Li KN, Ying LL, Du N, Wang Y, Huang HZ, Wang YH, Xu LC, Zhao Q, Song G, Hu YB, Li WT, Yan Y, Chen C, He XH. Radiofrequency ablation with or without capecitabine maintenance therapy for lung oligometastases from colorectal cancer. World J Gastroenterol 2025; 31(35): 110152 [DOI: 10.3748/wjg.v31.i35.110152]
Corresponding Author of This Article
Xin-Hong He, MD, Doctor, Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Xuhui District, Shanghai 200032, China. xinhong.he@shca.org.cn
Research Domain of This Article
Oncology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ke-Ning Li, Lei-Lei Ying, Nan Du, Ying Wang, Hao-Zhe Huang, Yao-Hui Wang, Li-Chao Xu, Qing Zhao, Ge Song, Wen-Tao Li, Yan Yan, Chao Chen, Xin-Hong He, Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Ke-Ning Li, Lei-Lei Ying, Nan Du, Ying Wang, Hao-Zhe Huang, Yao-Hui Wang, Li-Chao Xu, Qing Zhao, Ge Song, Wen-Tao Li, Yan Yan, Chao Chen, Xin-Hong He, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Yu-Bin Hu, Department of Tumor and Vascular Interventional Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350000, Fujian Province, China
Co-corresponding authors: Chao Chen and Xin-Hong He.
Author contributions: Li KN, and Ying LL wrote the original draft, they contributed equally to this article, they are the co-first authors of this manuscript; Chen C, He XH and Li KN designed the study; Chen C and Li KN designed the methodology of study and analyzed all data; He XH, Chen C, Du N, Wang Y, Huang HZ, Xu LC, Zhao Q, Song G, Hu YB, Li WT, Yan Y, Wang YH performed the ablation procedure as well as documented all data related to radiofrequency ablation; He XH made thoroughly review and editing of the manuscript; He XH and Chen C contributed equally to this article, they are the co-corresponding authors of this manuscript; All authors thoroughly reviewed and endorsed the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82072034.
Institutional review board statement: The study was reviewed and approved by the Fudan University Shanghai Cancer Center Institutional Review Board (No. 1612127-18) and Fujian Cancer Hospital Ethics Committee (No. K2025-206-01).
Informed consent statement: This is a retrospective study, so informed consent was waived.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The datasets generated and analyzed during this study are not publicly available due to institutional ethical regulations and patient confidentiality protections. However, de-identified data supporting the findings of this study are available from the corresponding author (Chen C, chaochen_cc@fudan.edu.cn) upon reasonable request. Data requests will be reviewed by the institutional ethics committee to ensure compliance with privacy policies. Approved requests may require a formal data sharing agreement outlining terms of use, including prohibitions on re-identification attempts and restrictions on redistribution. All shared data will remain anonymized, consistent with the original study protocol.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xin-Hong He, MD, Doctor, Department of Interventional Radiology, Fudan University Shanghai Cancer Center, No. 270 Dongan Road, Xuhui District, Shanghai 200032, China. xinhong.he@shca.org.cn
Received: May 30, 2025 Revised: July 7, 2025 Accepted: August 15, 2025 Published online: September 21, 2025 Processing time: 111 Days and 10 Hours
Abstract
BACKGROUND
No clear guidelines for long-term postoperative maintenance therapy have been established for patients with lung oligometastases from colorectal cancer (CRC) who achieve radiological no evidence of disease after radiofrequency ablation (RFA) treatment. We compared the outcomes of patients with lung oligometastases from CRC after RFA plus maintenance capecitabine with RFA alone.
AIM
To determine whether adding capecitabine to RFA improves prognosis compared with RFA alone.
METHODS
This multicenter retrospective study included consecutive patients from two tertiary cancer centers treated for pulmonary oligometastases from CRC between 2016 and 2023. Subjects were assigned to RFA plus capecitabine (combined) or RFA alone (only RFA) groups. Primary outcomes included overall survival (OS) and progression-free survival (PFS) survival and the secondary outcome was local tumor progression (LTP). The OS, PFS, and LTP rates were compared between the two groups. In addition, prognostic factors were identified using univariate and multivariate analyses.
