Efficacy and safety of computed tomography-guided coablation for hepatic malignancies

Abstract

BACKGROUND

Coablation, which combines cryoablation and thermal ablation within a single probe, has emerged as a novel locoregional therapy for hepatic malignancies. However, prospective clinical evidence regarding its efficacy and safety remains limited.

AIM

To investigate the efficacy and safety of computed tomography (CT)-guided coablation in patients with hepatic malignancies in a prospective single-arm study.

METHODS

In this prospective, single-arm study, patients with hepatic malignancies underwent CT-guided coablation. The primary outcomes were safety and local tumor progression (LTP), and the secondary outcome was progression-free survival (PFS). Subgroup analyses were performed to evaluate the factors that influence clinical outcomes.

RESULTS

A total of 71 patients with 88 focal liver lesions (mean size: 4.2 ± 2.0 cm) underwent coablation. Among these patients, 55, 15, and 1 had one, two, and three targeted lesions, respectively. The median follow-up period was 12 months. The cumulative LTP rates at 3, 6, and 12 months were 0%, 1.4%, and 5.6%, respectively. An ice ball-to-lesion maximum cross-sectional area ratio ≥ 1 was associated with a significantly lower incidence of LTP than a ratio < 1 was [hazard ratio (HR) = 0.036; 95% confidence interval (CI): 0.003-0.391; P = 0.006]. The PFS rates at 3, 6, and 12 months were 100%, 98.6%, and 88.7%, respectively. Univariate and multivariate Cox regression analyses revealed an Eastern Cooperative Oncology Group performance status of 0 (HR = 0.094; 95%CI: 0.016-0.549; P = 0.008) and an ice ball area-to-lesion maximum cross-sectional area ratio ≥ 1 (HR = 0.079; 95%CI: 0.013-0.490; P = 0.006) as independent predictors of improved PFS. The primary treatment-emergent adverse events (TEAEs) were subcapsular hepatic hematoma (8.2%) and postoperative fever (4.1%). No serious TEAEs were reported.

CONCLUSION

CT-guided coablation appears to be a safe and effective treatment modality for hepatic malignancies, providing favorable local tumor control and short-term PFS, particularly for patients with tumors located in high-risk anatomical regions.

Key Words: Coablation; Cryoablation; Thermal ablation; Computed tomography-guided; Hepatic malignancies; Local tumor progression; Progression-free survival

Core Tip: This prospective study suggests that computed tomography-guided coablation, which involves the integration of cryoablation and thermal ablation through a single probe, is a safe and effective treatment modality for hepatic malignancies and provides favorable local tumor control with minimal complications. Notably, an ice ball-to-lesion area ratio ≥ 1 may serve as an independent predictor of improved outcomes, particularly for tumors in high-risk locations.

INTRODUCTION

Hepatic malignancies remain a major global health burden and are a leading cause of cancer-related mortality worldwide[1-3]. Although surgical resection and liver transplantation are considered curative treatments, a substantial proportion of patients are not eligible because of tumor burden, comorbidities, or advanced disease at diagnosis[4,5]. Consequently, image-guided locoregional therapies, including transarterial embolization and percutaneous ablation, have become integral components of multidisciplinary treatment strategies for hepatic malignancies[6].

Thermal ablation techniques, including radiofrequency ablation and microwave ablation, are widely recommended for select patients with early-stage hepatic malignancies[5,7]. These methods destroy tumors via coagulative necrosis and generally achieve favorable outcomes. However, their efficacy may be limited for lesions near high-risk structures, where reduced thermal delivery is needed, and because of the heat-sink effect from adjacent blood flow, which can increase local recurrence[8].

Cryoablation offers an alternative with distinct advantages. The ice ball formed during freezing allows real-time visualization of the ablation zone, reducing collateral injury and enabling the treatment of tumors in high-risk locations. It may also induce antitumor immune responses through tumor antigen release, potentially enhancing systemic therapeutic effects[9-12]. Nevertheless, traditional cryoablation lacks intrinsic hemostatic properties, increasing the risk of bleeding and tumor seeding, especially in large or subcapsular lesions[13,14].

