Which ablation, for which tumor, in which patient?—reconsidering radiofrequency ablation for stage I non-small cell lung cancer

Surgical resection remains the standard of care for stage I non-small cell lung cancer (NSCLC), but up to one-fifth of patients are not operative candidates owing to medical comorbidities (1,2). For these patients, stereotactic ablative radiotherapy (SABR) has become the most widely adopted alternative, while image-guided thermal ablation occupies an established but less clearly defined role. The American Association for Thoracic Surgery (AATS) recently published expert consensus documents recognizing thermal ablation as a legitimate treatment option in this population and emphasizing the importance of multidisciplinary evaluation with thoracic surgical input (3-6). In this context, Christie and colleagues report one of the largest single-center experiences of computed tomography (CT)-guided radiofrequency ablation (RFA) for biopsy-proven stage I NSCLC in high-risk patients (7). In this commentary, I discuss the strengths and limitations of their findings, situate RFA within the broader landscape of thermal ablation modalities, and consider future directions for the field.

Christie and colleagues evaluated 111 patients (median age, 74 years; median Charlson comorbidity index, 6) with biopsy-proven stage I NSCLC who underwent CT-guided RFA between 2001 and 2018 (7). After a median follow-up of 30 months, overall survival (OS) was 86% at 1 year and 54% at 3 years, with a median survival of 39.5 months. Local progression in the treated lesion was detected by imaging criteria in 40% of patients, though histologically confirmed recurrence occurred in only 13%. Multivariate analysis identified tumor size less than 2 cm (P=0.043) and adenocarcinoma histology (P=0.01) as independent predictors of improved survival. The procedure was well tolerated, with no periprocedural mortality, and complications were largely limited to pneumothorax. Several features of this study merit recognition. The cohort exceeds 100 patients with biopsy-confirmed NSCLC, placing it among the largest in the RFA literature. All patients were evaluated and treated by thoracic surgeons, consistent with the multidisciplinary approach. The requirement for histological confirmation, not uniformly met in ablation series, enabled the identification of histology as a prognostic factor. Concomitant invasive procedures in 72% of patients, including fiducial placement to facilitate potential salvage SABR, reflect pragmatic real-world decision-making. The study builds on the early experience reported by the same group in 2007 (8), now with a substantially expanded cohort and longer follow-up.

To appreciate the contribution of Christie and colleagues, RFA must be situated within the broader landscape of image-guided thermal ablation. Three modalities are in current clinical use: RFA, microwave ablation (MWA), and cryoablation. Their physical principles, technical profiles, and biological consequences differ in clinically meaningful ways (Table 1). RFA generates frictional heat through high-frequency alternating current and is principally limited by the heat-sink effect, in which blood flow in vessels larger than approximately 3 mm and air flow in adjacent airways dissipate thermal energy in perivascular and peribronchial tumors (9-11). The 3-year OS of 54% in the Christie series compares favorably with the 3-year OS of 48% in Zhang and colleagues’ meta-analysis of 1,525 patients and is consistent with the 2-year OS of 69.8% reported in the only prospective multicenter trial, ACOSOG Z4033 (12,13) (Table 2). The rate of pneumothorax requiring drainage (69%) is strikingly higher than in either the Z4033 trial (~6%) or the pooled literature (27.2%), likely reflecting both the severity of underlying pulmonary disease and the high rate of concomitant procedures.

MWA achieves higher intratumoral temperatures and a more uniform ablation zone in a shorter time, with substantially less heat-sink susceptibility. These advantages translate into better outcomes for tumors larger than 2 cm or near mediastinal vessels (21,22). Single-arm series for stage I NSCLC report 1-year local control of 96% and 3-year OS of 43–93% in medically inoperable cohorts (14-16). The LUMIRA randomized trial directly comparing RFA and MWA found no significant difference in oncological outcomes or major complications (23), but many high-volume centers have shifted toward MWA during the latter half of the period covered by Christie’s series.