RESULTS
Combination therapy (RFA + capecitabine, n = 148) and RFA monotherapy (n = 99) were compared in patients with CRC and lung metastases. The median OS was 37.8 months (22.4, 50.3), the PFS was 18.7 months (13.0, 36.5), and the LTP was 31.5 months (20.0, 52.4) in the Only RFA group. The OS increased significantly (P = 0.011) and the LTP decreased at all time points (P < 0.001) in the combined group. The multivariate cox analysis revealed that combined chemotherapy significantly improved OS, with hazard ratios ranging from 0.29 to 0.35 (all P < 0.015) after adjusting for demographic, tumor, and treatment-related factors. The risk of death was consistently lower in the combination therapy group compared to RFA monotherapy.
CONCLUSION
RFA prolongs survival and local control in patients with CRC pulmonary oligometastases. Adjuvant capecitabine increases OS and reduces LTP compared to RFA alone, but PFS did not significantly change.
Core Tip: This multicenter retrospective analysis demonstrates that adding maintenance capecitabine after achieving no evidence of disease with radiofrequency ablation (RFA) significantly improves survival outcomes in colorectal cancer patients with lung oligometastases. Compared to RFA alone, the RFA-plus-capecitabine group showed superior 5-year overall survival and significantly reduced local tumor progression, although progression-free survival was unchanged. This study provides the first evidence supporting capecitabine maintenance therapy following RFA-induced no evidence of disease as a strategy to enhance long-term survival and local control in this oligometastatic population.
Citation: Li KN, Ying LL, Du N, Wang Y, Huang HZ, Wang YH, Xu LC, Zhao Q, Song G, Hu YB, Li WT, Yan Y, Chen C, He XH. Radiofrequency ablation with or without capecitabine maintenance therapy for lung oligometastases from colorectal cancer. World J Gastroenterol 2025; 31(35): 110152
The global incidence and mortality rates of colorectal cancer (CRC) are high[1,2]. Despite significant advances in early diagnosis and treatment that have markedly improved the prognosis of CRC, approximately 50% of patients develop distant metastases during the course of the disease[3]. Notably, pulmonary metastases, which account for 15%-20% of the metastases, significantly influence patient outcomes[4]. The management of CRC lung metastases has changed significantly over the past decade; minimally invasive local therapies such as radiofrequency ablation (RFA) are now more common than surgical resections, particularly in patients with oligometastatic disease[5]. Oligometastasis is an intermediate status between locally advanced and widespread disease that affects ≤ 3 metastatic organs and includes ≤ 5 metastatic lesions[6]. Patients with oligometastasis can achieve long-term survival after local treatment[7].
RFA, which reduces morbidity and shortens recovery times, is a promising therapeutic option for patients with limited pulmonary metastases. Furthermore, lesions that are not surgically accessible can be treated with RFA[8]. RFA can achieve no evidence of disease (NED) status in a subset of patients, with survival outcomes comparable to metastasectomy[2,4,9,10]. However, the recurrence rate after ablation therapy is 32.6%[8], and an optimal postoperative maintenance treatment regimen has not been established. In patients with advanced CRC, initial induction chemotherapy or local-regional treatment followed by maintenance therapy is the standard approach to prolonging disease control and improving overall survival (OS)[11,12]. Oral capecitabine, a fluoropyrimidine derivative, is widely used as maintenance therapy due to its favorable toxicity profile and convenient administration[13-16]. Capecitabine maintains disease stability in patients with metastatic CRC (mCRC). However, the effects of capecitabine in patients achieving NED after RFA are unclear.
This multicenter retrospective study aimed to evaluate the outcomes after RFA with or without capecitabine maintenance therapy in patients with lung oligometastases from CRC. A cohort of 247 patients treated at our institutions was analyzed to determine whether adding capecitabine maintenance therapy to RFA enhances progression-free survival (PFS), OS, and local tumor progression (LTP) compared to RFA alone. The results of this study provide valuable insights into optimizing therapeutic strategies for patients with oligometastatic CRC lung lesions and inform future randomized controlled trials.
