A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation—part 2: systematic review of evidence regarding resection extent in generally healthy patients

Introduction

Treatment options for clinical stage I (cI) non-small cell lung cancer (NSCLC) have evolved. Smaller tumors are being detected; average patient age is increasing, as is the number with co-morbidities. We need to match the treatment to the patient and tumor, avoiding both overtreatment and undertreatment.

Decision-making regarding stage I NSCLC is complex. Many short- and long-term outcomes are relevant. We aim to practice evidence-based medicine (EBM), but the available evidence is suboptimal and confusing. Multiple factors influence treatment selection and independently the prognosis, and evidence often only partially applies to an individual patient. Although clinicians are used to weighing various considerations and complex decision-making, better definition of the evidence regarding management of cI NSCLC is needed, including sources of uncertainty, and nuances of patients, tumors and settings that affect applicability.

We assessed the evidence regarding cI NSCLC, critically addressing confounders and limitations, to provide clarity and confidence in applicability in various circumstances. Furthermore, we developed a concise format that enhances application to individual patients. The project consists of 4 publications: Part 1 concisely summarizes the evidence and provides a framework to guide clinical decision-making (1), Part 2 (this paper) reviews evidence regarding surgery in generally healthy patients, Part 3 addresses surgery in specific patients and tumors (2), Part 4 focuses on evidence regarding SBRT and ablation (3).

Methods

General approach

The approach involved being as inclusive and as critical as possible, with attention to nuances about settings and characteristics of the available evidence to understand limitations and applicability. A detailed description of the approach is provided in the methods section of Part 1 (1). Briefly, the subject is stage cIA NSCLC (using the 8^th edition nomenclature throughout); interventions include lobectomy, segmentectomy, wedge resection, SBRT and ablation. The most relevant outcomes were chosen a priori: short-term treatment-related mortality, toxicity/morbidity, pain, quality-of-life (QOL) and long-term overall survival (OS), lung cancer specific survival (LCSS), freedom from recurrence (FFR), functional status and QOL.

Because few randomized controlled trials (RCTs) are available, we relied heavily on non-randomized comparisons (NRCs) that adjusted for confounding factors (i.e., factors independently influencing treatment selection and outcomes). We critically evaluated how well confounders were accounted for to assess the confidence that observed results reflect the intervention in question. Finally, we explored sources of ambiguity to promote understanding uncertainties and limitations of applicability.

Clinical decision-making requires weighing multiple considerations for an individual. This involves balancing not only many outcomes but many aspects of each—e.g., the strength of the evidence, the magnitude of the impact, uncertainty and how well this applies to an individual. In the Part 1 paper we provide a framework to manage this complexity—allowing clinicians to identify and focus on issues with the most impact in a particular setting for a patient. Here we develop the foundation, presenting the data in a manner that can at-a-glance provide an aggregate view of an outcome as well as the nuances and uncertainties of the data. A definition of what can be reasonably considered clinically meaningful facilitates assessing the impact of differences (described elsewhere; see Tab. S1-1 of Part 1) (1).

Evidence assessment

Literature search and study selection

We systematically searched English literature from 2000–2021; details are provided elsewhere (see app. 1-2 of Part 1) (1). Selected studies provided evidence relevant to the topic, focusing on RCTs and adjusted NRCs. For major outcomes we included all RCTs, and NRCs that adjusted for confounding and had ≥50 patients per arm. Each evidence table lists specific inclusion and exclusion criteria.

Study assessment

NRCs were assessed for confounding (bias) in order to appropriately interpret findings. The assessment of NRCs is summarized below (details provided in Appendix 2-1).

Potential confounders

A comprehensive list of potential confounders was identified a priori from known prognostic factors, patterns of care and treatment discrepancies. These included non-medical patient-related factors (e.g., age, sex, race, education, socioeconomic, marital status), medical patient-related factors [e.g., comorbidities, comorbidity severity, performance status (PS)], discrepancies in stage classification [e.g., node assessment, positron emission tomography (PET) use], time period (treatments skewed towards different periods), facility factors (treatments skewed towards different facility types), treatment quality (e.g., margin adequacy, experience, technical aspects), favorable tumor selection [e.g., smaller, ground glass (GG), indolent tumors, conversion to lobectomy if upstaging suspected/encountered].

