Abstract
Background
Laparoscopic resection is the standard treatment for resectable colorectal liver metastases (CRLM). While the safety profile using combined ablation and resection (CARe) to treat CRLM has been documented, its efficacy has not been compared with that of resection alone in the laparoscopic setting. The aim of this study was to compare the short- and long-term outcomes of laparoscopic CARe with those of laparoscopic resection alone for multiple CRLM.
Methods
Patients with multiple CRLM who underwent laparoscopic resection at three medical centres from 2018 to 2023 were included. Perioperative and oncological outcomes were compared between the two groups. Propensity score matching (PSM) was performed.
Results
Of the 218 included patients, 67 (30.7%) underwent laparoscopic CARe, and 151 (69.3%) underwent laparoscopic resection alone. After PSM, 49 matched pairs of patients were included for each group. The postoperative complication rate was similar between the two groups (P = 0.964). The median recurrence-free survival (RFS) (11.8 vs. 12.1 months, P = 0.759) and overall survival (OS) (not reached, P = 0.656) were not significantly different between the two groups. Multivariate analysis revealed that ≥ 4 CRLM [hazard ratio (HR) = 1.86, 95% confidence interval (CI) 1.09–3.15, P = 0.022] and synchronous metastases (HR = 2.00, 95% CI 1.21–3.31, P = 0.007) and was independently associated with RFS, whereas bilobar distribution (HR = 3.20, 95% CI 1.04–9.82, P = 0.042) was independently associated with OS. No statistically significant differences were observed in the timing of recurrence (P = 0.666), the site of recurrence (P = 0.279), or the treatment administered after recurrence (P = 0.641) between the two groups.
Conclusions
Laparoscopic CARe may be considered as a useful treatment strategy for multiple CRLM.
Graphical abstract
Keywords: Colorectal liver metastases, Laparoscopy, Minimally invasive surgery, Ablation, Liver resection
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related death worldwide [1]. Liver metastases occur in approximately half of patients with colorectal cancer [2, 3]. Additionally, colorectal liver metastases (CRLM) are also the leading cause of colorectal cancer-induced death. Liver resection is the most effective treatment for CRLM [4]. The 5 year survival rate of patients with CRLM who undergo radical surgery can reach 50%, which is significantly higher than that of patients who do not receive surgery [5, 6]. However, more than 70% of patients who undergo resection will experience recurrence, most frequently in the liver [7]. Fortunately, repeat resection for recurrent CRLM still yields perioperative and oncologic outcomes comparable to those of the initial resection [8–10]. Therefore, the preservation of adequate liver parenchyma and a reduction in postoperative abdominal adhesion are essential for the management of CRLM.
Compared with open surgery, laparoscopic resection can reduce postoperative abdominal adhesions and provide favourable conditions for repeat resection in patients with recurrent CRLM. Laparoscopic surgery also improves perioperative outcomes, accelerates postoperative recovery, and shortens the time interval between surgery and adjuvant treatment [11–14]. Currently, laparoscopic hepatectomy has become the standard treatment for CRLM.
For resectable multiple CRLM, combined ablation and resection (CARe) preserves more of the liver parenchyma, thereby avoiding major hepatectomy and reducing the incidence of postoperative liver failure [15]. For unresectable multiple CRLM, CARe provides an opportunity for radical surgery and yields perioperative and long-term outcomes comparable to those of patients with resectable CRLM who undergo resection alone [16]. CARe has been shown to be a safe alternative for the treatment of multiple CRLM [15–24]. Laparoscopic CARe has the advantages of both preserving more of the liver parenchyma and minimal invasion, and it has recently begun to be implemented in the treatment of CRLM [25, 26].
Laparoscopic ablation is preferred when the target lesion’s location is unfavourable, when there is a risk of thermal damage to adjacent organs or bile ducts, or when other abdominal surgeries are being performed. Moreover, recent studies have demonstrated that laparoscopic ablation is as effective as open or percutaneous ablation, further supporting its use in these scenarios [27, 28].
Although the efficacy and safety of laparoscopic resection and laparoscopic ablation have been well established, the results of the use of laparoscopic CARe in the treatment of multiple CRLM remain uncertain. The aim of this study was to compare the short-term and long-term outcomes of laparoscopic CARe with those of laparoscopic resection alone for the treatment of multiple CRLM.
