A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation—part 4: systematic review of evidence involving SBRT and ablation

Introduction

Treatment options for stage cI non-small cell lung cancer (NSCLC) have evolved. Detected tumors are smaller and biologically less aggressive. Patients are older and comorbidities more frequent. Choosing the best treatment is complex; multiple short- and long-term outcomes are relevant. The available evidence is suboptimal, confusing, with many confounders—factors that affect both treatment selection and outcome. We need a better understanding of the evidence, sources of uncertainty, and nuances of patients, tumors and settings that affect the applicability thereof.

This project strives to comprehensively evaluate the evidence regarding stage cI NSCLC, critically addressing confounders and limitations. Furthermore, we sought to assemble this in a concise format that enhances clinical decision-making for individual patients. The project consists of 4 publications: Part 1 summarizes the evidence and provides a framework to guide clinical decision-making (1), Part 2 reviews evidence regarding surgery in generally healthy patients (2), Part 3 addresses specific patients and tumors (3), and Part 4 (this paper) focuses on evidence regarding SBRT and ablation.

Methods

General approach

Details of the general approach are provided elsewhere (Methods section of Part 1) (1). Briefly, the focus is patients with stage cIA NSCLC (using the 8th edition nomenclature throughout). Interventions include lobectomy, segmentectomy, wedge resection, SBRT and ablation. Relevant outcomes were chosen a priori: treatment-related mortality, toxicity/morbidity, pain, functional capacity, quality-of-life (QOL), overall survival (OS), lung cancer specific survival (LCSS), and freedom-from-recurrence (FFR).

Because few randomized controlled trials (RCTs) are available for this topic, we relied heavily on non-randomized comparisons (NRCs) that adjusted for confounders. How well confounders were addressed was critically evaluated to judge the confidence that observations could be attributed to the intervention in question. Furthermore, we explored sources of ambiguity to understand uncertainties and limitations of applicability.

Literature search, study selection and evidence assessment

We performed a systematic literature search in PubMed from 2000–2021. Details of the search strategy, selection and review process are provided elsewhere (see App. 1-2 of Part 1) (1). Each table lists specific inclusion and exclusion criteria.

Study quality was assessed using a general tool (4) and an adaption thereof specific to stage I NSCLC (described in App. 2-1 of Part 2) (2). Residual confounding in seven a priori defined domains is shown in the evidence tables along with the confidence that observed results reflect the treatment intervention. The domains include non-medical and medical patient-related factors, discrepancies in stage classification, time period, facility factors, treatment quality and favorable tumor selection.

Aggregation of evidence

A quantitative meta-analysis was deemed inappropriate due to the degree and variability of residual confounding. Instead, thoughtfully structured tables reflecting nuances of the patients, treatments and tumors provide an aggregate impression of the strengths, weaknesses and applicability of the data. We have used color coding, essentially layering a heat map onto the tables to facilitate gaining an overview without getting lost in details. This presents the data in a manner that provides an aggregate view of an outcome at-a-glance as well as nuances and uncertainties of the data. The table structure is noted as a subtitle. We aim to enhance individualized decision-making through this comprehensive yet nuanced presentation.

Results

General results of SBRT vs. surgery

Short-term outcomes

Treatment-related morbidity and mortality

Treatment-related mortality is meaningfully lower for SBRT than surgery (90-day mortality ~1% vs. ~3%, respectively, Table S4-1) (5-14). The difference is more pronounced in adjusted NRCs and slightly diminished with VATS surgery.

