Ablation of pulmonary oligometastasis in advanced hepatocellular carcinoma treated with Lenvatinib: a retrospective multicenter study.

Introduction
In hepatocellular carcinoma (HCC), the lung is the most common metastatic site, accounting for 30%–50% of all extrahepatic metastases.1,2 Systemic therapy is the standard treatment for advanced HCC with pulmonary metastases.
3
Oligometastasis, defined as a limited number of pulmonary metastases, represents a subtype and transition point between localized disease and widespread metastases.
4
However, current guidelines do not distinguish this subtype from advanced HCC.
5
This subtype is commonly encountered because of the large number of patients with HCC.
6
Oligometastasis may persist for a prolonged period before progressing to widespread metastatic disease.7–9 In addition, metastases can promote invasion of the primary tumor.
10
Thus, eliminating metastases could improve the prognoses of patients with HCC.
11
Aggressive interventions, such as surgery or ablation of limited metastases, can lead to better outcomes.
12
Moreover, transitioning tumors from diffuse to localized status may halt their development into polymetastatic disease.12,13 Image-guided ablation therapy, such as microwave ablation (MWA), radiofrequency ablation (RFA), and cryoablation, has attracted considerable interest as a minimally invasive approach for intrathoracic metastases.14,15 Recently, patients with pulmonary metastases from various cancers have been treated with ablation,11,16 resulting in a high proportion of sustained complete response (CR) and relatively low morbidity.
17

Kim et al.
18
demonstrated the efficacy of local therapy in patients with lung metastases of HCC; however, their study included a small sample size and limited comprehensive analyses. To the best of our knowledge, no large-scale study has evaluated the clinical efficacy of Lenvatinib combined with pulmonary metastasis ablation. Lenvatinib, a tyrosine kinase inhibitor, has been approved as the recommended treatment for advanced HCC
19
; however, its clinical benefit as monotherapy is limited. This study aimed to evaluate the survival benefits of ablation of pulmonary oligometastasis (PO) in patients with advanced HCC.

Materials and methods

Patients and study design
This multicenter, propensity-matched cohort study included patients diagnosed with advanced HCC and PO between January 2018 and June 2022 from six hospitals (including Sun Yat-Sen University Cancer Center, The First Affiliated Hospital of Sun Yat-sen University, The Second Affiliated Hospital of Guangzhou Medical University, Chinese PLA General Hospital, The Third Affiliated Hospital of Sun Yat-sen University, and The First Affiliated Hospital of Jinzhou Medical University). The follow-up period ended on June 30, 2024. This study was conducted in accordance with the Declaration of Helsinki and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.20,21 The ethics committee of each center approved this retrospective study and waived the requirement for informed consent. This study has been registered at Research Registry (researchregistry10750).

Patient inclusion and exclusion criteria
Patients fulfilling the following criteria were enrolled in the study: (1) diagnosis of primary HCC, confirmed histologically or clinically based on the criteria of the American Association for the Study of Liver Diseases
22
; (2) presence of synchronous pulmonary metastases, defined as metastases detected within 1 month of HCC diagnosis; (3) pulmonary-only metastases detected at ⩽5 sites, with a maximum diameter of ⩽3 cm; (4) treated with Lenvatinib as first-line systemic therapy for ⩾3 months prior to study inclusion, resulting in controlled intrahepatic tumors and no metastatic progression; (5) underwent locoregional treatment, including transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC), 3–7 days before Lenvatinib initiation; (6) Child–Pugh class A or B and Eastern Cooperative Oncology Group performance status of 0 or 1; and (7) no history of other malignancies. Controlled intrahepatic tumors were defined as tumors showing partial response (PR) or stable response based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST).
23

Patients were excluded from the analysis for the following reasons: (1) recurrent HCC; (2) advanced HCC treated with Lenvatinib as second-line systemic therapy; (3) age <18 or >75 years; (4) advanced HCC with more than five pulmonary metastases or other nonlung metastases; (5) no response to Lenvatinib; (6) metastatic lesion size >3 cm; (7) patients who received any additional intrahepatic locoregional therapy (TACE, HAIC, or intrahepatic ablation) after the initiation of Lenvatinib and before radiologic progression were excluded; (8) incomplete clinical data; or (9) lost to follow-up within 3 months. Patients were divided into the Len group (receiving Lenvatinib alone) or the Ablation + Len group (receiving Lenvatinib and undergoing ablation of PO).