Materials and methods
Study design and patients
This multicentre, retrospective cohort study was approved by the Institutional Ethics Review Committee of the hospital. Patients with multiple CRLM who underwent laparoscopic resection at the First Affiliated Hospital of University of Science and Technology of China, Anhui Provincial Cancer Hospital, and the Affiliated Hospital of Qingdao University from 2018 to 2023 were included. Patients were divided into laparoscopic CARe and laparoscopic resection groups on the basis of the surgical procedure employed. All patients were pathologically confirmed to have colorectal liver metastases. Patients who underwent percutaneous ablation combined with laparoscopic resection or those requiring conversion from laparoscopic to open surgery were excluded.
Surgical procedure and definition
The final decision regarding the surgical procedure for all patients was made by a multidisciplinary team after a comprehensive preoperative evaluation. CARe was conducted when at least one lesion measuring less than 20 mm was deemed technically unresectable or would result in insufficient future liver remnant. The detailed procedures are described in previous studies [23, 25]. In brief, a 5-trocar approach with an abdominal CO2 pressure of 12–14 mmHg was used in laparoscopic surgery. After liver mobilization, the extent of resection was planned based on preoperative imaging and intraoperative ultrasound scanning; then, the liver parenchyma was transected via an ultrasonic scalpel or/and a Cavitron ultrasonic surgical aspirator (CUSA). Laparoscopic contrast-enhanced ultrasound was used to locate the lesions needing ablation and to determine the puncture location and angle. The sequence of ablation and resection was determined by the operator on the basis of the intraoperative conditions. Ablation with multiple angles was performed to ensure that the ablation margin extended at least 5 mm beyond the lesions when necessary.
Synchronous liver metastases were defined as those detected at the time of colorectal cancer diagnosis or surgery for the primary lesion [29]. The difficulty of laparoscopic liver resection was graded according to the Iwate score [30, 31]. Burden of disease was computed using the formula: (tumour burden score)2 = (maximum diameter)2 + (number of leisons)2 [32]. Postoperative complications within 30 days were graded according to the Clavien-Dindo classification system [33]. Overall survival (OS) was calculated from the date of operation to the date of death. Recurrence-free survival (RFS) was calculated from the date of operation to either the date of disease recurrence (as determined by radiographic findings) or the date of death. Recurrence was divided into early (RFS < 6 months), intermediate (RFS 6–12 months), and later (RFS ≥ 12 months) recurrence [34].
Outcomes and follow-up
The primary outcome was postoperative complications within 30 days. The secondary outcomes included operation time, blood loss, postoperative hospital stay, RFS, OS, recurrence patterns, and post-recurrence treatment.
Serum CEA and CA199 levels and CT (or MRI) assessments of the lung, abdomen, and pelvis were performed every 3 months for the first 2 years after surgery and then twice a year thereafter. The last follow-up time was December 2024.
Statistical analysis
The data were analysed using the statistical software package R version 4.4.2 (http://www.R-project.org). Nearest neighbour matching with an optimal calliper of 0.2 was employed for 1:1 propensity score matching (PSM). Matching parameters used to reduce confounding biases in the propensity model included age, sex, BMI, location of primary tumour, lymph node metastasis, type of metastases, metastatic distribution, metastatic number, maximum diameter, tumour burden score, difficulty-score, CEA level, neoadjuvant treatment, and simultaneous colorectal resection. Continuous variables were analysed via either Student’s t test or the Mann–Whitney U test. For categorical variables, the chi-square test, Mann‒Whitney U test, or Fisher’s exact test was utilized. The results are presented as the mean ± standard deviation (SD)/median (interquartile range, IQR)/n (%) where appropriate. The Kaplan‒Meier method with the log-rank test was used to compare PFS and OS between the two groups. The Cox proportional hazards regression model was used to identify the factors associated with patient survival. Statistical significance was considered at P < 0.05.
Results
Baseline characteristics
A total of 698 consecutive patients underwent hepatectomy during the study period. Ultimately, 151 patients who underwent laparoscopic resection and 67 patients who underwent laparoscopic CARe were enrolled for analysis (Fig. 1). In the laparoscopic resection group, the 151 patients had 412 lesions identified and resected. In the laparoscopic CARe group, the 67 patients had 296 lesions identified, including 160 lesions that were resected and 136 lesions that were ablated.
Fig. 1.
