Mid- to Long-term Outcome of Laparoscopic Ultrasound-guided Radiofrequency Ablation for Malignant Hepatic Tumors

doi:10.21203/rs.3.rs-2989511/v1

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Mid- to Long-term Outcome of Laparoscopic Ultrasound-guided Radiofrequency Ablation for Malignant Hepatic Tumors

https://doi.org/10.21203/rs.3.rs-2989511/v1

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Surgical resection remains the gold standard for the treatment of patients with hepatocellular carcinoma (HCC) and liver metastases (LM), especially those from colorectal cancers. However, the majority of patients are not candidates for surgical resection due to unresectable disease, the presence of extrahepatic disease, or concurrent medical conditions. Several authors have reported the long-term outcome of fully percutaneous radiofrequency ablation (RFA) for HCC and colorectal cancer liver metastasis (CRCLM). However, there are only a few studies on long-term outcomes, including local recurrence and survival, of fully laparoscopic ultrasound-guided radiofrequency ablation (LURFA) for patients with malignant hepatic tumors. This study is to evaluate the long-term outcomes of LURFA in malignant hepatic tumors that are difficult to be curatively treated with the percutaneous approach or laparoscopic liver resection (LLR) according to IWATE Criteria and the results show that full LURFA for malignant hepatic tumors is associated with low morbidity, low LR, and feasible outcomes even after long-term follow-up. It requires advanced skills for clearly identifying the target tumor, precise needle placement and constant real-time intraoperative ultrasound monitoring to achieve complete ablation and an effective oncological outcome.

Health sciences/Oncology

Health sciences/Oncology/Surgical oncology

Radiofrequency ablation (RFA) is an alternative therapy for hepatocellular carcinoma (HCC) and metastasis when resection cannot be performed. It has also been shown to achieve effective and reproducible local tumor control with minimal morbidity in patients with small HCC and LM (8). Ultrasound-guided RFA of hepatic tumors can be performed by percutaneous, laparoscopic, and open surgical approaches. Percutaneous RFA has generally been accepted as an effective therapy for unresected primary and metastatic hepatic tumors (9, 10). However, this procedure has limitations when the tumor is located close to the liver surface and situated adjacent to the diaphragm or internal organs. For these tumors, LURFA can offer a safer and more effective approach. Additionally, the laparoscopic approach allows the surgeon to inspect the peritoneal cavity and discover more tiny and satellite tumors. LURFA has also been shown to reduce procedural morbidity and mortality compared to the open surgical approach (11–13). Nevertheless, laparoscopic resection of tumors in upper liver segments is associated with higher technical difficulties (14–16). In this situation, LURFA can be concomitant with surgical resection to achieve curative treatment with low morbidity.

Several authors have reported the long-term outcome of fully percutaneous RFA for HCC and colorectal cancer liver metastasis (CRCLM) (17, 18). However, there are only a few studies on long-term outcomes, including local recurrence and survival, of fully laparoscopic RFA for patients with malignant hepatic tumors (19, 20).

The purpose of this study is to evaluate the outcome of patients treated fully with LURFA for malignant hepatic tumors that are difficult or impossible to cure with the percutaneous approach or laparoscopic liver resection (LLR) with a long-term follow-up for up to 10 years after treatment.

Patients

This study was approved by the Institutional Review Board. This was a retrospective analysis of prospectively maintained data of using LRFA for malignant hepatic tumors, in which the surgeries were performed between January 2011 and December 2016, and the patients had follow-up until December 2021. The treatment approaches of the patients were discussed in the multidisciplinary meeting. The treatability by LURFA was based on tumor location, size, and distribution. All procedures were performed with curative intent.

Sixty-two consecutive patients with malignant hepatic tumors (37 hepatocellular carcinomas and 25 metastatic colorectal cancers) who could not be curatively treated by percutaneous RFA or LLR were enrolled and completely underwent LURFA. Patients who had concurrent surgical resection were excluded.

Based on the tumor location of the Morioka Consensus/IWATE Criteria for LLR, the patients were divided into two groups. In Group A (N = 33), the tumor location was at S4a, S7, S8, or S1/9. In Group B (N = 29), the tumor location was at a location within the rest of the hepatic segments.

Operative and ablative technique

All LURFAs were executed by a single interventional radiologist experienced in image-guided percutaneous RFA and two surgeons experienced in laparoscopic surgery at a single institution.