Outcomes and definitions
The primary endpoint was progression-free survival (PFS), defined as the time from the initiation of Lenvatinib to tumor progression (according to RECIST v1.1) or the last follow-up.
24
Secondary endpoints included overall survival (OS) and tumor response. OS was defined as the time from the initiation of Lenvatinib to death or the last follow-up. Patients who were alive at the follow-up date were considered censored. The progression patterns were classified into three types. Type 1 was defined as progression in the lung or lung associated with any other organs. Type 2 was defined as progression occurring only in the liver. Type 3 was defined as progression in the liver associated with other non-lung organs or only in other non-lung organs (such as bone, lymph nodules, and paranephros).
Portal vein tumor thrombus (PVTT) was classified based on the extension of the tumor thrombus into the portal venous system as follows: type I, tumor thrombus involving the segmental branches of the portal vein or higher; type II, tumor thrombus involving the right or left portal vein; and type III, tumor thrombus involving the main portal vein.
25
The albumin–bilirubin grade was determined to evaluate liver function.
26
Pulmonary metastases were diagnosed by two experienced radiologists as new lung nodules showing enhancement on computed tomography (CT) or positron emission tomography/CT with primary HCC in the liver or pathologically confirmed pulmonary metastases of HCC.

Lenvatinib treatment
Patients with body weight ⩾60 kg were prescribed 12 mg Lenvatinib, and those with body weight <60 kg were prescribed 8 mg Lenvatinib. Lenvatinib was administered orally once daily. The drug dose was reduced, or treatment was interrupted in patients who developed grade ⩾3 severe adverse events (AEs) or unacceptable grade 2 drug-related AEs.

Ablation procedure
Ablation therapy was conducted 3 months after Lenvatinib administration. The individualized ablation scheme, including ablation modality (MWA, RFA, and cryoablation), frequency, duration, and power output, was determined by a multidisciplinary team based on the size and location of each tumor, its relationship with the surrounding organs, and patient preference. RFA was used for metastases <2 cm in diameter distant from pulmonary vessels. MWA was preferred for metastases >2 cm in diameter because of the broader thermal field. Cryoablation was used for tumors near the chest wall to minimize pleural and thoracic nerve stimulation. The optimal route for ablation needle insertion was determined using CT. Single metastases typically required one ablation session, while multiple metastases required several rounds of ablation, with a recommended interval of 3–4 weeks between sessions.
CT measurements of the ablation zone were obtained 3–4 weeks after ablation and served as the baseline for subsequent imaging follow-up. Stability, decreased size without enhancement, or disappearance of ablated lesions on CT indicated complete ablation. The use of TACE or HAIC was determined based on liver function, tumor status, clinician recommendation, and patient preference. Details of the TACE and HAIC procedures are provided in the Supplemental Materials.

Follow-up assessment
The follow-up period ended on June 30, 2024. Tumor assessments were performed every 4 weeks until radiological progression. Intrahepatic tumor status at 3 months was evaluated using mRECIST,
23
and tumor response at 6 months was assessed using RECIST v1.1.
24
Ablated pulmonary metastases in the Ablation + Len group were excluded from the 6-month tumor response evaluation. CR was defined as the disappearance of all intratumoral arterial enhancement. PR was defined as a reduction in the diameter of target tumors by ⩾30%. Progressive disease (PD) was defined as an increase in the total diameter of target tumors by ⩾20% or the appearance of new lesions. Stable disease (SD) was defined as the absence of CR and PR. The objective response rate (ORR) was the sum of CR and PR, and the disease control rate (DCR) was the sum of CR, PR, and SD.