Short-term toxicity/morbidity appears lower after SBRT vs. surgery, although direct comparison is hampered by the different nature and timing of complications. Grade ≥3 toxicity within 6–12 months of SBRT is reported in 2–5% (Table S4-2) (15-34). The rate is similar for central vs. peripheral tumors (using appropriate dose-fractionation adjustments). Central tumors (1–2 cm from the proximal tracheobronchial tree) tend to be associated with hemoptysis, pericardial effusion, and esophagitis and peripheral tumors with dermatitis, rib fractures, and chest wall pain. SBRT toxicity accumulates over time; ~10–20% of patients experience grade ≥3 toxicity by ~2 years. The rate of grade ≥3 toxicity appears slightly higher in prospective controlled trials than prospective databases, and in inoperable vs. operable patients. Similar toxicity (and survival/control) rates are seen among generally accepted dose/fractionation schemes (e.g., 1× 30–34 Gy, 3× 18–20 Gy, 5× 10–11 Gy, 8× 7.5 Gy; selected based on tumor location and adjacent tissues at risk) (23,26,35).

Short-term QOL

Approximately 25–30% of patients reported meaningful worsening of QOL at 3 months after SBRT and an equal proportion a meaningful improvement in a large study (34). Similar results were noted at 1 and 4 months in another smaller study (36). QOL averaged across the entire cohort, however, is unchanged after SBRT in multiple studies (see subsequent QOL section).

Long-term outcomes

Survival

Several RCTs comparing SBRT to resection in healthy patients closed after accruing only a few patients (Figure 1). The STARS and ROSEL RCTs compared SBRT and lobectomy in lobectomy-eligible patients with cI-IIA NSCLC (≤4 cm). Both were closed due to poor accrual (STARS after 4 years, ROSEL after 2 years). Pooled results (58 patients, median follow-up 35–40 months) demonstrated better OS after SBRT [hazard ratio (HR) 0.14, P=0.037]; there was no difference in recurrence-free survival (RFS, HR 0.69, P=0.53) or local, regional and distant failure rates (37). There were no apparent imbalances among the patient cohorts [mean age 67, 98% performance status (PS) 0–1, 87% cIA]. The results are provocative; however, the limited accrual limits having confidence in the findings.

Figure 1 Closed randomized studies of SBRT vs. surgery.
Closed RCTs of SBRT vs. surgery showing the resection extent, tumor size and the type of patients involved, as well as the final accrual. Lobe, lobectomy; Periph, peripheral; SBRT, Stereotactic body radiation therapy.

Several RCTs in good-risk patients are ongoing (Figure 2). The VALOR study (38) compares SBRT to lobectomy or segmentectomy (target accrual 670, results anticipated in 2027). A randomized phase II study of SBRT vs. surgical resection in cIA in China (POSTILV) (39) remains active, seeking to enroll 76 patients from 2012–2021. The prolonged period and limited size of this study raises concerns.

Figure 2 Ongoing RCTs of SBRT vs. surgery for lung cancer.
Ongoing RCTs of SBRT vs. surgery showing the resection extent, tumor size and the type of patients involved, with accrual targets and anticipated timeline. Lobe, lobectomy; SBRT, Stereotactic body radiation therapy; Seg, segmentectomy; VA, US Veterans Administration Healthcare System.

Table 1 (7,9,10,13,40-57), Table 2 (8,9,40,42,49,58-63), and Figure S4-1A,S4-1B summarizes adjusted NRCs of SBRT vs. surgery. Surgery involved lobectomy in most studies. OS favors surgery in almost all studies, especially those that adjusted extensively for confounders. This is less true in studies with short follow-up, consistent with the observation that downsides manifest early after surgery and later for SBRT (7). It is unclear if T-stage has an impact; however, most patients had small tumors.

The difference in OS is clinically relevant (20–30% 5-year absolute difference). Figure 3 depicts extensively adjusted OS of patients with a comorbidity score of 0 and eligible for surgery (41). The results were confirmed in patients recommended to have surgery but refused. Worse 5-year OS after SBRT than resection (42% vs. 64%) was similarly found after extensive propensity-matching of patients in whom surgery was recommended but who declined for non-medical reasons in another study (40).