The combined cryoablation and thermal ablation system (coablation) integrates freezing and heating mechanisms within one probe, aiming to enhance tumor destruction, improve ablation completeness, and provide hemostatic effects. Early clinical data suggest[15,16] the favorable safety and efficacy of computed tomography (CT)-guided coablation in patients with hepatic metastases, but overall evidence in patients with hepatic malignancies remains limited and warrants further study.

Therefore, the aim of this prospective study was to evaluate the efficacy and safety of CT-guided coablation in patients with hepatocellular carcinoma and colorectal cancer liver metastases, with a particular focus on local tumor control and treatment-related complications.

MATERIALS AND METHODS

Study design and participants

This prospective clinical study was conducted in accordance with the tenets stipulated in the Declaration of Helsinki and Good Clinical Practice. The investigation was performed at Peking University Cancer Hospital (Beijing, China) and approved by the institutional Ethics Review Board (No. 2018KT59).

The inclusion criteria: (1) Patient age > 18 years; (2) Histologic or clinical diagnosis of hepatocellular carcinoma or pathological examination results indicating liver metastases; (3) Child-Pugh class A-B disease; (4) Eastern Cooperative Oncology Group performance status of 0-2; (5) A life expectancy of at least 3 months; and (6) Adequate organ function (hemoglobin ≥ 90 g/L, absolute neutrophil count > 1.5 × 10⁹/L, platelet count > 100 × 10⁹/L, and alanine aminotransferase/aspartate aminotransferase levels ≤ 2.5 times the upper limit of normal).

The exclusion criteria: (1) Tumor invasion into blood vessels, bile ducts, or adjacent organs; (2) Serious underlying diseases such as heart failure, severe respiratory disease, or renal failure; (3) Pregnancy or lactation; and (4) Allergy to one of the drugs used for anesthesia or one of their excipients.

Procedures

During treatment, the patients were subjected to electrocardiogram monitoring. Puncture path planning was carried out under the guidance of CT, and the purpose of the ablation (curative ablation or palliative ablation), needle placement plan, number of ablation probes, and ablation protocol were determined according to the condition of the lesion.

A coablation system (Hygea Medical Technology Co., Ltd., China) equipped with disposable sterile probes (model: 12G; length, 150 mm or 180 mm) was used for treatment. A GE Discovery RT CT scanner was used for imaging. Initially, the right puncture needle reached the target with the assistance of CT. Next, the cryoablation mode was selected, with a freezing time of 15-20 minutes and a minimum freezing temperature of -196 °C. The rewarming mode was subsequently turned on, the rewarming time ranged from 5 minutes to 7 minutes, and the highest temperature was 80 °C (Figure 1). One or more ablation sites were required per tumor lesion according to the ablation experience of the manufacturer, with an additional 0.5-1.0 cm ablation margin applied to the surrounding tissue. Approximately 1-3 cycles were performed; CT scanning was conducted every 5-10 minutes during the procedure to determine the size of the ice balls covering the lesions and to identify complications. After the treatment was completed, the ablation probe was removed, and reexamination with abdominal CT was performed to detect any complications.

Figure 1 Working mechanism of coablation. The figure was obtained from Siemens computed tomography. When liquid nitrogen and absolute ethanol are used as the refrigeration and heating media, the achievable temperature extremes are -196 °C and 80 °C, respectively.

Follow-up

After coablation, the vital signs of the patients were closely monitored, and a series of symptomatic treatments (such as liver protection) was administered. Enhanced abdominal CT or magnetic resonance imaging was performed at 3, 6, and 12 months after treatment. Treatment efficacy was evaluated through CT or magnetic resonance imaging using the modified response evaluation criteria in solid tumors standard. Liver and kidney function analyses and routine blood examinations were performed. Treatment safety was evaluated using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). The primary outcomes were 12-month local tumor progression (LTP) after coablation and safety. The secondary outcomes included the presence of new liver cancer and progression-free survival (PFS).