Study flow chart. CRLM colorectal liver metastases, CARe combined ablation and resection
In the whole cohort, patients in the laparoscopic CARe group presented a greater number of lesions (3 vs. 2, P < 0.001), greater bilobar distribution (67.16% vs. 40.46%, P < 0.001), and smaller tumour diameters (2.0 vs. 2.7 cm, P = 0.013) than did those in the laparoscopic resection group. No significant differences were observed for the other variables. After PSM, 49 matched pairs of patients were included for each group. The demographics and baseline characteristics of the patients before and after PSM are shown in Table 1.
Table 1.
Demographics and baseline characteristics before and after propensity score matching
| Variable | Before PSM | After PSM | ||||||
|---|---|---|---|---|---|---|---|---|
| Laparoscopic resection (n = 151) | Laparoscopic CARe (n = 67) | P | SMD | Laparoscopic resection (n = 49) | Laparoscopic CARe (n = 49) | P | SMD | |
| Age, years | 59.54 ± 8.33 | 57.19 ± 9.93 | 0.094 | 0.237 | 57.41 ± 9.62 | 58.90 ± 9.22 | 0.436 | 0.162 |
| Sex | 0.453 | 0.107 | 1.000 | 0.000 | ||||
| Female | 42 (27.81) | 22 (32.84) | 16 (32.65) | 16 (32.65) | ||||
| Male | 109 (72.19) | 45 (67.16) | 33 (67.35) | 33 (67.35) | ||||
| BMI, kg/m2 | 24.41 ± 3.08 | 24.47 ± 3.39 | 0.908 | 0.016 | 25.07 ± 3.07 | 24.28 ± 3.56 | 0.245 | 0.221 |
| Primary tumor location | 0.096 | 0.245 | 0.840 | 0.041 | ||||
| Rectum | 86 (56.95) | 30 (44.78) | 23 (46.94) | 24 (48.98) | ||||
| Colon | 65 (43.05) | 37 (55.22) | 26 (53.06) | 25 (51.02) | ||||
| Lymph nodal metastasis | 0.269 | 0.171 | 0.825 | 0.044 | ||||
| No | 52 (34.44) | 18 (26.87) | 14 (28.57) | 15 (30.61) | ||||
| Yes | 99 (65.56) | 49 (73.13) | 35 (71.43) | 34 (69.39) | ||||
| Type of metastases | 0.091 | 0.260 | 1.000 | 0.000 | ||||
| Metachronous | 68 (45.03) | 22 (32.84) | 21 (42.86) | 21 (42.86) | ||||
| Synchronous | 83 (54.97) | 45 (67.16) | 28 (57.14) | 28 (57.14) | ||||
| Distribution | < 0.001 | 0.782 | 0.839 | 0.041 | ||||
| Unilobar | 105 (69.54) | 22 (32.84) | 22 (44.90) | 21 (42.86) | ||||
| Bilobar | 46 (30.46) | 45 (67.16) | 27 (55.10) | 28 (57.14) | ||||
| Number of lesions | 2.00 (2.00, 3.00) | 3.00 (2.00, 5.00) | < 0.001 | 0.482 | 3.00 (2.00, 4.00) | 3.00 (2.00, 4.00) | 0.878 | 0.040 |
| Max diameter, cm | 2.70 (1.75, 3.65) | 2.00 (1.50, 2.85) | 0.013 | 0.270 | 2.50 (1.50, 3.20) | 2.10 (1.50, 2.90) | 0.368 | 0.023 |
| Tumor burden score | 3.72 (3.01, 5.00) | 4.18 (3.34, 6.15) | 0.057 | 0.315 | 4.03 (2.97, 4.88) | 3.91 (2.83, 4.72) | 0.782 | 0.068 |
| Difficulty score | 5.00 (3.00, 6.00) | 5.00 (3.00, 6.00) | 0.412 | 0.144 | 5.00 (3.00, 6.00) | 5.00 (3.00, 6.00) | 0.805 | 0.072 |
| CEA, ng/mL | 7.20 (3.51, 31.25) | 7.17 (3.53, 20.88) | 0.603 | 0.056 | 9.33 (3.93, 38.99) | 7.20 (3.41, 24.07) | 0.240 | 0.066 |
| Simultaneous colorectal resection | 0.634 | 0.071 | 0.825 | 0.045 | ||||
| No | 101 (66.89) | 47 (70.15) | 34 (69.39) | 35 (71.43) | ||||
| Yes | 50 (33.11) | 20 (29.85) | 15 (30.61) | 14 (28.57) | ||||
| Neoadjuvant therapy | 0.410 | 0.126 | 1.000 | 0.000 | ||||
| No | 49 (32.45) | 18 (26.87) | 14 (28.57) | 14 (28.57) | ||||
| Yes | 102 (67.55) | 49 (73.13) | 35 (71.43) | 35 (71.43) | ||||
| Adjuvant therapy | 0.756 | 0.045 | 0.806 | 0.049 | ||||
| No | 31 (20.53) | 15 (22.39) | 10 (20.41) | 11 (22.45) | ||||
| Yes | 120 (79.47) | 52 (77.61) | 39 (79.59) | 38 (77.55) | ||||
Statistically significant results are reported in bold
Results in table are expressed as mean ± SD/median (IQR)/n (%)
PSM propensity score matching, CARe combined ablation and resection, BMI body mass index, CEA carcinoembryonic antigen
Perioperative outcomes
There was no mortality within 90 days in either the laparoscopic or the open group. The postoperative complication rates were comparable between the laparoscopic CARe and laparoscopic resection groups in both the whole (P = 0.413) and matched (P = 0.964) cohorts.