MATERIALS AND METHODS
Patient population
The study included 247 consecutive CRC patients from Fudan University Shanghai Cancer Center and Fujian Cancer Hospital with lung oligometastases who underwent initial RFA between January 2016 and December 2023. The ethics committees of both participating centers approved this investigation. Due to the retrospective nature of the study, patient informed consent was waived. Lung metastases of colorectal origin were clinically diagnosed after detecting new lesions by computed tomography (CT) or positron emission tomography (PET)-CT or by serial CT images of enlarging known lung defects. Histologic confirmation was attained via lung biopsy when possible. The inclusion criteria at the time of RFA were as follows: (1) Histologically confirmed CRC with a completely resected primary tumor, as documented by surgical and pathological reports; (2) The primary tumor must have been completely removed via surgery with adequate margins, as confirmed by postoperative imaging and clinical follow-up; (3) No evidence of local-regional recurrence as determined by imaging [CT, magnetic resonance imaging (MRI), or PET-CT] and clinical examination; (4) Patients must have ≤ 5 pulmonary metastatic lesions, with each lesion ≤ 3 cm in maximum diameter and lesions must be confirmed as mCRC via imaging (CT, MRI, or PET-CT) or biopsy; (5) No evidence of extrapulmonary metastases as determined by imaging (CT, MRI, or PET-CT) and clinical evaluation; (6) Comprehensive medical records, including clinical variables and CT data during the procedure and follow-up; and (7) Technical success of RFA with NED on CT imaging 1 month post-procedure. The exclusion criteria were as follows: (1) Prior local therapy for pulmonary metastases such as radiotherapy, re-ablation or other metastatic sites within 3 months of RFA; (2) Impaired normal organ function or inability to tolerate RFA; (3) Active concurrent malignancies or extrapulmonary metastases at the time of RFA; and (4) Patients who received neoadjuvant chemotherapy within 6 months prior to RFA. In this multicenter retrospective study, patients with CRC pulmonary oligometastases treated between 2016 and 2023 were categorized into the RFA-plus-capecitabine (combined) group (n = 148) or RFA alone (only RFA) group (n = 99) based on individualized therapeutic decisions by multidisciplinary tumor boards at both institutions. Patients in the combined group received oral capecitabine as maintenance therapy within 4 weeks after RFA at a standard dose of 1000 mg/m2 twice daily from day 1 to day 14 of a 21-day cycle. Dose adjustments were permitted in cases of drug intolerance. Notably, no dose reductions were implemented for grade 1 or 2 hematologic adverse events or grade 1 nonhematologic adverse events.
The following clinical data were retrospectively collected from medical records: Age, sex, maximum tumor diameter, number of pulmonary metastases, primary tumor location, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) level at the initial RFA, tumor node metastasis classification of primary CRC, interval between primary CRC resection and RFA, chemotherapy use before lung RFA, history of previous lung metastasectomy, RFA needle type, and complications such as intra-alveolar hemorrhage (IAH) or pneumothorax. Synchronous tumors were defined as lesions occurring before or within 3 months after the surgery for CRC; other tumors were considered metachronous tumors[17]. Standardized data collection protocols were implemented in both centers to ensure consistent clinical variable collection, imaging assessments, and follow-up schedules.
RFA procedures
Three senior interventional radiologists (He XH, Wang Y, and Xu LC) with > 10 years of experience in CT-guided thoracic interventions conducted the RFA procedures using a 64-slice spiral CT scanner (Philips Healthcare, Amsterdam, The Netherlands). Scanning parameters were as follows: Tube voltage, 120 kVp; Tube current, 130-250 mA; Collimation, 0.625 mm; Slice thickness, 3 mm; Pitch, 0.758-1.015; Rotation time, 0.5 seconds; Field of view, 350 mm; And matrix, 512. CT fluoroscopic guidance was omitted to prevent unnecessary exposure of the radiologists to radiation.
