 0.82(1.76-3.77) 0.146 Liver metastases Synchronous ( Metachronous ( 1.43(0.60-3.40) 0.420 DFI (months) ≥ 12 ( < 12 ( 1.37(0.32-5.82) 0.666 TBS 1.10(0.86-1.42) 0.457 Tumor number Single ( Multiple ( 0.49(0.23-1.04) 0.063 Guidance Grayscale US-guided ( Sonazoid CEUS-guided ( 0.98(0.44-2.18) 0.964 Maximal tumor size < 3 cm ( ≥ 3 cm ( 14.12(4.83-41.25) <0.001* 7.95(2.59-24.37) <0.001* Segment 1/2/3/4 ( 5/6/7/8 ( 0.99(0.46-2.14) 0.978 Perivascular No ( Yes ( 3.82(1.91-7.65) <0.001* 2.33(1.07-5.09) 0.034* Subcapsular No ( Yes ( 0.67(0.33-1.34) 0.253 US visualization Poor vision ( Clear vision ( 1.04(0.52-2.08) 0.912 Depth ≤ 8 cm ( > 8 cm ( 5.13(2.55-10.33) <0.001* 3.19(1.44-7.09) 0.004*
- 5 LTP: local tumor progression; BMI: body mass index; CEA: carcinoembryonic antigen; EDH: extrahepatic disease; DFI: disease-free interval; TBS: tumor burden score; US: ultrasound; CEUS: contrast-enhanced ultrasound.
- 6 *p < 0.05 was considered a significant difference.
The subgroup analyses of LTP are summarized in Figure 3. In the subgroup of tumors with poor US visibility, 12 of 81 (14.8%) and 4 of 108 (3.7%) tumors developed LTP in the grayscale US-guided and Sonazoid CEUS-guided groups, respectively (p = 0.032) (Figure 4(A)). In the subgroup of tumors with a clear vision, no significant difference was found between the two groups (p = 0.559) (Figure 4(B)).
PHOTO (COLOR): Figure 3. Subgroup analyses of comparison of grayscale US-guided and Sonazoid CEUS-guided ablation for predicting local tumor progression-free survival (LTPFS) based on study variables among matched patients after propensity-score matching. BMI: body mass index; CEA: carcinoembryonic antigen; EHD: extrahepatic disease; DFI: disease-free interval; US: ultrasound.
PHOTO (COLOR): Figure 4. Kaplan–Meier curves of subgroup analysis for lesions with poor vision and clear vision on grayscale ultrasound (US). (A) local tumor progression-free survival (LTPFS) curve for lesions with poor vision on grayscale US. (B) LTPFS curve for lesions with clear vision on grayscale US.
Before PSM, IR occurred in 31.6% (50/158) of patients in the grayscale US-guided group and 42.7% (38/89) of patients in the Sonazoid CEUS-guided group (Figure 2(C), p = 0.001). After PSM, 38.9% (28/72) and 40.3% (29/72) of patients in the grayscale US-guided and the Sonazoid CEUS-guided group, respectively, developed IR. No significant differences were found between the two groups regarding IR (Figure 2(D); p = 0.511).
In univariate analyses, extrahepatic disease (EDH) and nodal status of the primary tumor were factors associated with IR (Supplementary material, Table S1). In multivariate analysis, EDH (HR, 2.070; 95% CI, 1.202–3.565; p = 0.009) was a significant factor associated with IR (Supplementary material, Table S2).
Before PSM, the incidence of complications was 6.32% (10/158) in the grayscale US-guided group and 10.11% (9/89) in the Sonazoid CEUS-guided group (p = 0.284). The minor and major complication rates were similar between the two groups. After PSM, there was no significant difference in the rates of major (5.6% vs. 6.9%, p = 0.374) or minor (4.2% vs. 2.8%, p > 0.99) complications related to ablation between the two groups.
Before PSM, the procedure time was significantly longer in the Sonazoid CEUS-guided group than in the gray scale-guided group [50.0 (range, 15-120) vs. 40.0 (range, 13–110), p < 0.001)]. After PSM, there was no statistically significant difference in procedure time between the two groups [42.5 (range, 15–110) vs. 45.0 (range, 13–120), p = 0.113]. Table 4 summarizes the comparison of the procedure time and incidence of complications between the two groups before and after PSM.
Table 4. the comparison of procedure time and incidence of complications in the two groups before and after PSM.
Before PSM After PSM Grayscale US-guided ( Sonazoid CEUS-guided ( Grayscale US-guided ( Sonazoid CEUS-guided ( Procedure time 40 (range, 13-110) 50 (range, 15-120) <0.001 42.5 (range, 15-110) 45 (range, 13-120) 0.113 Complications 10 9 0.284 7 7 > 0.99 Minor 4 3 > 0.99 3 2 > 0.99 Biloma 3 3 Moderate pleural effusion 1 1 Bile duct dilatation 1 2 1 Major 6 6 0.301 4 5 > 0.99 Liver infarction 1 1 Liver abscess 4 4 3 3 Encapsulated effusion 1 1 1 Pleural effusion 1 1
- 7 PSM: propensity score matching; US: ultrasound; CEUS: contrast-enhanced ultrasound.
- 8 *p < 0.05 was considered a significant difference.
Sonazoid CEUS-guided ablation achieved a non-inferior LTP and IR rate and did not increase the procedure time or complication rate compared to grayscale-guided ablation. Sonazoid CEUS with an extended window is a powerful adjunct for targeting liver metastases that are poorly visualized on grayscale US. For tumors with the poor vision on grayscale US, Sonazoid CEUS guidance helps obtain better local tumor control.
According to previous reports, the incidence of LTP after percutaneous thermal ablation for CRLM ranges from 4.1% to 32.6% [[
Compared with grayscale US, CEUS is more sensitive for detecting malignant liver tumors, particularly smaller tumors [[
A systematic review of 32 studies reported major complication rates of 4.6%, minor complication rates of 5.7%, and mortality rates of 0.15% in MWA [[
This study has some limitations. First, this was a retrospective study, and bias in the selection of different guidance approaches was inevitable. Although baseline information was balanced after PSM, the raw data were damaged because some patients were excluded from the final analysis. Second, the evaluation of tumor visibility based on the decisions of radiologists is subjective, which may be inevitable because of the subjective nature of US examinations. Third, 1-month follow-up may not be sufficient for detecting residual tumors at the ablation site, and the definition of complete ablation is a relative concept.
In conclusion, grayscale US or Sonazoid CEUS guidance for the percutaneous ablation of CRLM does not appear to affect LTP, IR, or complications. The use of Sonazoid CEUS guidance was conducive to decreasing the LTP rate for tumors with poor vision on grayscale US and detecting more tumors for curative ablation. Thus, we recommend Sonazoid CEUS as a better choice for tumors with poor vision on grayscale US.
No potential conflict of interest was reported by the author(s).
Data cannot be shared publicly because the data from this study may contain potentially sensitive patient information. Data are available from the corresponding author upon request.
By Si Qin; Jingwen Zhou; Rui Cui; Yao Chen; Yimin Wang and Guangjian Liu
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