Methods of multivariable adjustment

Multivariable regression models the relationship between multiple covariates and an outcome. Simultaneous adjustment for multiple confounders requires a substantial sample size—generally ~10 events (e.g., deaths) for each covariate. Propensity scoring models the relationship between confounders and treatment assignment, collapsing all confounders into a single propensity score. While theoretically advantageous when there are many confounders and few events, whether propensity or multivariable methods more accurately estimate treatment effect is unclear (4,5). Several propensity adjustment methods exist (propensity score adjustment, matching, inverse weighting); performance of each depends on characteristics of the data and question at hand (4-6).

Assessment of confidence study results reflect the treatment of interest

Relevant NRCs were assessed using a general tool to assess overall risk of bias (7). Additionally, we developed an assessment specific to stage I lung cancer, based on the a priori list of potential confounders (details in Appendix 2-1). Two reviewers rated each domain in each study and intervention, assigning an overall degree of confidence that outcomes reflect the treatment intervention; discrepancies were resolved by discussion. The independent assessments were largely consistent (and similar to the general tool rating), providing confidence in the process. The evidence tables include the consensus ratings for residual confounding.

Aggregation of studies

A quantitative meta-analysis is deemed inappropriate because of frequent residual confounding in various domains with variable severity. It is more useful to aggregate the studies in a manner that highlights similarities and differences, with ordering that allows patterns to emerge. This facilitates an overall qualitative impression that is more conducive to guiding clinical decision-making.

To achieve this, we have thoughtfully constructed tables. Color coding rapidly provides an overall impression (despite inclusion of levels of details if close scrutiny is needed). This essentially layers the concept of a heat map onto a traditional table. We explored various ways of ordering table entries, eventually settling on what was most revealing regarding the presence/absence of an association. The table structure is noted as a subtitle. We believe that visual representation of the outcomes, uncertainties and effect modifiers provides a summary that enhances point-of-care clinical judgment.

Results

Short-term outcomes

Treatment related mortality

Several RCTs reveal no difference in mortality by resection extent in healthy patients. The Lung Cancer Study Group (LCSG821) trial, conducted in the 1980s, reported no significant mortality difference between sublobar resection (2/3^rd segmentectomy) and lobectomy via thoracotomy (1% vs. 2% respectively) (8). In a US-based RCT (CALGB140503, 2007–17) 90-day mortality was not statistically different for sublobar resection vs. lobectomy (1.2% vs. 1.7%; 80% VATS resection, 60% wedge among sublobar resection) (9). No mortality occurred for either segmentectomy or lobectomy in a large Japanese RCT (JCOG0802, 2009–14, n=1,106) (10) and a smaller European RCT (n=108) (11).

Studies of perioperative mortality with adjustment for confounders (Table S2-1) (12-18) have frequently reported minimally lower mortality after lesser resection, but the magnitude of the difference is not clinically meaningful. A difference of >1% was only noted in one study (wedge resection vs. lobectomy) in subgroups of thoracotomy and patients with a forced expiratory volume in 1 second (FEV1) of <60% (12).

Similar (unadjusted) mortality for lesser resection and lobectomy is reported in large database studies (e.g., 30-day mortality of 1.51%, 1.55% and 1.6%, P=0.87 for wedge resection, segmentectomy and lobectomy in an NCDB study [2003–11] (16); 90-day mortality 3.7% and 4% for sublobar resection and lobectomy in a SEER-Medicare study [2003–9] (19); 90-day mortality of 0.5%, 0.7% and 1.2% for wedge, segment and lobectomy, respectively, in a 2010 Japanese national study) (20). However, an Australian study reported unadjusted 90-day mortality of 4.5% and 2.6% for sublobar resection and lobectomy, respectively [2008–14] (21).

Treatment-related morbidity

Treatment-related morbidity is similar in large RCTs between sublobar resection and lobectomy in healthy patients (any morbidity, 51% vs. 54% CALGB, 51% vs. 48% JCOG0802; grade ≥3 14% vs. 15% CALGB, 4.5% vs. 4.9% JCOG0802, each study using different grading definitions; and grade ≥3 pulmonary complications, 7% vs. 10% CALGB, 2.4% vs. 1.8% JCOG0802, respectively) (9,10). A nonsignificant trend towards lower grade ≥3 complications in wedge vs. segmentectomy was seen in the CALGB study (11% vs. 19%, P=0.13) (9). The small European RCT also found no significant difference in overall 90-day morbidity (17% segmentectomy vs. 26% lobectomy, P= NS) (11).

Adjusted NRCs suggest slightly lower grade ≥3 complications after sublobar resection (Table S2-1, borderline clinically significant). The 90-day unadjusted grade ≥3 complication rate was low in the 2010 Japanese national experience (4.4% wedge, 7.1% segmentectomy, 8.7% lobectomy) (20).