Patients were placed in prone, supine, or contralateral-dependent positions for sustained patient comfort and stability while ensuring optimal RFA routing to targeted lesions. Chest CT scans were obtained to facilitate procedural planning. Unenhanced CT images were compared with previous contrast-enhanced diagnostic CT views to identify lesions of interest, determine cross-sections, and establish chest landmarks. Lidocaine was administered at the puncture sites to induce local pleural anesthesia. In addition to CT monitoring, multi-tined (RITA Medical Systems Inc., Fremont, CA, United States) or multipolar (CelonLab POWER; Olympus Corp, Tokyo, Japan) RFA needles were inserted at predetermined directions and angles. Electrode targets snaring was confirmed with CT in all cases before conducting ablations.
RFA was administered at a high-frequency current (460-480 kHz) to heat the tissue around the needle electrodes, causing focal coagulative necrosis but sparing more peripheral zones. The goal was to ablate tissue at least 5 mm beyond the lesion borders. If intraoperative complications, such as IAH or atelectasis, obscured the extent of ablation, at least two ablation cycles were administered to raise impedance before cessation. After finishing the ablation, the electrodes were withdrawn, and CT scans (same parameters) were repeated to verify complete tumor ablation and check for associated complications, including pneumothorax and hemorrhage. Chest radiographs (posterior-anterior and lateral views) were acquired within 1 day after the ablation.
Complication severity was graded per common terminology criteria for adverse events v5.0 criteria[18]. Pneumothorax management followed standard protocols: Grade 1 (asymptomatic) required observation; Grade 2 (symptomatic) underwent needle aspiration; Grade 3 (respiratory compromise) mandated chest tube drainage. IAH was managed conservatively with supplemental oxygen for hypoxemia (grade ≥ 2).
Follow-up and outcomes
Baseline contrast-enhanced chest CT studies were performed 1 month after ablations and repeated at 3-month intervals for 1 year, followed by 4-6-month intervals. If the CT results were unclear, fluoro-2-deoxyglucose-PET and/or contrast-enhanced MRI was performed. To ensure methodological consistency across both centers (Fudan University Shanghai Cancer Center and Fujian Cancer Hospital), standardized data collection protocols were implemented, encompassing uniform imaging acquisition parameters, follow-up schedules, and centralized response assessment criteria. Two dedicated thoracic radiologists (> 10 years’ experience in oncologic imaging) independently evaluated all studies according to modified response evaluation criteria in solid tumors criteria. To ensure inter-reader consistency, discordant interpretations were resolved through joint re-evaluation by a third senior thoracic radiologist (> 15 years’ specialization), whose adjudication determined the outcome.
The primary outcomes were OS and PFS. OS was defined as the time from the first RFA treatment to death by any cause. PFS was defined as the interval from RFA to local or distant disease progression or death by any cause. The secondary outcome, LTP, was radiologically defined as new tumor foci within or contiguous to the ablation zone, presuming prior CT-confirmed complete ablation (≥ 5 mm margin). The final follow-ups were concluded on December 31, 2024.
Statistical analysis
The patients were stratified into two groups according to the therapeutic modality received. Descriptive analyses were performed for the entire study cohort. Continuous data were expressed as mean and standard deviation or median and interquartile range (quartiles 1-3) where applicable. Categorical variables were presented as percentages. Comparisons were made using the χ2 test for categorical variables, one-way analysis of variance for normally distributed data, Wald’s test and the Kruskal-Wallis test for skewed distributions. Multivariate Cox regression analysis was performed to evaluate the independent association between different therapeutic modalities and OS. The extended Cox model approach was applied to models adjusted for various covariates. Covariates were selected based on prior findings and clinical considerations. Survival curves were generated using the Kaplan-Meier method, and statistical significance was evaluated using log-rank tests. All analyses were conducted using R software, version 3.3.2 (available at http://www.R-project.org, The R foundation), and free statistics, version 1.4. Statistical significance was determined by a two-sided P value less than 0.05.