LURFAs were performed using previously reported surgical techniques, including mobilizing the liver (21). The arrangement of the entrance position of the scope and the ultrasound probe was demonstrated (Fig. 1). S1 tumors were approached from the lesser sac. Under real-time ultrasound guidance, the entrance route of the radiofrequency ablative needle was carefully selected to avoid penetrating through the major portal or hepatic veins as much as possible. When the target lesions were identified and measured, the radiofrequency ablative needle was placed percutaneously into the lesions. The ablative needle, ultrasound probe and scope were kept parallel to each other as much as possible. If needed, ascites were created to prevent excessive bending of the laparoscopic ultrasound probe to obtain good visualization of the target lesions and coordinate the direction/angle of the probe with an ablative needle, especially in the difficult ablation location (Fig. 2). All ablations were performed under constant real-time laparoscopic ultrasound monitoring using an RFA system composed of an internally cooled system (Cool-tip RF Ablation System; Covidien, Boulder, Colo) according to the manufacturer’s recommendations. Ablation was performed until the tumor was completely covered by hyperechogenic microbubbles. Technical success was defined as two things. First, all target lesions were completely identified, and the radiofrequency ablative needle was precisely placed through them. Second, the hyperechogenic change encompassed the whole targeted tumor during ablation.

Postoperative and Follow-up Evaluation

The image modalities for the follow-up were contrast-enhanced CT or MRI. CT/MRI was performed after LURFA within 4–6 weeks to evaluate the ablation efficacy. The subsequent follow-up assessment was scheduled at 3–6 month intervals according to the patient's status and the guidelines of the institution. Local recurrence (LR) was defined as tumor foci appearing in contact with the ablation zone. Univariate and multivariate LR analyses were performed on selected variables, including Group A/B (tumor location), tumor type, tumor number, and maximum tumor size.

Adverse Events

Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Grades 1–5.

Statistical Analysis

The distributional properties of continuous variables were expressed by the mean standard deviation (SD), median, and range; categorical variables were presented by frequency and percentage; and the survival curves of survival outcomes were estimated by the Kaplan‒Meier method. The survival outcomes between the diagnosis groups were examined using a log-rank test. Multivariate analysis using the Cox proportional hazards model was performed to estimate the adjusted effects of prognostic factors on recurrence outcome. A two-sided P value < 0.05 was considered statistically significant. All statistical analyses were conducted using SAS version 9.4 software and R software version 4.2.

A total of 62 consecutive patients with 93 malignant hepatic tumors underwent LRFA. Three patients received ablative procedures twice, and one patient received ablative procedures four times. The demographic and lesion data are shown in Table 1.

Table 1

The demographic and lesion data
Age (year)	61.4\(\pm\)11.8 (38–85)
Sex
Female	23 (36.2%)
Male	39 (63.8%)
Tumor number	1.5 (1–6)
Maximum tumor size (cm)	2.2\(\pm\)0.8 (0.8-5)
Tumor type
HCC	37 (58.9%)
CRCLM	25 (41.1%)
Hospital stay (day)	4 (2–13)

All ninety-three tumors, which had a mean diameter of 22 mm (8–50 mm) and a mean number of 1.5 (1–6 tumors) and were present in 62 patients, were successfully treated. The technical success of LURFA was 100% (93/93). According to the Morioka Consensus/IWATE Criteria for LLR, 53.2% of the patients (33/62) had tumors in difficult locations (segments I, VII, VIII, and Iva) (Table 2). Over a median follow-up period of 92.4 months (range, 60 to 123 months), the 1-year, 2-year, 3-year 5-year, 8-year and 10-year cumulative incidences of local recurrence were 6.9%, 13.8%, 17.2%, 17.2%, 20.9% and 20.9%, respectively (Fig. 3). The median overall survival was 51.6 months. In the patients with hepatocellular carcinoma, the 1-year, 2-year-, 3-year, 5-year and 8-year survival rates were 97.2%, 91.7%, 80.6%, and 55.6%, 40.1%, respectively. In the patients with metastatic colorectal cancers, the 1-year, 2-year, 3-year, 5-year, and 8-year survival rates were 100%, 72.7%, 36.4%, 27.3%, and 14.6%, respectively (Fig. 4). The mean hospital stay was 4 days (range 2–13 days). The multivariate LR analyses showed no risk factor with statistical significance (p < 0.05) (Table 3). Grade 3 adverse events occurred in 4.8% (3/62) of the patients. No greater than grade 3 adverse events were observed. There was no thirty-day mortality.

Table 2

Segmental location of tumors (= 112) treated by laparoscopic ultrasound-guided radiofrequency ablation. S = Couinaud’s segment
Segmental location of ablated hepatic tumors (Couinaud’s segment), N = 62 (%) (Couinaud’s segment) N = 62 (%)
S1/9	3 (4.8%)
S8	16 (25.8%)
S7	8 (12.9%)
S4a	6 (9.6%)
S4b	2(3.2%)
S2	8 (12.9%)
S3	5 (8.0%)
S5	7 (11.3%)
S6	7 (11.3%)

Table 3

Risk factor analysis
Variable	Multivariate analysis
	HR (95% CI)	P value
Group
B	1
A	2.5 (0.7, 9.3)	0.1784
Tumor type
HCC	1
CRC	3.0 (0.9, 10.3)	0.0858
Tumor number	0.4 (0.1, 1.2)	0.0925
Maximum tumor size	0.6 (0.3, 1.4)	0.2355

RFA was introduced in the early 1990s and was accepted as an effective therapy by the early 2000s, given its efficacy and relatively low morbidity (6, 8, 20). Radiofrequency ablation (RFA) has become an alternative therapy for malignant hepatic tumors when resection cannot be performed, especially those from HCC, colorectal cancers, and neuroendocrine tumors (6, 7, 21). LURFA has been shown to be superior in terms of local tumor control at difficultly precise targeting locations, more aggressive ablation with real-time intraoperative ultrasound monitoring, and ablating multiple hepatic lesions with less risk of surrounding organ injuries. With LURFA, comparable local control and reduction of procedural morbidity and mortality to the open surgical approach have also been demonstrated. Although this technique has been widely applied clinically, there are still few data on malignant hepatic tumors treated with full LURFA in terms of long-term outcomes beyond 5 years (11, 20–22).