Statistical analysis
Categorical variables were compared using Chi-squared or Fisher’s exact test, as appropriate, and presented as proportions and percentages. Propensity score matching (PSM) analysis was performed using a multivariate logistic regression model, incorporating tumor size, tumor number, alpha-fetoprotein (AFP) levels, PVTT, hepatic vein tumor thrombus (HVTT), metastasis distribution, number and size of metastases, presence of portal hypertension, and antiviral therapy status. Patients were matched in a 1:1 ratio using the nearest neighbor method with a caliber of 0.05, as previously described.27,28 The standardized mean difference (SMD) was <0.10, indicating adequate balance. Variables with a significance level of p ⩽ 0.100 in the univariate analyses were included in the multivariate Cox regression models. To address potential bias in baseline characteristics, inverse probability treatment weighting (IPTW) was conducted.29,30 The balance of these characteristics was examined using SMD.
For the adjusted multivariate analysis, the adjusted hazard ratio (HR) for PFS and OS was calculated using Cox proportional hazards regression analysis, with 95% confidence interval (CI) for the risk of events. Confounders were progressively adjusted to assess robustness and identify potential risk factors. The variables included tumor size, tumor number, locoregional therapy, intrahepatic tumor status, AFP level, PVTT type, metastasis distribution, metastasis number, and metastasis size. The selection of confounders was based on patient characteristics prior to treatment and expert considerations. A post hoc calculation revealed that a power of >80% was achieved for the primary outcome.
Survival curves for OS and PFS were constructed using the Kaplan–Meier method with the log-rank test. All statistical tests were two-sided, and p < 0.05 was considered to indicate statistical significance. Statistical analyses were performed using SPSS software (version 22.0; SPSS Inc., Chicago, IL, USA), R software (version 4.1.3; http://www.r-project.org), and PASS software (version 2021, V21.0.3; NCSS, LLC, Kaysville, USA). Detailed statistical analyses are provided in the Supplemental Materials.

Results

Baseline characteristics
The results are reported in compliance with the STROBE recommendations for quality assurance. A flowchart of patient selection is shown in Figure 1. Of the 1268 patients with advanced HCC who received Lenvatinib, 384 patients with PO met the inclusion criteria and were eligible for enrollment, including 202 patients in the Len group and 182 in the Ablation + Len group. The median duration of follow-up was 23.0 (5.5–48.0) months in the Len group and 34.5 (4.5–52.0) months in the Ablation + Len group. In the entire cohort, 80, 66, and 36 patients in the Ablation + Len group underwent RFA, MWA, and cryoablation, respectively. All patients in the Ablation + Len group achieved complete ablation of PO. The Ablation + Len group had a higher proportion of patients with ⩽2 metastases (47.8% vs 36.1%, p = 0.021) and metastases size <2 cm (52.7% vs 40.6%, p = 0.016) than the Len group (Table 1). PSM generated 159 pairs of patients with balanced characteristics between the two groups. The SMD was well-balanced after IPTW (all less than 0.1; Figure S1). Table S1 shows the baseline comparisons between the censored and enrolled cases. Table S2 presents the baseline characteristics of the IPTW cohort. The three ablation modalities did not significantly affect PFS or OS in the entire cohort or PSM cohort (Figure S2). TACE and HAIC had no significant effect on PFS or OS in the Len (Figure S3) or Ablation + Len group (Figure S4) in the entire or PSM cohort.

Efficacy evaluation
The status of intrahepatic tumors was evaluated at 3 months using the mRECIST criteria. The PR and SD status of intrahepatic tumors were not significantly different between the two groups in the entire (p = 0.184), PSM (p = 0.715), or IPTW (p = 0.136) cohort (Table 2). At the 6-month evaluation, PO was completely ablated in the Ablation + Len group. In the PSM cohort, the ORR and DCR were 64.8% and 84.9% in the Len group and 74.8% and 89.7% in the Ablation + Len group, respectively. The proportions of CR, PR, SD, and PD did not differ significantly between the two groups in the entire (p = 0.002), PSM (p = 0.037), or IPTW (p = 0.018) cohort (Table 2).