RESULTS
Patient groups
Between January 2016 and December 2023, 1523 patients with lung metastases from CRC underwent RFA at the two institutions. After rigorous screening, 247 patients were included in the study and divided into combined (n = 148) and only RFA (n = 99) groups (Figure 1). Baseline patient characteristics are summarized in Table 1. The mean patient age was 58.0 years (49.0, 66.0), and the study included 151 (61.1%) males and 96 (38.9%) females. Primary rectal cancer tumors occurred in 159 (64.4%) patients, primary left-sided colon cancer tumors occurred in 52 (21.1%) patients, and primary right-sided colon cancer tumors occurred in 36 (14.6%) patients. KRAS mutations were present in the primary tumors of 93 (37.7%) patients, and 154 (62.3%) patients had no KRAS mutations in the primary tumors. A total of 332 pulmonary metastases with a mean diameter of 1.0 cm (0.8, 1.5) were detected. Metachronous pulmonary metastases were detected in 139 (56.3%) patients, and synchronous pulmonary metastases were detected in 108 (43.7%) patients. After RFA, 53 (21.5%) of patients developed pneumothorax and 44 (17.8%) of patients developed alveolar hemorrhage. Most pneumothoraces were low-grade (grade 1: 42, 17.0%; grade 2: 8, 3.2%) with only 3 cases (1.2%) requiring chest tubes (grade 3). IAH was predominantly grade 1 (39, 15.8%); 5 cases (2.0%) required transient oxygen support (grade 2). No grade 4/5 events occurred. The median follow-up duration after the initial RFA was 40 months (range: 12-109).
Mortality was significantly lower in the combination therapy group (RFA plus capecitabine) than in the RFA monotherapy group at the end of the follow-up period [5.4% (8/148) vs 17.1% (17/99)]. Median OS, PFS, and LTP for the overall cohort were 37.8 months (22.4, 50.3), 18.7 months (13.0, 36.5), and 31.5 months (20.0, 52.4), respectively. The cumulative 1-, 3-, and 5-year OS rates were 99.1%, 95.4%, and 80.0%, respectively. The cumulative 1-, 3-, and 5-year PFS rates were 81.8%, 43.4%, and 26.2%, respectively, and the cumulative 1-, 3-, and 5-year LTP rates were 3.2%, 18.2%, and 33.8%, respectively (Figure 2).
Figure 2 Kaplan-Meier curves.
A: For overall survival in patients with colorectal cancer lung metastases undergoing radiofrequency ablation (median, 37.8 months); B: For progression-free survival in patients with colorectal cancer lung metastases undergoing radiofrequency ablation (median, 18.7 months); C: For local tumor progression in patients with colorectal cancer lung metastases undergoing radiofrequency ablation (median, 35.6 months).
Although the cumulative 1-, 3-, and 5-year OS rates were similar between the groups (combined: 99.2%, 95.9%, and 88.7% vs RFA only: 97.9%, 94.7%, and 69.1%, respectively), the long-term survival improved significantly in the combined group (log-rank P = 0.011), with survival curve divergence becoming clinically meaningful over time. Cumulative 1-, 3-, and 5-year PFS rates were not significantly different (combined: 83.1%, 46.8%, and 27.8% vs only RFA: 79.8%, 38.4%, and 23.7%; P = 0.143). Of note, the combination strategy significantly reduced cumulative 1-, 3-, and 5-year LTP rates (1-year: 2.0% vs 5.1%; 3-year: 10.9% vs 28.8%; 5-year: 22.7% vs 49.0%; P < 0.001), with absolute risk differences exceeding 6% at each time (Table 2 and Figure 3).