Figure 3 SBRT vs. lobectomy in patients without comorbidities.
Overall survival in patients with stage cI NSCLC and without comorbidities treated by full-dose SBRT (biologically effective dose of ≥100 Gy) vs. lobectomy. All were surgery-eligible and had a Charlson-Deyo score of 0 (NCDB, 2008-12). (A) Propensity-matched patients and (B) propensity-matched subset who were recommended to have surgery but refused. Reproduced with permission from Rosen et al. (41). SBRT, stereotactic body radiation therapy.

However, addressing confounding is inherently difficult when one treatment is typically selected for robust and another for compromised patients. Better outcomes are consistently reported in operable vs. inoperable patients (24,64-66). Among matched patients in studies reporting this, the proportion of patients with PS ≥2 was 2–59% for SBRT and 0–17% for surgery (44,45,51,54,56,57). The proportion with a Charlson-Deyo score of ≥2 was 14–55% for surgery and 13–61% for SBRT (7-10,40,42,49,51,54,56,58-60,62). Unsuspected node involvement occurred in 14% (range 3–21%) of surgical patients (unknown among SBRT patients) (6,41,44,45,47,49-52,54,56-58,62,67). Furthermore, 0–70%, of the “matched” SBRT patients were designated as “medically inoperable” (44,47,50-52,54,56). Thus, concern of residual confounding remains (e.g., severity of comorbidities, frailty), despite attempts to account for comorbidities. Of note, while LCSS consistently favors surgery, this is less frequently statistically significant.

Recurrence

We think the best measure of recurrence is FFR and locoregional FFR (LR-FFR). Locoregional recurrence is most easily defined similarly for SBRT and surgery (an issue with inherently different treatments). DFS/RFS mixes recurrence and unrelated deaths. Recurrence is affected by the follow-up duration and protocol.

NRCs of recurrence after SBRT vs. resection (Table 3) have generally involved only limited adjustment for confounders (43,44,47,48,50-57,60,61,68-72). Generally, more recurrences are reported after SBRT, but one study found the opposite (despite short follow-up in surgical patients) (51). The number of studies, limited adjustment for confounders and ambiguities of outcome assessment hamper confidently drawing conclusions about recurrence after SBRT vs. resection. A prospective trial of SBRT followed by resection 10 weeks later found viable tumor in 40% of patients—but the relevance of this finding is unclear given the much lower rate of local failure after SBRT (73).

Long-term QOL

Multiple studies show that SBRT has no negative impact on QOL (Table 4) (20,26,34,36,74-87) despite mostly using the more sensitive EORTC assessment (vs. the SF-36). The minimal impact on QOL is seen despite many PS2 patients and most being deemed medically inoperable. Assessing the average for the entire cohort can obscure relevant subsets: 25–30% of patients are meaningfully worse and a similar proportion meaningfully better 3–24 months after SBRT in both global QOL and physical functioning (34). In this study of 382 patients the proportion with worsening physical functioning tended to increase between 12–24 months) (34).

Long-term toxicity

While short-term toxicity following SBRT is low, prospective studies report 10–30% grade ≥3 late toxicity (Table S4-2A) (17,29,80,84,88-96). Most studies reported treatment-related toxicity, but some adverse events may be attributable to underlying poor health. Approximately 25% of patients had a PS of ≥2. Operable patients may have slightly less late toxicity (Table S4-2B) (24,34,97).

Pulmonary function tests (PFTs)

PFTs were used as a surrogate for functional capacity in the absence of direct data on functional capacity. The reported average long-term decline in PFTs (Table S4-3) (17,29,80,84,88-96) after SBRT is low and not clinically meaningful. However, a substantial proportion of patients experienced a ≥10% decline (~40–50%) or a ≥25% decline (~15–25%). Fewer patients experienced a ≥10% or ≥25% improvement. The average baseline FEV1 (64%) or DLCO (58%) in these SBRT patients was fairly high. As noted in 2 studies, 10–20% of SBRT patients used oxygen pre-treatment, an additional 3% required it later (88,89).