PFS in the Len and Ablation + Len groups
In the entire cohort, progression occurred in 175 of the 202 patients (86.6%) in the Len group and 143 of the 182 patients (78.6%) in the Ablation + Len group. The number of progression events was significantly different between the two groups (p = 0.037). The median PFS was 10.5 ± 0.6 months (95% CI, 9.3–11.7) in the Len group and 13.0 ± 0.7 months (95% CI, 11.7–14.3) in the Ablation + Len group. The 6-, 12-, and 24-month PFS rates were 85.6%, 38.4%, and 5.4% in the Len group and 89.0%, 56.4%, and 18.1% in the Ablation + Len group, respectively (Table S3). In the PSM cohort, the 6-, 12-, and 24-month PFS rates were 91.8%, 37.1%, and 8.1% in the Len group and 95.0%, 65.2%, and 19.1% in the Ablation + Len group, respectively. PFS was significantly better in the Ablation + Len group than in the Len group in the entire (HR, 0.62; 95% CI, 0.49–0.78; p < 0.001; Figure 2(a)), PSM (HR, 0.62; 95% CI, 0.49–0.80, p < 0.001; Figure 2(b)), and IPTW (HR, 0.62; 95% CI, 0.49–0.81, p < 0.001) cohorts (Figure 2(c)).
Univariate and multivariate Cox regression analyses of the PSM cohort revealed that Lenvatinib therapy (HR, 1.62; 95% CI, 1.25–2.09; p < 0.001), tumor number >3 (HR, 1.36; 95% CI, 1.04–1.79; p = 0.026), absence of locoregional therapy (HR, 1.65; 95% CI, 1.18–2.31; p = 0.004), intrahepatic tumors in SD status (HR, 2.66; 95% CI, 1.99–3.57; p < 0.001), and PVTT type III (HR, 1.67; 95% CI, 1.14–2.46; p = 0.009) were risk factors associated with poorer PFS (Table 3). Stratified analysis of PFS demonstrated that Ablation + Len outperformed Len significantly across most variables (Figure S5).

OS analysis in the Len and Ablation + Len groups
In the entire cohort, 99 of the 202 patients (49.0%) in the Len group and 71 of the 182 patients (39.0%) in the Ablation + Len group experienced cancer-related death (p = 0.049). The median OS was 23.0 ± 1.2 months (95% CI, 20.7–25.3) in the Len group and 31.3 ± 1.2 months (95% CI, 28.9–33.7) in the Ablation + Len group. In the entire cohort, the 1-, 2-, and 3-year OS rates were 86.3%, 47.5%, and 19.0% in the Len group and 91.5%, 65.2%, and 26.2% in the Ablation + Len group, respectively (Table S4). In the PSM cohort, the corresponding OS rates were 89.8%, 55.8%, and 8.2% in the Len group and 97.4%, 64.2%, and 27.7% in the Ablation + Len group. OS was significantly longer in the Ablation + Len group than in the Len group in the entire (HR, 0.61; 95% CI, 0.45–0.83; p = 0.001; Figure 2(d)), PSM (HR, 0.60; 95% CI, 0.42–0.86; p = 0.006; Figure 2(e)), and IPTW (HR, 0.61; 95% CI, 0.44–0.85; p = 0.001) cohorts (Figure 2(f)). The univariate and multivariate analyses of OS after PSM are shown in Table S5. A stratified analysis of OS revealed that Ablation + Len outperformed Len significantly across most variables (Figure S6).

Sensitivity analysis
After stepwise adjustment for confounders in PFS analysis, the final adjusted HR from the multivariate analysis was 0.64 (95% CI, 0.51–0.82; Table S6). The multivariate analysis of PFS using the PSM cohort yielded an adjusted HR of 0.60 (95% CI, 0.46–0.77), and the multivariate analysis of the IPTW cohort yielded an adjusted HR of 0.68 (95% CI, 0.53–0.87; Table S7). After stepwise adjustment of variables in OS analysis, the adjusted HR from the multivariate analysis was 0.70 (95% CI, 0.50–0.96; Table S6). The multivariate analysis of OS using the PSM cohort yielded an adjusted HR of 0.56 (95% CI, 0.38–0.81), and the multivariate analysis of OS using the IPTW cohort yielded an adjusted HR of 0.65 (95% CI, 0.46–0.93; Table S7). The PFS with a power of 0.9960 and the OS with a power of 0.9926 imply sufficient reliability (Table S8).