Univariate analysis of OS in the CRC patients with lung oligometastases revealed that tumor diameter ≥ 1 cm [hazard ratio (HR) = 3.2, 95% confidence interval (CI): 1.57-6.55; P = 0.001], alveolar hemorrhage (HR = 7.5, 95%CI: 3.34-16.84; P < 0.001), and lesions > 1 cm from the pleural surface (HR = 0.38, 95%CI: 0.17-0.86; P = 0.02) were significantly associated with survival outcomes. Age tended to be inversely associated with survival outcomes (HR = 0.96 per year, 95%CI: 0.93-1.00; P = 0.065), and left-sided primary tumors tended toward poorer survival compared to rectal tumors (HR = 2.38, 95%CI: 0.93-6.09; P = 0.07). No significant associations were detected between survival outcomes and sex, KRAS mutation status, tumor markers (CA19-9, CEA), mediastinal proximity, or metastatic timing. Notably, alveolar hemorrhage conferred a 7.5-fold increased mortality risk, and anatomic positioning relative to the pleural surface emerged as a potential protective factor. Larger tumor diameter independently predicted adverse outcomes (Table 3).
Table 3 Univariate analysis of factors associated with overall survival in colorectal cancer patients with lung metastases.
Variables
HR (95%CI)
P value (Wald’s test)
Sex
Female
1 (Reference)
Male
0.74 (0.34-1.64)
0.464
Age
0.96 (0.93-1)
0.065
KRAS
Wild-type
1 (Reference)
Mutated
1.43 (0.64-3.18)
0.388
CA19-9
< 27 U/mL
1 (Reference)
≥ 27 U/mL
1.23 (0.42-3.61)
0.703
CEA
< 5 ng/mL
1 (Reference)
≥ 5 ng/mL
1.82 (0.8-4.15)
0.155
Location
Left
1 (Reference)
Right
0.91 (0.41-2.01)
0.821
Diameter
3.2 (1.57-6.55)
0.001
Distance between the lesion and the mediastinum or great vessels
≤ 1 cm
1 (Reference)
> 1 cm
0.77 (0.34-1.74)
0.529
Distance between the lesion and the pleural surface
Multivariate Cox proportional hazards analysis revealed that combination therapy was associated with a significantly reduced mortality risk across all adjusted models. The covariates were chosen based on established prognostic factors in mCRC as per European Society for Medical Oncology guidelines[5] and landmark RFA studies[8,19,20]. Compared to the only RFA group (reference group), the HR for the combined group ranged from 0.35 (95%CI: 0.15-0.81; P = 0.011) in the crude analysis to 0.31 (95%CI: 0.12-0.79; P = 0.014) in the fully adjusted model (model-4), which incorporated tumor characteristics (diameter, anatomic positioning), molecular markers (KRAS, CEA), and procedural complications (pneumothorax). The consistency of risk reduction persisted despite progressive adjustment for sex, age, histopathologic features (neural/Lymphovascular invasion), and metastatic timing (P < 0.05 for all models). The observed event rates supported the beneficial effects of combined therapy. Mortality in the combined group was 5.4% (8/148) and mortality in the only RFA group was 17.2% (17/99). These results indicate that adjuvant chemotherapy after RFA confers a robust survival advantage in patients with CRC and lung oligometastases, independent of baseline clinicopathologic confounders (Table 4).
Table 4 Multivariate Cox proportional hazards analysis of the association between whether chemotherapy was combined after radiofrequency ablation and overall survival in colorectal cancer patients with lung metastases.
As noted in current guidelines[5,6], multiple modalities exist for managing oligometastatic CRC, including surgical resection, systemic therapy, and emerging local ablative techniques. RFA may provide comparable survival outcomes to surgery in patients with lung oligometastases from CRC. Maintenance therapy is the preferred treatment mode after first-line induction chemotherapy or locoregional therapy in patients with advanced CRC. However, to our knowledge, the use of capecitabine as maintenance therapy after patients achieved mCRC-NED with RFA has not been investigated. In the present study, 247 patients with lung oligometastases from CRC underwent CT-guided percutaneous RFA to achieve NED. The survival outcomes are encouraging and suggest that adjuvant capecitabine maintenance after RFA provides long-term benefits to prolong disease control for these patients.