Cryoablation operates on an entirely different principle. Rapid tissue cooling via the Joule-Thomson effect of high-pressure argon gas produces intracellular and extracellular ice crystal formation, followed by osmotic injury, microvascular thrombosis, and apoptotic cell death during the thaw phase (24,25). Three features distinguish it from heat-based modalities. First, the ice ball is directly visible on CT, allowing real-time confirmation of margins relative to adjacent critical structures (24-27). Second, cryoablation preserves the collagenous architecture of the treated tissue, reducing the risk of bronchial or vascular injury when ablating tumors near central structures (28,29). Third, the procedure is substantially less painful and can often be performed under local anesthesia alone, an important consideration in elderly patients with limited cardiopulmonary reserve. We have previously reported our experience with percutaneous cryoablation in 22 patients with medically inoperable stage I NSCLC (17), in whom the mean tumor diameter was 1.4 cm and the median Charlson comorbidity index was 5, a cohort closely matched in comorbidity profile to that described by Christie and colleagues (7). In this series, the 3-year OS was 88%, the 3-year local control rate was 97%, and pulmonary function was preserved at 3 to 6 months after cryoablation. In an earlier report, we also documented the feasibility of cryoablation for pulmonary nodules in the residual lung after pneumonectomy, an extreme example of the high-risk anatomy in which the preservation of normal lung tissue offered by ablation may represent the only realistic local treatment option (30). Subsequent prospective multicenter trials including ECLIPSE and SOLSTICE have confirmed the safety and durability of cryoablation in the lung (18,19), and Moore and colleagues have reported a 5-year survival rate of 67.8% for medically inoperable stage I NSCLC treated with cryoablation (20).

The prognostic significance of tumor size below 2 cm, the central finding of the Christie study, is concordant across modalities. Dupuy and colleagues reported a 2-year OS of 83% for tumors <2 cm in their prospective RFA trial, and our own cryoablation cohort, in which the mean tumor diameter was 1.4 cm, achieved a 3-year OS of 88% (9). The clinically meaningful question is no longer “does ablation work?” but “which ablation, for which tumor, in which patient?”

Among the methodological considerations raised by the Christie study, the temporal context of accrual is the most consequential. The 2001–2018 period spans a transformation in the very definition of “early-stage lung cancer”. Low-dose CT screening, introduced on a large scale after the 2011 National Lung Screening Trial, has progressively enriched the stage I population with ground-glass opacity (GGO)-dominant adenocarcinomas, many of which exhibit indolent behavior and excellent long-term outcomes regardless of the local therapy chosen. The JCOG0804/WJOG0507 trial reported a 5-year recurrence-free survival of 99.7% after sublobar resection for GGO-dominant lung cancers with a consolidation-to-tumor ratio ≤0.25 (31), and contemporary cryoablation series for GGO-dominant lesions have reported essentially no local recurrences at median follow-up exceeding two years (32). The Christie cohort predates the era in which such lesions came to dominate screening-detected stage I NSCLC, and the authors do not provide a subgroup analysis by radiological tumor morphology. For an elderly patient with a 1.2 cm part-solid GGO-dominant adenocarcinoma detected on screening, the relevant comparator may not be the pooled RFA literature but the 99.7% recurrence-free survival reported for sublobar resection in JCOG0804.

Two further methodological points deserve brief mention. The discrepancy between imaging-based (40%) and histologically confirmed (13%) local progression underscores the unresolved problem of ablation-specific response criteria, a limitation shared across thermal ablation modalities. The prognostic advantage of adenocarcinoma over squamous cell carcinoma is consistent with literature spanning SABR, thermal ablation, and surgical resection (33,34), and likely reflects underlying tumor biology rather than modality-specific sensitivity to radiofrequency energy.

Christie and colleagues have provided a valuable contribution to the ablation literature: a large, carefully selected, biopsy-proven cohort of high-risk patients treated by thoracic surgeons, with long-term follow-up and identification of clinically meaningful prognostic factors. Looking forward, the role of thermal ablation is likely to be shaped by two emerging developments.

The first is the transition from percutaneous to bronchoscopic delivery. CT-guided percutaneous ablation, whether RFA, MWA, or cryoablation, carries a substantial risk of pneumothorax, which was the dominant procedural complication in the Christie series. Transbronchial approaches, including transbronchial RFA as evaluated in the recent BRONC-RFII multicenter trial (35) and transbronchial cryoablation (36), may eliminate this complication while leveraging advances in navigational bronchoscopy for accurate probe placement. For the high-risk population described by Christie and colleagues, in whom even a moderate pneumothorax can precipitate respiratory decompensation, the reduction in procedural morbidity may matter as much as oncological efficacy.

The second development is the integration of ablation with systemic immunotherapy. Thermal ablation induces immunogenic cell death, releasing tumor-associated antigens and altering the tumor microenvironment in ways that may potentiate immune checkpoint inhibition (37,38). Early clinical data with combinations of MWA or cryoablation with immune checkpoint inhibitors have shown encouraging response rates in advanced NSCLC (39,40). Cryoablation may be particularly suited to this synergy, as it triggers a robust type I interferon-dependent antitumor immune response (41). The Christie cohort was accrued predominantly in the pre-immunotherapy era. Future studies should evaluate ablation not in isolation but as part of an integrated multimodal strategy.

The question is no longer whether thermal ablation works for high-risk patients with stage I NSCLC. The question is how to integrate it optimally into a personalized treatment strategy for each patient by selecting the right modality, the right delivery platform, and the right systemic partner.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Shanghai Chest. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2026-0017/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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