Our study presents the results from a long-term 10-year follow-up series of 62 patients with 93 hepatic malignant tumors who were completely treated with laparoscopic ultrasound-guided RFA without concurrent surgical resection. The results confirm the previously reported observations that LURFA is safe with low morbidity (4.8%) and a short hospital stay, allowing patients to receive systemic therapy as soon as possible. The survival analysis showed that the overall survival was better for HCC than for CRCLMs (Fig. 5). This probably contributed to the different stages of the disease. Overall, the 5-year and 10-year LR rates in this study were 17.2% and 20.9%, respectively, which is also comparable to the literature (7, 23). Our results demonstrated that full LURFA is safe and effective, allowing patients to be discharged earlier and to receive adjuvant therapy as soon as possible. As described in the past, contiguous recurrence is still considered a true failure of the technique (11). According to our results, after LRFA of malignant liver tumors with long-term follow-up, the LR rate will still increase beyond the 5-year follow-up period (Fig. 3). To our knowledge, this smaller portion of LR that occurs beyond 5 years is rarely discussed in the literature. We emphasize that it is important to maintain regular imaging follow-up of these patients beyond the first few years after ablation.

The accessibility of upper liver segments for resection under laparoscopy and even for percutaneous RFA is associated with higher technical difficulties (15, 16). Ledoux G. et al. suggested that thermal ablation for liver tumors located in segments S7, S8, and/or S4a were independent risk factors for LR (14). Moreover, these segments are also "difficult laparoscopic segments" and include S1, for resection procedures according to the Morioka Consensus/IWATE Criteria (17, 24). For these segments, ultrasound probe positioning under laparoscopy is also generally difficult. The probe might require bending and result in probe damage and disorientation of the ablative needle on ultrasound images. Therefore, LURFA is more technically demanding than open or percutaneous ablation and requires a high level of expertise (20, 22). Because of the importance of precise targeting and aggressive ablation, we proposed varied approach positions based on the liver anatomy, creating ascites to be an ultrasound contact medium and/or liver mobilization to conquer the difficulty (Fig. 1–2). This may account for the 100% technical success rate in our study. In contrast to percutaneous RFA, Solbiati et al. and Shady et al. reported that in 6–7% of patients, primary technical success cannot be achieved (10, 25). Ledoux G. et al. even suggested some points to address this difficulty, including thoracoscopic and/or transdiaphragmatic approaches and switching to a mini-incision (14).

In our study, the multivariate analysis showed that the tumor type and tumor number seemed to be risk factors for local tumor control but still had no statistical significance. This may be because of the smaller sample size. However, some data showed that the tumor location, ablation margin, blood vessel proximity and number of tumors were significant risk factors for LR (11, 14, 23, 26).

This study has limitations. First, it is a retrospective analysis and small cohort of patients, so selection bias probably exists. Further evidence is necessary to recommend ablation versus hepatectomy, especially in randomized controlled trials. Some ongoing randomized trials might provide more evidence for this dilemma (7, 27, 28). Second, the ablative tumor number and tumor size were relatively small (median tumor number = 1.5, median tumor size = 22 mm) in this study. Compared to surgery, the efficacy of dealing with multiple tumors of various sizes is still unclear. Third, the thermal ablation modality was only the RFA system with a single ablative needle. Recently, new-generation microwave ablation technologies have been developed to overcome the limitations of RFA (29, 30). Future studies should apply this thermal ablative method to clinical practice.

In conclusion, this study showed that full LURFA for malignant hepatic tumors is associated with low morbidity, low LR, and feasible outcomes even after long-term follow-up. It requires advanced skills for clearly identifying the target tumor, precise needle placement and constant real-time intraoperative ultrasound monitoring to achieve complete ablation and an effective oncological outcome.

Data Availability

No datasets were generated or analysed during the current study.

Competing interests

Drs. Ming-Chih Chern, Chung-Wei Lin and Tzu-Jung Tsai have no conflicts of interest or financial ties to disclose.

Author contributions

Dr. Chern wrote the main manuscript text and prepared figures.

Dr. Chern and Dr. Tsai prepared figures and tables.

All authors reviewed the manuscript.

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No competing interests reported.

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Mid- to Long-term Outcome of Laparoscopic Ultrasound-guided Radiofrequency Ablation for Malignant Hepatic Tumors

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