Subgroup analysis of the effects of intrahepatic tumor status on prognosis
The PSM cohort included 221 patients with PR and 97 patients with SD (Table 3). PFS (HR, 0.34; 95% CI, 0.26–0.44; p < 0.001; Figure 3(a)) and OS (HR, 0.21; 95% CI, 0.14–0.31; p < 0.001) were significantly different between the SD and PR groups (Figure 3(b)). In patients with SD status, no significant difference was detected in PFS (HR, 0.77; 95% CI, 0.51–1.17; p = 0.230; Figure 3(c)) or OS (HR, 0.62; 95% CI, 0.37–1.03; p = 0.071; Figure 3(d)) between the Len and Ablation + Len groups. Conversely, in patients with PR status, PFS (HR, 0.50; 95% CI, 0.37–0.69; p < 0.001; Figure 3(e)) and OS (HR, 0.57; 95% CI, 0.34–0.95; p = 0.030; Figure 3(f)) were significantly different between the two groups.

Progression patterns in the Len and Ablation + Len groups
As shown in Table S9, patients in the Ablation + Len group showed a higher proportion of type 2 progression and a lower proportion of type 1 progression compared with the Len group before and after PSM. Progression patterns were significantly different between the Len and Ablation + Len groups in the entire (p = 0.005) and PSM (p = 0.017) cohorts. Analysis of post-progression survival (post-OS) revealed significant differences in post-OS (both p < 0.001) among the three types of progression pattern in the entire (p < 0.001, Figure 4(a)) and PSM (p < 0.001, Figure 4(b)) cohorts. Specifically, the type 2 progression pattern (the liver-only type) had the best post-OS among the three types. No significant difference in post-OS was detected between the two groups in the entire (HR, 1.19; 95% CI, 0.87–1.63; p = 0.500) and PSM (HR, 1.07; 95% CI, 0.75–1.53; p = 0.900) cohorts (Figure S7). Thus, ablation of oligometastasis mainly prolonged OS by extending PFS.

Treatment-related AEs
The main AEs are listed in Table S10. Most patients experienced AEs. Patients with grades 1–2 AEs received symptomatic treatment or dose reduction to alleviate symptoms. For grades 3–4 AEs, treatment was temporarily discontinued until the AEs were alleviated or resolved. Among patients in the Ablation + Len group, the most common AEs were related to chest pain, particularly for tumors near the chest wall. Analgesia was administered before ablation. Seven cases (3.8%) of severe pneumothorax occurred, necessitating closed drainage of the pleural cavity. A total of 64 patients with Child–Pugh class B were included in our cohort. These patients took liver-protecting medicine after Lenvatinib administration. Four patients in the Len group and five in the Ablation + Len group developed severe liver toxicities (elevated alanine transaminase, elevated aspartate transaminase, and hyperbilirubinemia) during treatment; these nine patients had Child–Pugh class B and required dose reductions/interruptions.