Short-term pain, QOL

Few QOL studies have parsed results to sublobar resection, so extrapolation from general studies is required. Presumably most symptoms are incision-related—thus largely driven by the approach (VATS vs. open); resection extent can be mainly expected to impact dyspnea.

A prospective study shows that symptoms after lung resection mostly resolve within several months (Figure 1A,1B) (22). Similarly, QOL studies report the initial impairment in many domains is improved by 3–6 months (see subsequent QOL section)—especially after VATS resection. The impact of sublobar resection is unclear (studies are confounded by varying VATS use).

Figure 1 (A,B) Symptoms and recovery after lung resection.
Prospective study of patient reported outcomes in patients undergoing lobectomy at MD Anderson (stage I, II NSCLC, 2004–08, n=60, 48% VATS). (A) Time course of the 5 most severe symptoms; 11-point scale from 0 (not present) to 10 (as bad as you can imagine). (B) Time to return to mild pain at 2 contiguous measurements. Reproduced with permission from Fagundes et al. (22). VATS, video-assisted thoracoscopic surgery.

A small RCT reported on QOL over 12 months (2013–17, n=108, closed after accruing 19% of the target) (11). Global QOL was significantly decreased at discharge and 6 weeks, returning to baseline by 3 months, with no difference between arms (segmentectomy vs. lobectomy). Interpretation is hampered because VATS was used for 23% of segmentectomies and 43% of lobectomies (P<0.03); furthermore, 44% of segmentectomies were arguably “lobe-like” (i.e., left upper trisegmentectomy, lingulectomy, or basilar quadri-segmentectomy). Pain outcomes were similar for segmentectomy vs. lobectomy throughout, but worse than baseline in both arms even at 12 months. Dyspnea was worse than baseline throughout the follow-up year (somewhat less after segmentectomy than lobectomy) (11).

Many studies of lobectomy (including RCTs, adjusted NRCs) report better outcomes with VATS vs. thoracotomy [including lower operative mortality, fewer complications, shorter hospital length of stay (LOS) and less pain] (23). A recent RCT of lobectomy by VATS vs. anterolateral thoracotomy found less pain and less QOL reduction in the VATS arm; the QOL impact resolved in most patients by 6 (VATS) to 12 weeks (thoracotomy) (24).

VATS is also beneficial in sublobar resections. An extensively adjusted NRC found fewer complications with VATS (rated as “very high” confidence that outcomes reflect VATS vs. open approach to segmentectomy) (25). A retrospective comparison of VATS vs. open segmentectomy found fewer pulmonary complications and shorter LOS after VATS (n=193, 2000-13, mostly healthy, lobectomy eligible patients) (26). Another retrospective comparison of VATS vs. open segmentectomy (n=104 vs. 121) found that VATS was associated with fewer pulmonary complications (15% vs. 30%, P=0.012), shorter LOS (5 vs. 7 days, P<0.001), and statistically non-significant differences in overall complications (26% vs. 34%), major complications (6% vs. 12%) and operative mortality (0 vs. 1.7%), respectively (27).

Nomori et al. assessed pain, comparing segmentectomy via thoracotomy, segmentectomy via hybrid-VATS (VATS camera with mini-thoracotomy) and lobectomy via complete VATS (n=220, 2012-15) (28). Short-term pain was less after VATS/hybrid-VATS than thoracotomy, but similar for hybrid-VATS segmentectomy or VATS lobectomy. By 3 months pain had resolved equally in all groups, with <5% requiring any analgesics (28).

Nuances and sources of ambiguity

The type of segmentectomy may play a role: multivariable analysis of a prospective study observed more grade ≥2 pulmonary complications following complex vs. simple segmentectomy (7.7% vs. 6.1%) (10). Complex segmentectomy was defined as requiring division of >1 intersegmental plane. However, another study found no difference in morbidity or mortality following complex (n=117) or simple (n=92) VATS segmentectomy (29).

Long-term outcomes

Survival

The LCSG821 RCT enrolled cN0 lung cancers ≤3 cm on the basis of CXR and not visible on (primarily rigid) bronchoscopy from 1982–88 (8,30,31). After intraoperative confirmation of T1N0 (frozen section of segmental, lobar, hilar, and mediastinal nodes)—patients were randomized to sublobar resection (67% segmentectomy) vs. lobectomy. A ≥2 cm margin was required; these tumors were undoubtedly primarily solid and resected via thoracotomy. In the final corrected analysis sublobar resection was associated with lower 5-year OS (56% vs. 73%; P=0.06), worse FFR (63% vs. 78%; P=0.04), and higher locoregional recurrence (5.4% vs. 1.9% per person per year, P=0.009) (30,31). However, present-day applicability of this evidence is questionable.