Large observational studies of smokers with moderate chronic obstructive pulmonary disease (COPD) indicate an FEV1 loss of ~50 mL/year or ~1.3%/year (absolute percent-predicted) (98-100). The decline is slower with more severe COPD and markedly diminished after smoking cessation (98-100). While there is individual variability, the chance of a >10% relative FEV1 decline in 1–2 years due to the natural history of COPD is very low, even in active smokers.

Nuances and sources of ambiguity

Modified fractionation schemes (e.g., 5 fractions while decreasing the biologic effective dose) have rendered SBRT for central tumors (1–2 cm from the proximal tracheobronchial tree) as safe and effective as in peripheral tumors (15,17,22). Toxicity concerns remain for ultra-central tumors (≤1 cm from the trachea, mainstem and lobar bronchi), especially with higher doses and fewer fractions (101-104). The HILUS and SUNSET trials are exploring hypofractionated regimens (8–15 fractions) (105,106). Grade 3 toxicity was noted in 22% and grade 5 in 15% in the HILUS trial (105), suggesting that segmentectomy or lobectomy if possible may be better treatment choices for ultra-central tumors.

Factors independently associated with long-term outcomes are not well-defined. Worse outcomes are reported with squamous vs. adenocarcinoma in some studies (multivariable HR ~1.7–2.4) (66,107), but not others (108,109), with rapidly growing tumors (multivariable HR ~1.4–1.5) (109), with high PET-avidity in some studies (multivariable HR ~4–6) (110) but not others (107,111), and larger tumors in some studies (multivariable HR ~1.2–9) (66,108,110,111) but not others (107,109,112). Reasonable outcomes are reported even for tumors >5 cm (113,114).

In conclusion, technical/anatomic factors may impact toxicity and treatment choice. Other tumor-related prognostic factors are not well-defined.

Summary of general evidence for SBRT vs. surgery

Short-term mortality is meaningfully better after SBRT than surgery. While significant acute morbidity/toxicity is low, 10–20% of SBRT patients experience grade ≥3 toxicity by 2 years. Average QOL is not decreased after SBRT. Comparing across studies, this is clearly better than surgery, which causes major short-term QOL impairment, and sustained long-term impairment after open resection (less so after VATS). On average, PFTs are minimally decreased after SBRT, although 20–40% of SBRT patients experience a clinically meaningful decrease after 1–2 years. Preservation of PFTs with SBRT is clinically relevant vs. lobectomy, at most marginally meaningful vs. segmentectomy.

Completed RCTs are inconclusive due to limited accrual. Ongoing RCT results in good risk and high-risk patients are anticipated in 2024–26. Adjusted NRCs quite consistently demonstrate a highly clinically relevant detriment in OS and LCSS for SBRT vs. lobectomy or vs. sublobar resection. This is most apparent in more extensively-adjusted NRCs. Nevertheless, adjustment for confounders is inherently challenging when comparing SBRT and surgery.

SBRT vs. surgery in older patients

Short-term outcomes

Mortality and toxicity

A US National Cancer Database (NCDB) study of post-treatment mortality found little difference in 30- and 90-day mortality for SBRT vs. surgery below age 70 (Figure 4) (5). In older patients there is a clinically meaningful benefit to SBRT. This was confirmed in propensity-matched cohorts (moderate confidence that confounders are accounted for) (5). Similarly, another NCDB study of healthy patients (Charlson score 0) age ≥80 noted better unadjusted 90-day mortality for SBRT (0.7%) vs. lobectomy (3.3% by VATS, 6.7% by thoracotomy, 5.6% total) (6).

Figure 4 Short-term mortality by age and treatment modality.
Post-treatment 90-day mortality of early stage lung cancer patients by age cohorts; Unadjusted rates and hazard ratio in propensity-matched groups. Data taken from Stokes et al. (5). Lobe, lobectomy; SBRT, stereotactic body radiotherapy; SL, sublobar resection.