Before PSM, the operation time was longer in the laparoscopic CARe group (235 vs. 200 min, P = 0.020). However, the blood loss amount (100 vs. 100 mL, P = 0.608), blood transfusion rate (2.99% vs. 5.30%, P = 0.687), and postoperative hospital stay (7 vs. 7 days, P = 0.993) were comparable between the two groups. After PSM, the operation time (217.0 vs. 220.0 min, P = 0.332), blood loss amount (100 vs. 60 mL, P = 0.944), blood transfusion rate (4.08% vs. 4.08%), and postoperative hospital stay (7 vs. 6 days, P = 0.808) were similar between the two groups (Table 2).
Table 2.
Perioperative outcomes before and after propensity score matching
| Variables | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| Laparoscopic resection (n = 151) | Laparoscopic CARe (n = 67) | P | Laparoscopic resection (n = 49) | Laparoscopic CARe (n = 49) | P | |
| Operation time, min | 200.00 (130.00, 301.00) | 235.00 (181.50, 331.00) | 0.020 | 217.00 (160.00, 305.00) | 220.00 (180.00, 332.00) | 0.332 |
| Blood loss, mL | 100.00 (50.00, 100.00) | 100.00 (50.00, 100.00) | 0.608 | 100.00 (50.00, 100.00) | 60.00 (50.00, 100.00) | 0.944 |
| Blood transfusion | 0.687 | 1.000 | ||||
| No | 143 (94.70) | 65 (97.01) | 47 (95.92) | 47 (95.92) | ||
| Yes | 8 (5.30) | 2 (2.99) | 2 (4.08) | 2 (4.08) | ||
| Complications (Clavien–Dindo) | 0.413 | 0.964 | ||||
| 1 | 29 (19.21) | 22 (32.84) | 11 (22.45) | 15 (30.61) | ||
| 2 | 19 (12.58) | 5 (7.46) | 5 (10.20) | 5 (10.20) | ||
| 3 | 1 (0.66) | 1 (1.49) | 0 (0.00) | 1 (2.04) | ||
| 4 | 1 (0.66) | 0 (0.00) | ||||
| Length of stay, days | 7.00 (5.00, 10.00) | 7.00 (5.00, 9.00) | 0.993 | 7.00 (5.00, 10.00) | 6.00 (5.00, 10.00) | 0.808 |
Statistically significant results are reported in bold
Results in table are expressed as median (IQR)/n (%)
PSM propensity score matching, CARe combined ablation and resection
Survival analysis
The median follow-up time of all patients was 27.5 months. The median RFS was shorter in the laparoscopic CARe group than in the laparoscopic resection group (11.8 vs. 17.0 months, P = 0.003). The median OS in the laparoscopic resection group was not reached, and there was no significant difference between the two groups (P = 0.461) (Fig. 2). After PSM, there was no significant difference in the median RFS (11.8 vs. 12.1 months, P = 0.759) or OS (not reached, P = 0.656) between the two groups (Fig. 3).
Fig. 2.
Recurrence-free survival, overall survival before propensity score matching. A recurrence-free survival (P = 0.003). B overall survival (P = 0.690). CARe combined ablation and resection
Fig. 3.