Discussion
Systemic therapy is currently recommended for advanced HCC.
31
However, guidelines from the American Association for the Study of Liver Diseases,
32
American Society of Clinical Oncology,
33
National Comprehensive Cancer Network,
34
European Society for Medical Oncology,
35
and European Association for the Study of the Liver35,36 do not specifically address PO. The lung is a common site of metastasis in patients with HCC, and limited pulmonary metastases are relatively common.2,37 However, the treatment and prognosis of PO have not been thoroughly studied, warranting further exploration to obtain clinical evidence.
Ablation therapy is a relatively painless and well-tolerated option for pulmonary metastases.38–40 However, strong clinical evidence is required to establish the feasibility of this technique for treating PO. In this study, we demonstrated that the PFS and OS were significantly longer in the Ablation + Len group than in the Len group, possibly because the first ablation can precisely inactivate oligometastasis, substantially reducing local tumor burden and delaying disease progression.
41
The second ablation combined with systemic therapy may reduce tumor heterogeneity and lower the risk of drug resistance.
42
We hypothesize that the ablation of pulmonary metastases reduced Lenvatinib resistance.
The positive outcomes after ablation of PO support guidelines recommending ablation of oligometastasis when primary tumors are under effective control. We also demonstrated that the three ablation modalities showed no survival difference in the Ablation + Len group. Analysis of survival difference between subgroups revealed no difference in OS and PFS between the Len and Ablation + Len groups when intrahepatic tumors were in SD status. However, significant differences in OS and PFS were noted in the PR cohort. Thus, primary tumors must be effectively controlled to benefit from the ablation of PO. Notably, most patients with HCC die of liver-related complications rather than metastases, primarily because of the high intrahepatic tumor burden.
43
Thus, liver disease should be carefully assessed when considering the ablation of metastases, as liver disease is the leading cause of morbidity and mortality.44,45
No difference in intrahepatic tumor status was detected between the two groups before ablation. However, 6 months after ablation, the Ablation + Len group exhibited superior control efficacy than the Len group, indicating that ablation of metastases contributed significantly to improving tumor control. Furthermore, patients in the Ablation + Len group experienced a higher proportion of liver-only progression and a lower proportion of lung or lung-related progression. Locoregional therapy was effective for liver-only progression, enhancing tumor control and resulting in the best post-OS outcome among the three progression types. Pneumothorax was the most common AE associated with ablation of pulmonary metastases. However, it resolved spontaneously in most cases. The second most common AE was cough, which typically resolved without treatment. We did not observe any clinical deterioration in respiratory function, although spirometry was not performed after ablation.
This study had several limitations. First, it was a retrospective study, which implies unavoidable bias among patients receiving the two treatments. Although we conducted multicenter studies to obtain more comprehensive and reliable results, randomized controlled trials are needed to fully evaluate the efficacy of ablation for PO. Second, we did not include atezolizumab and bevacizumab combination therapy, which has been the first-line treatment for advanced HCC since 2020, due to the higher costs of these drugs compared with Lenvatinib in China. Third, this study recruited patients between January 2018 and June 2022 from six hospitals, and many patients died during the follow-up. The post-progression treatment modality, hepatic functional reserve parameters, and performance status at progression were not recorded. In addition, the generalizability of the results to the populations of Western countries requires further verification.

Conclusion
Our study demonstrated that combining the ablation of PO with Lenvatinib prolonged OS and PFS compared with Lenvatinib alone. In the subgroup analyses, patients did not achieve survival benefits from metastasis ablation when the primary tumors were in SD status, but both OS and PFS improved significantly when the primary tumors were in PR status. In addition, the Ablation + Len group showed a higher proportion of liver-only progression.

Supplemental Material

sj-doc-1-tam-10.1177_17588359261432042 – Supplemental material for Ablation of pulmonary oligometastasis in advanced hepatocellular carcinoma treated with Lenvatinib: a retrospective multicenter study

Supplemental material, sj-doc-1-tam-10.1177_17588359261432042 for Ablation of pulmonary oligometastasis in advanced hepatocellular carcinoma treated with Lenvatinib: a retrospective multicenter study by Ye Li, Yigong Ren, Hui Li, Ruixia Li, Hongji You, Yanyang Zhang, Wei Wang, Mingyu Liu, Zhimei Huang, Qunfang Zhou and Feng Duan in Therapeutic Advances in Medical Oncology

sj-docx-2-tam-10.1177_17588359261432042 – Supplemental material for Ablation of pulmonary oligometastasis in advanced hepatocellular carcinoma treated with Lenvatinib: a retrospective multicenter study

Supplemental material, sj-docx-2-tam-10.1177_17588359261432042 for Ablation of pulmonary oligometastasis in advanced hepatocellular carcinoma treated with Lenvatinib: a retrospective multicenter study by Ye Li, Yigong Ren, Hui Li, Ruixia Li, Hongji You, Yanyang Zhang, Wei Wang, Mingyu Liu, Zhimei Huang, Qunfang Zhou and Feng Duan in Therapeutic Advances in Medical Oncology