Data regarding toxicity of SBRT has not been parsed to specific age cohorts. However, the average patient age in general studies of SBRT is ~70–75. Comparing across studies suggests less grade ≥3 short-term toxicity after SBRT (5–10%) than surgery (10–20%) in older cohorts (Table S4-2 and see Older Patients section of Part 3) (3).

Long-term outcomes

No RCTs have addressed SBRT vs. resection in older patients. Adjusted NRCs (Table 5 and Figure S4-2) (6,9,11,12,42,58,67-70,115-117) demonstrate worse OS and LCSS after SBRT than surgery (with few exceptions). The difference in adjusted OS is clinically relevant (5–25% absolute difference). Differences were more often statistically significant in the more extensively-adjusted studies. The differences don’t appear to vary by the extent of surgical resection, age cohorts or tumor size. Adjusted NRCs addressing recurrence found worse RFS and higher locoregional recurrence after SBRT than surgery (Table 3) (53,68,70).

QOL and long-term toxicity

Data regarding QOL in older SBRT patients was not identified. An adjusted NRC of long-term toxicity in older patients (Figure S4-3, low confidence rating) noted that post-resection complications primarily occur within 1 month; subsequently few additional morbidities develop. In contrast, after SBRT early toxicity is unusual, but a consistent higher incidence of toxicity over time leads to a cumulative equal incidence for SBRT and surgery by 2 years (7).

Summary of SBRT vs. surgery in older patients

SBRT is associated with a clinically meaningful short-term mortality benefit vs. surgery (1–4%). This is more pronounced as age increases, and for open resection (vs. VATS). Morbidity is higher initially after surgery, but late toxicity after SBRT renders the overall incidence relatively equal after 2 years. Surgery (especially open) impairs QOL; SBRT has little impact.

Several extensively adjusted NRCs in older patients suggest meaningfully worse OS after SBRT vs. surgery; often differences were not statistically significant. Age and tumor size do not appear to affect the differences.

SBRT vs. surgery in compromised patients

Short-term outcomes

Short-term outcomes after SBRT have not been specifically addressed in compromised patients. Most of the SBRT patients in the general evidence tables were deemed medically inoperable. However, average reported characteristics (FEV1 >60%, DLCO >50%, PS 0,1 in >75%) leaves uncertainty regarding short-term outcomes in patients with FEV1 or DLCO <40% or PS ≥2. Speculation suggests that outcomes would be worse than the general reported results of SBRT.

Long-term outcomes

Survival and recurrence

Two RCTs in high-risk patients were initiated but had limited accrual (ACOSOG Z4099 (118) and SABRTooth (119), Figure 1). No long-term results have been published, but the limited enrollment leaves little hope that results would be revealing.

The STABLE-Mates trial (120) is ongoing, comparing SBRT to sublobar resection in cI-IIA high risk patients as defined by the ACOSOG criteria (FEV1 or DLCO <50%, or 2 minor criteria including age ≥75, FEV1 or DLCO 51–60%, Figure 2). The target accrual is 272, with results expected in 2024.

Few NRCs with limited adjustment have compared SBRT with surgery in compromised patients (Table 6 and Figure S4-4) (7,9,49,58,71,72,121,122). Results suggest worse OS and LCSS after SBRT than surgery (mostly not statistically significant). The adjusted OS difference was meaningful (10–20%). A multivariable analysis parsed by FEV1% did not suggest greater differences with lower FEV1 or by resection extent—LCSS was consistently worse (mostly statistically non-significant) after SBRT vs. lobectomy (FEV1% 51–80% HR 1.3; 31–50% HR 1.26; ≤30% HR 1.55) and vs. sublobar resection (FEV1% 51–80% HR 1.47; 31–50% HR 2.01; ≤30% HR 1.45) (9). Whether FFR or LR-FFR is worse after SBRT than surgery in compromised patients is unclear (few reported NRCs, Table 3) (71,72).