Statistical analysis

This prospective exploratory study enrolled patients on the basis of recruitment feasibility to provide preliminary evidence on the safety and efficacy of the coablation system. No formal power calculations were performed; however, the results are intended to inform the design of future adequately powered randomized controlled trials. Continuous variables are reported as the mean ± SD or median (interquartile range). Kaplan-Meier estimates were used for LTP and PFS. Independent prognostic factors were identified by univariate and multivariate Cox regression analyses. A two sided value of P < 0.05 was considered to indicate statistical significance. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, United States).

RESULTS

Baseline characteristics

Between July 2018 and September 2020, a total of 71 patients (49 males, 22 females) with 88 focal liver lesions were enrolled and successfully underwent coablation. The mean lesion size was 4.2 ± 2.0 cm. With respect to the distribution of disease, 55 patients presented with a single lesion, 15 presented with two lesions, and 1 patient presented with three lesions. Histologically, 39 patients (54.9%) were diagnosed with hepatocellular carcinoma, while 32 (45.1%) had liver metastases. A total of 23 lesions were located in high-risk anatomical zones: 14 subcapsular lesions, 4 adjacent to the gastrointestinal tract, 2 near the gallbladder, and 3 near the kidney. The median maximum cross-sectional area of the ice balls was 12.8 cm² (interquartile range: 10.8-19.8). The detailed baseline characteristics are summarized in Table 1.

Table 1 Demographic and clinical characteristics of patients, mean ± SD/n (%).

Characteristics	All patients (n = 71)
Age (years)	56.9 ± 10.9
Sex
Male	49 (69.1)
Female	22 (30.9)
Type of tumor
HCC	39 (54.9)
Liver metastasis	32 (45.1)
Number of lesions
Single	55 (77.5)
Multiple	16 (22.5)
Liver tumor size (cm)	4.2 ± 2.0
≤ 5	53 (74.6)
> 5	18 (25.4)
Child-Pugh class
A	68 (95.7)
B	3 (4.3)
ECOG performance status
0	16 (22.5)
1	55 (77.5)
Maximum lesion area, (cm2), median (IQR)	8.8 (5.2-15.2)
Maximum area of ice ball, (cm2), median (IQR)	12.8 (10.8-19.8)
Ice ball area-to-lesion area ratio
< 1	14 (19.7)
≥ 1	57 (80.3)

IQR: Interquartile range; HCC: Hepatocellular carcinoma; ECOG: Eastern Cooperative Oncology Group.

Clinical outcomes

The median follow-up period for the entire cohort was 12.0 months (range: 8.0-12.0 months). Technical success was achieved in 100% (88/88) of the targeted tumors. During the follow-up period, the cumulative LTP rates at 3, 6, and 12 months post-treatment were 0%, 1.4%, and 5.6%, respectively. Similarly, the PFS rates were 100%, 98.6%, and 88.7% at the same intervals.

Notably, an ice ball-to-lesion maximum cross-sectional area ratio ≥ 1 was associated with a significantly lower incidence of LTP than a ratio < 1 was [hazard ratio (HR) = 0.036; 95% confidence interval (CI): 0.003-0.391; P = 0.0062]. Multivariate Cox regression analysis revealed an Eastern Cooperative Oncology Group performance status of 0 (HR = 0.094; 95%CI: 0.016-0.549; P = 0.008) and an area ratio ≥ 1 (HR = 0.079; 95%CI: 0.013-0.490; P = 0.006) as independent predictors of superior PFS (Figure 2).

Figure 2 Lesion close to the gallbladder. Images from a 61-year-old man diagnosed with hepatocellular carcinoma who underwent coablation. A: Computed tomography (CT) image showing a lesion close to the gallbladder before coablation; B: The area of the ice ball was 3.9 cm × 3.5 cm; C and D: Three-month follow-up CT images show the previous ablation zone (orange arrow) and the absence of local recurrence after coablation.