Recurrence-free survival, overall survival after propensity score matching. A recurrence-free survival (P = 0.759). B overall survival (P = 0.656). CARe combined ablation and resection
According to the Cox regression model, before PSM, multivariate analysis revealed that ≥ 4 metastases [hazard ratio (HR) = 1.60, 95% confidence interval (CI) 1.08–2.38, P = 0.019] was independently associated with RFS. After PSM, multivariate analysis revealed that ≥ 4 metastases (HR = 1.86, 95% CI 1.09–3.15, P = 0.022) and synchronous metastases (HR = 2.00, 95% CI 1.21–3.31, P = 0.007) was independently associated with RFS (Table 3). Before PSM, multivariate analysis revealed that simultaneous colorectal resection (HR = 2.44, 95% CI 1.33–4.48, P = 0.004) was associated with OS. After PSM, multivariate analysis revealed that bilobar distribution (HR = 3.20, 95% CI 1.04–9.82, P = 0.042) was associated with OS (Table 4).
Table 3.
Univariate and multivariate analysis of recurrence-free survival before and after propensity score matching
| Variables | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| Univariate P | Multivariate | Univariate P | Multivariate | |||
| P | HR (95%CI) | P | HR (95%CI) | |||
| Male | 0.361 | 0.412 | ||||
| Age ≥ 65 years | 0.851 | 0.673 | ||||
| BMI ≥ 24 kg/m2 | 0.377 | 0.568 | ||||
| Colon | 0.107 | 0.223 | ||||
| Lymph nodal metastasis | 0.438 | 0.346 | ||||
| Synchronous metastases | 0.002 | 0.069 | 1.44 (0.97–2.13) | 0.004 | 0.007 | 2.00 (1.21–3.31) |
| Bilobar | < 0.001 | 0.063 | 1.41 (0.98–2.02) | 0.085 | 0.133 | 1.45 (0.89–2.35) |
| Number ≥ 4 | < 0.001 | 0.019 | 1.60 (1.08–2.38) | 0.002 | 0.022 | 1.86 (1.09–3.15) |
| Diameter ≥ 3 cm | 0.432 | 0.626 | ||||
| Tumor burden score ≥ 6 | 0.012 | 0.569 | 1.14 (0.73–1.78) | 0.060 | 0.483 | 1.31 (0.61–2.80) |
| Difficulty score ≥ 9 | 0.555 | 0.922 | ||||
| CEA ≥ 10 ng/mL | 0.233 | 0.494 | ||||
| Simultaneous colorectal resection | 0.052 | 0.678 | 1.09 (0.74–1.60) | 0.129 | ||
| Laparoscopic CARe | 0.004 | 0.262 | 1.24 (0.85–1.80) | 0.759 | 0.776 | 1.07 (0.67–1.72) |
| Neoadjuvant therapy | 0.129 | 0.144 | ||||
| Adjuvant therapy | 0.223 | 0.558 | ||||
Statistically significant results are reported in bold
PSM propensity score matching, HR hazard ratio, CI confidence interval, BMI body mass index, CEA carcinoembryonic antigen, CARe combined ablation and resection
Table 4.