QOL and PFT studies

QOL after SBRT specifically in compromised patients has not been reported. However, SBRT probably has little average impact because many patients in QOL studies (Table 4) were PS ≥2 or medically inoperable.

Most studies of PFT changes after SBRT (Table S4-3) included a broad spectrum of patients with relatively good PFTs. Limited data specifically on compromised patients suggests that SBRT is well tolerated: no change or a slight improvement was noted in FEV% in patients with GOLD III-IV COPD (88) or cohorts with low baseline FEV1 [average 40% (123) or <50% (89)]. Others report similar findings (29). Multivariable analysis of the RTOG0236 trial revealed no correlation of any PFT parameters and pulmonary toxicity (96). While this is reassuring, the effect of SBRT on severely compromised patients (e.g., FEV1 or DLCO of <40%) is unclear.

Complications/toxicity

Yu et al. compared complications/toxicity after SBRT vs. surgery in propensity-matched high- and low-risk cohorts (7). The cumulative incidence of chest morbidity (cardiopulmonary, esophageal) was nearly double in high- vs. low-risk cohorts with either surgery or SBRT, but the relative benefit of SBRT over surgery was similar in high- and low-risk cohorts (Figure S4-5). Other comparative data was not identified.

Nuances and sources of ambiguity

Interstitial lung disease (ILD), a heterogeneous group of diffuse parenchymal lung diseases, deserves specific discussion. Non-fibrotic ILDs includes multiple inflammatory, multinodular and cystic lung disorders; these are not associated with lung cancer, often acute, and usually respond well to treatment of the underlying etiology (124). Fibrotic ILDs are more common, portend a high risk (10–20%) of developing lung cancer, and a risk of radiation-related toxicity. Fibrotic ILDs may be caused by connective tissue disorders, hypersensitivity pneumonitis, and pneumoconiosis. Most concerning is idiopathic pulmonary fibrosis (IPF): it is frequently progressive, life-limiting and associated with radiation toxicity (124). However, categorization of fibrotic vs. non-fibrotic ILD is imperfect. ILD can overlap with obstructive lung disease (combined pulmonary fibrosis and emphysema)—also associated with development of lung cancer, worse outcomes, and treatment-related complications (125-128). Additionally, some patients have incidentally-noted interstitial lung abnormalities, which may not be progressive or require a unique treatment plan (129).

The first step, establishing whether interstitial imaging findings represent actual ILD, requires a knowledgeable pulmonologist and often a multidisciplinary ILD team. The next step is estimating prognosis—3-year mortality of ILD varies from 10% to 75% (124). Additionally, ~10%/year of IPF patients develop random acute exacerbations, with a 3-month median survival (124).

The third step, treatment selection, is difficult. IPF patients typically have poor DLCO and significant restrictive pulmonary compromise. A recent systematic review of toxicity noted SBRT was associated with high treatment-related toxicity (25%) and mortality (16%, Table S4-4) (130). Treatment-related ILD mortality was 7% in studies that appear to focus on mild ILD vs. 22% in the remainder (130). Surgery had better outcomes, but the patients are likely not comparable. An increased risk of post-operative ILD exacerbation is associated with a history of exacerbations, preoperative steroids, usual interstitial pneumonia pattern, and reduced lung function (131,132). Reported 3-year survival of ILD patients with lung cancer is 50–60% (130).

Other major comorbidities rendering patients compromised are not clearly tied to greater risk or efficacy of any treatment. Tumor characteristics influencing the effectiveness of surgery, SBRT, or ablation are discussed elsewhere in this and the Parts 2 and 3 papers (2,3).

Summary of outcomes in patients with limited pulmonary reserve

Extrapolation from general evidence and older patients suggests a meaningful short-term mortality and morbidity benefit for SBRT over surgery. This may be accentuated in more compromised patients and slightly diminished with VATS resection, less clearly by sublobar resection.