Safety and complications

The co-ablation procedure was well tolerated, with no serious treatment-emergent adverse events (TEAEs) of grade 3 or higher reported. The overall incidence of TEAEs was 12.7%. Specific complications included postoperative fever in three patients (4.1%) and hepatic subcapsular hematoma in six patients (8.2%), all of which were managed conservatively and deemed clinically acceptable.

DISCUSSION

In this prospective cohort study, we evaluated the safety and efficacy of CT-guided coablation in patients with hepatic malignancies. Coablation achieved a high technical success rate and favorable local tumor control, with a low incidence of major complications, indicating a favorable safety profile. Moreover, the ice ball area-to-lesion area ratio was identified as an independent predictor of PFS, suggesting that coablation may represent an effective and safe treatment option for selected patients.

The LTP and survival outcomes observed in the present study are consistent with those reported in previous studies of cryoablation and thermal ablation for liver tumors[10,17-26]. Compared with radiofrequency ablation and microwave ablation, cryoablation has been associated with comparable outcomes in selected patient populations[9]. The relatively low LTP rate observed in our cohort may be attributable to the improved visualization of the ablation zone and more precise control of treatment margins[11,27,28].

The potential mechanisms underlying the favorable outcomes of coablation may be multifactorial. Cryoablation induces tumor destruction through rapid freezing, resulting in intracellular ice crystal formation, cell membrane disruption, and microvascular thrombosis. Repeated freeze-thaw cycles further increase tumor cell death through mechanical and ischemic injury[29]. In addition, cryoablation may stimulate antitumor immune responses by promoting the release of tumor antigens[12]. In contrast to conventional cryoablation, the coablation system integrates a subsequent thermal coagulation phase, which may increase cytotoxicity through thermal stress and protein denaturation. Importantly, this thermal phase also provides a hemostatic effect along the puncture tract, which may reduce bleeding and tumor seeding.

Tumors located in high-risk anatomical regions remain a major challenge in percutaneous ablation[30]. Conventional thermal ablation is associated with an increased risk of collateral injury when lesions are adjacent to critical structures such as the gastrointestinal tract, gallbladder, diaphragm, or major vessels[31]. In these situations, incomplete ablation may occur because of the need to limit thermal intensity. In our study, a substantial proportion of lesions were located in high-risk regions, including subcapsular tumors and those adjacent to the gastrointestinal tract, gallbladder, and kidney. Notably, no major complications were observed, and local tumor control remained favorable. These findings suggest that coablation may expand the indications for percutaneous ablation in patients with tumors traditionally considered challenging or unsuitable for conventional thermal techniques.

From a clinical perspective, coablation may offer a promising strategy for individualized treatment planning in patients with hepatic malignancies. This technique may be particularly beneficial for patients with tumors located in high-risk anatomical regions, large tumors, or those at increased risk of bleeding. In addition, the immunomodulatory effects of cryoablation provide a potential rationale for combination strategies with systemic therapies, including immune checkpoint inhibitors[32,33]. Future studies should explore the role of coablation in multimodal treatment strategies and its potential impact on long-term oncological outcomes.

Several limitations of this study should be acknowledged. First, this was a single-center study with a relatively small sample size, which may limit the generalizability of the findings. Second, the absence of a control group precluded direct comparison with conventional ablation techniques. Third, the heterogeneous cohort and inclusion of both curative and palliative intents may have confounded the interpretation. Fourth, although the follow-up duration was adequate for early outcomes, longer follow-up is needed to assess long-term survival and recurrence. Fifth, the lack of a formal power calculation reduces statistical robustness. Finally, the absence of quality-of-life and immune biomarker assessments limits the understanding of the underlying mechanism. Therefore, multicenter randomized controlled trials with stratified analyses and extended follow-up are warranted to validate these findings and define the optimal clinical indications of coablation.

CONCLUSION

CT-guided coablation appears to be a safe and effective treatment modality for hepatic malignancies, providing favorable local control and short-term PFS, particularly for patients with tumors located in high-risk anatomical regions. Further multicenter randomized studies with longer follow-up periods are warranted to validate these findings.

ACKNOWLEDGEMENTS

The authors would like to express their sincere gratitude to all the patients who participated in the study and their families.