Notably, the reported 5-year OS rate after CRC lung metastasectomy is 68.0%-81.2%[21,22]. Our data demonstrate that RFA-based therapy achieved 5-year OS of 88.7% in the combined group, being comparable with these results; thus, RFA is an acceptable therapeutic option for lung oligometastases from CRC, particularly for lesions unsuitable for surgery. Importantly, the addition of capecitabine maintenance mitigated the high recurrence risk post-ablation (5-year LTP 22.7% vs 49.0% in RFA-only, P < 0.001), without introducing significant chemotherapy-related toxicity. Moreover, the 3-year PFS rate after RFA was 43.4%, similar to the reported PFS rate of 28%-44% after metastasectomy[23,24]. Several recent studies reported 3-year PFS rates of 31.2%-41.0% after RFA treatment for lung metastases from CRC[25,26]. Biologically, capecitabine targets residual micro-metastases at ablation margins which may be enhanced by RFA-induced tumor sensitization[27], thereby reducing LTP as observed (5-year LTP: 22.7% vs 49.0%; P < 0.001). However, the inability of capecitabine to suppress dormant extrapulmonary metastatic clones likely contributes to the observed dissociation between PFS and OS[10]. Methodologically, PFS encompasses both local and distant progression; undetected micro-metastases or insufficient statistical power could mask subtle PFS differences. The OS advantage aligns with maintenance therapy principles in mCRC, where local control alters disease trajectory despite persistent systemic risk[5].
Although this study focused on pulmonary oligometastases, historical data for colorectal liver metastases show that 5-year OS rates following neoadjuvant chemotherapy combined with resection range from 51.2% to 81%[28-31]. In contrast, the 5-year OS rate in the combined treatment group of this study was 88.7%, suggesting that local ablation combined with maintenance therapy may confer superior prognosis for patients with pulmonary oligometastases. This discrepancy may be attributed to the distinct biological characteristics of liver vs lung metastases: Colorectal liver metastases often requires neoadjuvant chemotherapy to downstage unresectable lesions, whereas pulmonary oligometastases, owing to limited tumor burden and accessible anatomical location are better suited for curative local therapy[32-34]. Additionally, neoadjuvant chemotherapy is associated with grade 3 or higher complications such as neutropenia in 40%-50% of patients[31,35], while complications of RFA in this study were mild, primarily pneumothorax (21.5%) and alveolar hemorrhage (17.8%).
Adjuvant systemic therapy has improved disease-free and OS in patients with mCRC[36,37]. Most patients with mCRC eventually progress after first-line chemotherapy, and many agents have been evaluated for maintenance therapy after chemotherapy[16,38-42]. Prolonged chemotherapy in mCRC patients is often associated with cumulative toxicity, including oxaliplatin-induced neuropathy and irinotecan-induced steatohepatitis. Thus, efficient maintenance regimens with low toxicity that do not compromise survival are urgently needed. Capecitabine is approved for the treatment of mCRC[43]. Previous studies demonstrated that single-agent capecitabine may be appropriate for maintenance therapy after induction of XELOX or FOLFOX in patients with mCRC; the toxicity of capecitabine is acceptable[44,45]. Maintenance capecitabine therapy reduces the risk of disease progression in patients with mCRC-NED[43,46]. Thus, future randomized prospective trials in patients with mCRC-NED may use a lower starting dose of capecitabine.