NRCs of compromised patients consistently show long-term downsides for SBRT vs. surgery (10–20% worse 5-year OS). However, studies are limited, only partially adjusted, and results are mostly statistically non-significant. The patients are undoubtedly selected; limited data does not suggest a potential marker to guide treatment selection (e.g., cohorts of Charlson scores or FEV1%) (9).

Methods of ablation

Percutaneous ablation of lung tumors has been used for >20 years, including when there are contraindications to surgery or SBRT (e.g., poor PFTs, ILD, prior radiotherapy, difficult anatomy). It is not clear that one method of ablation is better than another (133); radiofrequency, microwave and cryoablation are most common. While many single-modality reports of lung ablation demonstrate reasonable local control and OS, comparative studies of ablation vs. SBRT or surgery are limited and not well-parsed to specific techniques, patients or tumors. Therefore, this section addresses all methods of percutaneous ablation collectively for all patients.

Short-term outcomes

Treatment-related toxicity

Several large series (>200 patients) (134-136) and systematic reviews (137) report pneumothorax (often presenting after several days) in 10–70% with 10–50% of these requiring a chest tube. Grade ≥3 morbidity is seen in 10–20%, and includes pleuritis, bleeding, lung abscess and pneumonia (each in ~1–3%). Similar frequencies were noted in smaller prospective studies (86,87,138). Larger series report a 30-day mortality of 0.3–0.5% (134-136); but 90-day mortality was 3.8% in a large study (NCDB, 2004–14, 1,009 ablation patients) (139).

Long-term outcomes

Survival

Adjusted NRCs (Table 7 and Figure S4-6) (59,139-149) demonstrate worse long-term outcomes after ablation than resection. The differences appear larger than for SBRT vs. resection (Table 1), but studies are limited and residual confounding makes interpretation difficult. Most studies report an average age of ~75, and a Charlson comorbidity score of ≥2 in 15–20%. Reported OS is low for early-stage NSCLC—likely reflecting both patients’ general health and treatment efficacy (ablation yields worse LCSS than resection).

One adjusted NRC (149) found no difference in DFS or recurrence pattern between microwave ablation vs. lobectomy; extensive residual confounding precludes drawing firm conclusions regarding recurrence.

QOL

Very limited data (Table 4) demonstrates a mild decrease in some parameters 1 month after percutaneous ablation, but no evidence of long-term QOL impairment (85-87).

PFTs

Ablation appears to have limited but variable impact on PFTs. At 3 months, an increase of 2–6% in the average FEV1 has been observed (85,86,138). At 12–24 months, average FEV1 is 1–5% lower in several studies (85,86,150) and increased 5% in one (albeit with frequent missing data); similar results are seen for DLCO (138). Regarding subsets, at 3 months 10–20% of patients experienced a >10% FEV1 increase and a similar proportion a ≥10% decrease (i.e., a meaningful change) (87,138). Similar findings are reported for DLCO (138). Long-term 20–30% of patients experienced a ≥10% increase in FEV1 or DLCO, with a similar proportion experiencing a ≥10% decrease (138).

Nuances and ambiguity

The mechanism of action of specific ablation modalities (radiofrequency, microwave or cryoablation) affects efficacy, technical considerations (ablation size, number of needle punctures, maintenance of tissue architecture, etc.), and risk of complications (151). For example, cryoablation may increase the risk of pneumothorax and bleeding by requiring more needle punctures, while the increased power of microwave can shorten treatment times—these features may weigh more heavily in particular cases. Local expertise with particular ablation modalities is important. Similarly, local expertise with advanced image guidance and percutaneous ablation vs. SBRT should weigh in choosing a treatment approach (152).