Univariate and multivariate analysis of overall survival before and after propensity score matching
| Variables | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| Univariate P | Multivariate | Univariate P | Multivariate | |||
| P | HR (95%CI) | P | HR (95%CI) | |||
| Male | 0.900 | 0.533 | ||||
| Age ≥ 65 years | 0.523 | 0.719 | ||||
| BMI ≥ 24 kg/m2 | 0.457 | 0.837 | ||||
| Colon | 0.049 | 0.058 | 1.87 (0.98–3.57) | 0.442 | ||
| Lymph nodal metastasis | 0.661 | 0.658 | ||||
| Synchronous metastases | 0.366 | 0.879 | ||||
| Bilobar | 0.029 | 0.083 | 1.80 (0.93–3.50) | 0.020 | 0.042 | 3.20 (1.04–9.82) |
| Number ≥ 4 | 0.075 | 0.324 | 1.41 (0.71–2.82) | 0.027 | 0.284 | 1.71 (0.64–4.53) |
| Diameter ≥ 3 cm | 0.526 | 0.768 | ||||
| Tumor burden score ≥ 6 | 0.439 | 0.368 | ||||
| Difficulty score ≥ 9 | 0.448 | 0.998 | ||||
| CEA ≥ 10 ng/mL | 0.291 | 0.601 | ||||
| Simultaneous colorectal resection | 0.001 | 0.004 | 2.44 (1.33–4.48) | 0.011 | 0.051 | 2.64 (0.99–7.03) |
| Laparoscopic CARe | 0.691 | 0.321 | 0.68 (0.32–1.45) | 0.656 | 0.680 | 0.820 (0.32–2.10) |
| Neoadjuvant therapy | 0.756 | 0.502 | ||||
| Adjuvant therapy | 0.862 | 0.760 | ||||
Statistically significant results are reported in bold
PSM propensity score matching, HR hazard ratio, CI confidence interval, BMI body mass index, CEA carcinoembryonic antigen, CARe combined ablation and resection
Recurrence patterns and treatment
At the last follow-up, a total of 152 out of 218 patients had experienced recurrence. With respect to the timing of recurrence, 59 (38.82%) patients experienced early recurrence, 43 (28.29%) experienced intermediate recurrence, and 50 (32.89%) experienced later recurrence. With respect to the site of recurrence, 77 (50.66%) had intrahepatic recurrence, 45 (29.61%) had extrahepatic recurrence, and 30 (19.74%) had intra- and extrahepatic recurrence. Among patients who experienced recurrence, 36 (23.68%) underwent repeat liver resection, 12 (7.89%) underwent liver ablation, 82 (53.95%) patients received systemic therapy, and 22 (14.47%) received other treatments.
Before PSM, the recurrence rate was higher in the laparoscopic CARe group than in the laparoscopic resection group (80.60% vs. 64.90%, P = 0.020). After PSM, the recurrence rate was the same between the two groups (75.51% vs. 71.43%, P = 0.647). No statistically significant differences were observed in the timing of recurrence, the site of recurrence, or the treatment administered after recurrence between the two groups before or after PSM (Table 5).
Table 5.
Recurrence patterns before and after propensity score matching
| Variables | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| Laparoscopic resection (n = 151) | Laparoscopic CARe (n = 67) | P | Laparoscopic resection (n = 49) | Laparoscopic CARe(n = 49) | P | |
| Recurrence | 0.020 | 0.647 | ||||
| No | 53 (35.10) | 13 (19.40) | 14 (28.57) | 12 (24.49) | ||
| Yes | 98 (64.90) | 54 (80.60) | 35 (71.43) | 37 (75.51) | ||
| Recurrence timinga | 0.568 | 0.666 | ||||
| Early | 29(29.59) | 20(37.04) | 14 40.00) | 13 (35.14) | ||
| Intermediate | 30(30.61) | 13(24.07) | 10 (28.57) | 11 (29.73) | ||
| Later | 39(39.80) | 21(38.89) | 11 (31.43) | 13 (35.14) | ||
| Recurrence sitea | 0.126 | 0.279 | ||||
| Intrahepatic | 44 (44.90) | 33 (61.11) | 17 (48.57) | 22 (59.46) | ||
| Extrahepatic | 31 (31.63) | 14 (25.93) | 11 (31.43) | 11 (29.73) | ||
| Intra- and extrahepatic | 23 (23.47) | 7 (12.96) | 7 (20.00) | 4 (10.81) | ||
| Recurrence treatmenta | 0.446 | 0.641 | ||||
| Liver resection | 21 (21.43) | 15 (27.78) | 7 (20.00) | 10 (27.03) | ||
| Liver ablation | 6 (6.12) | 6 (11.11) | 2 (5.71) | 4 (10.81) | ||
| Systemic therapy | 57 (58.16) | 25 (46.30) | 20 (57.14) | 15 (40.54) | ||
| Others | 14 (14.29) | 8 (14.81) | 6 (17.14) | 8 (21.62) | ||
Statistically significant results are reported in bold
Results in table are expressed as n (%)
PSM propensity score matching, CARe combined ablation and resection
aPercentage and comparison of those patients who recurrent
Discussion
This study demonstrated that the use of laparoscopic CARe to treat CRLM yielded similar perioperative and oncological outcomes to those of laparoscopic resection alone after PSM. This is the first study to compare the safety and efficacy of these two types of surgery for multiple CRLM via PSM analysis.