The necessity of administering adjuvant systemic therapy for mCRC-NED patients is not supported by direct evidence. To the best of our knowledge, this is the first study focusing on the necessity of adjuvant chemotherapy after RFA for lung oligometastases from CRC. Auber et al[43] showed that the 5-year OS rate was 78% for patients with mCRC-NED receiving maintenance capecitabine therapy after surgical resection. Similarly, the present study demonstrated that the 5-year OS rate in the combined group was 88.7%. However, significant differences in PFS between the combined and only RFA groups were not detected. Consistent with previous reports, although not significant, PFS increased in patients who received maintenance therapy when compared with no maintenance group[47]. Palma et al[48] investigated the therapeutic efficacy of stereotactic ablative radiotherapy (SABR) in oligometastatic cancer. Their results demonstrated a 5-year PFS rate of 17.3% in the SABR group[48], which was lower than the 27.8% rate observed in our combined RFA and maintenance capecitabine group (combined). These findings suggest that the combined approach may offer a more favorable treatment option for pulmonary oligometastases from CRC. The 1-, 3-, and 5-year cumulative OS rates were higher in the combined group compared with the RFA group (P = 0.011). These findings suggest that adjuvant systemic therapy after RFA may prolong survival in patients with aggressive tumors. Adjuvant systemic therapy may reduce microscopic lesions[49]. A previous study[50] reported a 10% incidence of grade 3 adverse events in patients with CRC liver metastases receiving RFA combined with regorafenib and toripalimab, which is consistent with the 2% rate observed in our study.
The cumulative 1-, 3-, and 5-year LTP rates were 2.0, 10.9, and 22.7% in the combined group and 5.1%, 28.8%, and 49.0% in the RFA group, respectively. The differences in LTP rates may be due to patient selection for RFA. Low-risk patients with less history of colorectal liver metastases are often selected for RFA. Patients with fewer lesions and maximum tumor diameter < 3 cm are treated with RFA. Hence, their PFS rates were not significantly different between the two groups.
These findings suggest that RFA followed by capecitabine maintenance represents a tailored strategy for lung oligometastatic CRC. It balances the need for aggressive local control with the tolerability of long-term systemic therapy, addressing the variability in treatment response highlighted in clinical practice. Additionally, future randomized trials should standardize RFA protocols and validate this approach in broader populations.
While our findings suggest potential benefits of adjuvant capecitabine following RFA, several limitations inherent to the study design warrant careful consideration. First, the retrospective, non-randomized nature introduces the possibility of selection bias, as treatment allocation (only RFA vs RFA + capecitabine) was determined by multidisciplinary tumor boards based on individualized clinical factors rather than randomization. Although we employed rigorous multivariate Cox regression adjusting for key demographic, tumor-related, and procedural covariates including KRAS status, lesion characteristics, and complications, unmeasured confounders such as subtle performance status variations, patient preferences, or evolving institutional protocols may persist and influence survival outcomes. Second, the study cohort was derived exclusively from two tertiary centers in China, potentially limiting the generalizability of our results to broader populations with differing healthcare systems, genetic backgrounds, or practice patterns. Regional variations in CRC biology or access to alternative therapies could further affect extrapolation. Third, while standardized data collection and centralized imaging review mitigated inter-center variability, nuances in RFA technique execution or capecitabine dosing adjustments based on tolerance could introduce unquantified heterogeneity. Finally, the follow-up duration (median 40 months), while substantial, may be insufficient to capture very late recurrences or long-term toxicities definitively. These limitations underscore that our results should be interpreted as hypothesis-generating; prospective, multi-national randomized controlled trials are essential to confirm the efficacy and safety of this maintenance strategy and establish its role in clinical guidelines.
CONCLUSION
RFA confers prolonged survival and local control in patients with CRC pulmonary oligometastases. Adjuvant capecitabine increased OS and reduced LTP compared to RFA alone, but PFS was not significantly different. These findings warrant validation in prospective randomized controlled trials comparing RFA with vs without capecitabine maintenance, using OS as the primary endpoint and stratifying by baseline prognostic factors such as KRAS status, lesion characteristics. Future studies should incorporate translational substudies to elucidate the biological mechanisms underlying the OS/LTP-PFS dissociation observed, particularly exploring residual micro-metastatic disease and tumor dormancy. International collaborative randomized controlled trials would further assess generalizability and long-term safety, ultimately guiding evidence-based integration of local ablation and maintenance systemic therapy for oligometastatic CRC.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade B
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade B, Grade B
P-Reviewer: Bagus BI, Associate Professor, Indonesia; Hameed Y, PhD, Assistant Professor, Pakistan S-Editor: Fan M L-Editor: A P-Editor: Yu HG
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