Tumor-related factors can impact both efficacy and risks of ablation. Studies report >95% local control with tumors ≤2 cm, but considerably less for tumors >3 cm (153). Larger ablation zones increase the concern of complications; note that 8–10 mm of ablation beyond the tumor is recommended to reduce recurrence (154). Anatomical location, i.e., adjacent to pericardium, bronchus, pulmonary artery, diaphragm or blebs) affects concerns about toxicity. Patient-related factors may increase the risk of complications (e.g., degree of emphysema, ILD) (155).

Logistical issues affect deciding on the best treatment approach. Percutaneous ablation permits biopsy and treatment during the same session. Ablation is convenient, typically involving a single session. However, ablation is usually done under general anesthesia to control respiration and optimize tumor targeting.

Percutaneous ablation is an option for recurrence after prior radiotherapy. Furthermore, unlike radiotherapy or surgery, percutaneous ablation can be repeated as many times as necessary.

Summary of results of ablation vs. surgery or SBRT

Comparing across studies suggest that ablation is associated with a higher rate of short-term complications than SBRT. Short-term (90-day) mortality may be higher after ablation than SBRT comparing across studies (whether the patients are comparable is unclear). Surgery is associated with short-term pain and impairment of QOL in contrast to ablation. However, while some data suggests that 90-day mortality and an overall rate of Gr ≥3 complications is similar after ablation vs. surgery (especially VATS), this may be misleading because it is likely that the surgical patients are more carefully selected.

Adjusted NRCs indicate that OS or LCSS is clinically meaningfully worse after ablation vs. resection, and to a lesser degree after ablation vs. SBRT. However, the number of studies and degree of adjustment for confounders is limited. It is likely that many of the patients in these NRCs are compromised, but this is poorly characterized.

Key drivers of patient selection are avoiding patients likely to experience complications (severe emphysema, tumor surrounded by vessels) and technical factors limiting efficacy (e.g., tumor size).

Overall summary of SBRT or ablation vs. surgery

Outcomes for SBRT or ablation vs. lobectomy or sublobar resection are summarized in Table S4-5A-S4-5C. A benefit or detriment is qualitatively depicted relative to clinically meaningful differences, together with the confidence in and consistency of the evidence. This provides a succinct summary that can inform judgment for individual patients, as discussed in the Part 1 paper (1).

Conclusions

It is a major asset to have several treatment options for stage I NSCLC. In general, the short-term benefits of SBRT and ablation over surgery are clinically meaningful (e.g., mortality, morbidity/toxicity, QOL). This is offset by a clinically meaningful downside in long-term outcomes. In older patients the short-term benefits of SBRT and ablation are marginally increased, and the long-term downsides slightly diminished. In seriously compromised patients there is limited evidence, but it appears that short-term benefits are increased and long-term downsides diminished vs. surgery. Selection based on patient characteristics is poorly defined; tumor characteristics that influence technical feasibility of particular modalities are important considerations. ILD is particularly problematic due to the interplay of accurately diagnosing ILD, estimating relative prognosis of the ILD and lung cancer, and significant treatment-related toxicity and mortality.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease for the series “A Guide for Managing Patients with Stage I NSCLC: Deciding between Lobectomy, Segmentectomy, Wedge, SBRT and Ablation”. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1826/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1826/coif). The series “A Guide for Managing Patients with Stage I NSCLC: Deciding between Lobectomy, Segmentectomy, Wedge, SBRT and Ablation” was commissioned by the editorial office without any funding or sponsorship. FCD served as the unpaid Guest Editor of the series. HSP serves as an unpaid editorial board member of Journal of Thoracic Disease. HSP reports research funding from RefleXion Medical; consulting fees from AstraZeneca; honoraria and speaking fees from Bristol Myers Squibb; and advisory board fees from Galera Therapeutics; all unrelated to current work. DCM reports that he is the lead for an early career educational course on microwave ablation that is sponsored by Johnson & Johnson. BCB reports in the past 36 months, he receives grants from Veterans Affairs Central Office, American Cancer Society, Yale SPORE in Lung Cancer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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