Several previous studies have compared the perioperative outcomes of CARe with those of resection alone. Liu et al. [15] showed that CARe was associated with a reduced major hepatectomy rate (5.2% vs. 21.9%, P = 0.001), a lower incidence of postoperative hepatic insufficiency (0.0% vs. 5.2%, P = 0.023), and a shorter postoperative hospital stay (7 vs. 8 days, P = 0.019). de Graaff et al. [20] reported similar results, as they found that the incidence of liver failure after CARe was lower than that after resection alone (1.9% vs. 0.6%, P = 0.017). Xourafas et al. [19] reported that CARe could reduce postoperative morbidity (22% vs. 13%, P < 0.0001). Karanicolas et al. [21] found lower blood loss (300 vs. 500 mL, P < 0.01) and a shorter length of hospital stay (7 vs. 9 days, P < 0.01) in the CARe group. Although the results varied among these studies, it is clear that CARe offers advantages in terms of short-term surgical outcomes. However, the perioperative outcomes of laparoscopic CARe were not superior to those of laparoscopic resection in our study. Before PSM, the operative time significantly increased in the laparoscopic CARe group. After PSM, the operation time was still longer in the laparoscopic CARe group, but the difference was not significantly different. There may be two primary reasons for the longer operation time in the laparoscopic CARe group. First, a greater number of lesions requiring surgical intervention were present in the combined CARe group in this study. Additionally, laparoscopic ablation demands more specialized expertise, precise planning for ablation, and navigation of the learning curve associated with laparoscopic ablation techniques [28]. Collectively, despite a higher bilobar involvement rate and a greater number of lesions, laparoscopic CARe demonstrated no adverse impact on perioperative outcomes. These findings support its role as a safe and effective minimally invasive strategy for managing multiple CRLM.
Almost all previous studies reported no difference in long-term oncological outcomes between CARe and resection alone for patients with CRLM [15–24]. Similar results were found in our matched cohort, with comparable oncological outcomes between the laparoscopic CARe group and the laparoscopic resection group. However, the median RFS was shorter in the laparoscopic CARe group before PSM. The poorer RFS observed in the laparoscopic CARe group before PSM may be attributed to a larger number of CRLM and a higher proportion of bilobar distribution in these patients. The Cox proportional hazards regression model confirmed this possibility, with multivariate analysis revealing that the number of metastases was independently associated with RFS. This may be also attributed to the higher tumour burden leading to earlier recurrence in the laparoscopic CARe group, as well as suboptimal microscopic margin control associated with ablation. Although the number of metastases is no longer a limitation of surgery for CRLM, it remains a negative prognostic factor [36]. Masuda et al. [35] reported that for patients with < 4 lesions, the OS in the CARe group was worse than that in the resection group (5 year OS: 34.4% vs. 58.9%, P = 0.007). In contrast, for patients with ≥ 4 tumours, the OS was comparable between the two groups (5 year OS: 31.9% vs. 34.1%, P = 0.48). Furthermore, although the median RFS was shorter in the laparoscopic CARe group before PSM in our study, the two groups had similar recurrence patterns and OS. However, the median follow-up of 27.5 months, along with a considerable number of censored patients at early time points in the Kaplan-Meier curves, warrants cautious interpretation of the OS results.
Similar to previous reports, the most common recurrence site after hepatectomy was intrahepatic [17, 37]. The study by Imai et al. [17] showed no statistically significant difference in the recurrence site between the CARe group and the resection group, which aligns with our findings. Additionally, we found no significant differences in the timing or treatment of recurrence between the two groups. This may account for the lack of a significant difference in long-term survival between the two groups, despite the CARe group having more lesions, greater bilobar involvement, and a higher pre-matching recurrence rate. This observation is likely due to the availability of comparable and effective post-recurrence treatment options, which contributed to similar survival outcomes in both groups [34].
Laparoscopic CARe has been applied to the management of CRLM [25, 26], but few relevant studies exist. Serenari et al. [38] investigated the factors associated with textbook outcomes in liver surgery [39] following CARe for CRLM. Multivariate analysis revealed that the use of a minimally invasive approach was significantly associated with the achievement of optimal outcomes. Vandeputte et al. [26] reported that the minimally invasive approach led to improved perioperative outcomes. There are currently no studies comparing the outcomes between laparoscopic CARe and laparoscopic resection alone for CRLM. We believe that our findings support the efficacy and safety of laparoscopic CARe for CRLM from another perspective.
As mentioned previously, CARe is frequently employed in patients with high tumor burden. For these patients, numerous treatment options exist, including chemotherapy, molecular targeted therapy, immunotherapy, TACE, SBRT. However, this approach raises several potential concerns. First, it risks missing the ‘window of opportunity’ for surgery. Some patients experience early disease progression due to tumor resistance to chemotherapy, whereas others achieve a clinical complete response, which makes accurate delineation of surgical resection margins particularly challenging [40]. Second, chemotherapy-induced liver injury may increase the complexity of surgery and the risk of postoperative complications. For instance, oxaliplatin-associated sinusoidal injury has been shown to increase intraoperative blood loss and postoperative morbidity [41]. Moreover, studies have shown that oxaliplatin-related sinusoidal obstruction syndrome is also linked to earlier disease recurrence after radical surgery [42]. Recent evidence further suggests that perioperative chemotherapy does not confer additional survival benefits for patients with resectable CRLM, as demonstrated in both real-world data and randomized controlled trials (e.g., EORTC 40983 and JCOG0603) [43–45]. In line with this understanding, our institution’s multidisciplinary team prioritizes radical liver resection. Therefore, patients with CRLM considered suitable for surgical intervention, particularly those with resectable or borderline resectable disease, are prioritized for upfront surgery. Therefore, in our cohort, very few patients received preoperative treatments such as TACE, TARE, or SBRT, due to their potential to interfere with subsequent surgical procedures.
As previously reported, ablation has been shown to stimulate the tumor immune microenvironment and enhance the anti-tumor effects of immunotherapy [46]. Ablation elicits the release of tumor-associated antigens through physical destruction of tumor tissue. These released antigens are subsequently captured, processed, and presented to T cells, particularly CD8 + cytotoxic T lymphocytes, by antigen-presenting cells, thereby activating a specific anti-tumor immune response [47, 48]. Furthermore, thermal ablation also enhances the infiltration of anti-tumor immune cells, such as NK cells and CD8 + cytotoxic T lymphocytes [49, 50]. Immune checkpoint inhibitors (ICIs) function by blocking inhibitory signals within the immune system, thereby restoring the anti-tumor activity of T cells. Therefore, ablation may foster a favorable tumor microenvironment for immune cells, and its combination with ICIs would be particularly beneficial. The combination of ablation and ICIs has been demonstrated to enhance T cell-mediated anti-tumor immunity by promoting Th1 cell polarization, characterized by increased Th1 cytokine production and concomitant reduction of Th2 cytokines [51]. Consequently, we hypothesize that combining CARe with ICIs may represent a potential therapeutic strategy to improve outcomes in CRLM. Although the combination of ICIs and ablation exhibits synergistic anti-tumor effects in preclinical and clinical studies, robust clinical evidence supporting its efficacy remains limited. Future investigation into the combination of CARe and ICIs represents a notably interesting and important research avenue.
This study has several limitations. First, this study was a retrospective study with inevitable selection bias. Even with careful PSM analysis, selection bias may not have been completely avoided. Further prospective controlled studies with large sample sizes are needed to provide high-level clinical evidence. Second, the follow-up duration for survival in this study was relatively short. Hence, the long-term outcomes should be interpreted with caution. Third, our results may be influenced by the surgeons’ experience with laparoscopic ablation, which requires specialized training. Finally, there is no consensus on the selection criteria for ablation lesions at present, and this criterion is entirely determined by doctors on the basis of their experience.
Conclusion
In conclusion, this study demonstrated that laparoscopic CARe provides adequate safety and efficacy. Our findings suggest that laparoscopic CARe may be considered a viable treatment strategy for managing multiple CRLM.
Funding
This work was supported by the National Natural Science Foundation of China (No. 82170618), Anhui University Outstanding Youth Research Project (2024AH020016), Research Institute of Pioneer Medicine and Frontier Technology, Hefei Comprehensive National Science Center (2023IHM01020), Key Research and Development Program of Anhui Province (202204295107020019).
Declarations
Disclosures
Huachuan Song, Zhipeng Li, Shenyu Zhang, Xinyu Ling, Long Chen, Yongshuai Wang, Feng Zhang, Ruipeng Song, Fanzheng Meng, Lianxin Liu, Zehua Wu, Bing Han, and Jizhou Wang have no conflicts of interest to disclose.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Huachuan Song, Zhipeng Li and Shenyu Zhang have contributed equally to this work.
Contributor Information
Bing Han, Email: hanbing@qduhospital.cn.
Jizhou Wang, Email: wangjoe@ustc.edu.cn.
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