There are 2 major contemporary RCTs (Figure 2) (8-11,32-35). The CALGB140503 trial (9) randomized 697 patients with peripheral (outer 1/3), mostly solid tumors, ≤2 cm (total size) to sublobar resection (60% wedge) vs. lobectomy—mature results are awaited. The JCOG0802 trial (10,34) randomized 1,106 patients with peripheral (outer 1/3), part-solid tumors [88% with >0.5 consolidation/tumor ratio (CTR)], ≤2 cm (total size) to segmentectomy vs. lobectomy. A margin of ≥2 cm or a margin/tumor ratio ≥1 was required in both trials.

Figure 2 Major randomized controlled trials of lesser resection vs. lobectomy.
Graphic depiction of the 3 major randomized controlled trials. The x axis depicts the type of tumors included relative to proportion of solid/ground glass component, the z axis depicts tumor size, the y axis the resection extent. Three additional RCTs (German, STEPS and JCOG1706) are listed which have limited accrual. References: LCSG (8), CALGB (9), JCOG0802 (10), German (11), STEPS (32), JCOG1706 (33). CALGB, Cancer and Leukemia Group B; CTR, consolidation/tumor ratio; GG, ground glass appearance; IPF pts, Idiopathic pulmonary fibrosis patients; JCOG, Japan Cancer Oncology Group; LCSG, Lung Cancer Study Group; Lobe, lobectomy; Periph, peripheral; QOL, quality of life; Seg, segmentectomy; SL, sublobar; STEPS, Surgical Treatment of Elderly Patients.

Long-term results of the JCOG0802 trial have been published (35), with similar results after segmentectomy vs. lobectomy. These results are discussed elsewhere (2) because this study involves part-solid tumors.

Adjusted NRCs of segmentectomy or wedge vs. lobectomy in apparently healthy patients are shown in Table 1 (16,36-52), Table 2 (16,36,42,47,48,50,53-62), Table 3 (36,47,48,50,63-66) and Figures S2-1,S2-2,S2-3. Interpretation is challenging because of frequent limited accounting for confounders. Nevertheless, in aggregate, several observations can be made. First, the number of studies is impressive, and how inadequately most studies accounted for confounding factors. Second, the hazard ratios (HRs) for OS favor lobectomy (with few exceptions); while this could be due to confounders, the similar HRs for LCSS largely eliminates greater comorbidities among sublobar resection patients as an explanation. Third, statistically significant differences are seen in most studies involving wedge/sublobar resection vs. lobectomy, and in ~1/3^rd of studies involving segmentectomy vs. lobectomy or wedge vs. segment resection. There are no clear additional correlations—results do not seem to track with particular sources of confounding, larger studies, stage, time period or data source.

Several studies (Khullar, Eguchi, Razi) (16,52,53) are categorized as providing high confidence that outcomes are attributable to the resection extent. Two of these found better adjusted OS and LCSS after lobectomy. Figure 3 shows OS of propensity matched cohorts from the Khullar et al. study, which involved extensive matching with several additional analyses (size subsets, margin status, facility type, number of nodes assessed intraoperatively) (16).

Figure 3 Propensity-matched comparison of wedge resection, segmentectomy and lobectomy.
Comparison of resection extent in the National Cancer Database of cIA1,2 NSCLC [2003–6]. This study matched for 14 prognostic factors and performed multiple sensitivity tests; it is assessed to have a low level of residual confounding. Reproduced with permission from Khullar et al. (16). OS, overall survival.

On the other hand, Razi et al. found no difference in OS for the subset of cIA patients in whom unsuspected pN1 or pN2 nodes were found (52). This study involved extensive adjustment for confounders, including details of the node assessment and use of adjuvant chemotherapy (which was associated with better OS) (52). Possible reasons for the similar outcomes include that there is no inherent difference between segmentectomy and lobectomy, that any impact of resection extent is overshadowed by that of node involvement, or that a benefit to lobectomy stems from more accurate node assessment and adjuvant chemotherapy (despite being adjusted for). The latter hypothesis is supported by some studies (i.e., similar outcomes with sublobar resection vs. lobectomy when a similar nodal assessment was performed) (61,67,68). However, among adjusted studies overall there is no consistent correlation between long-term outcome differences and adjustment for either adjuvant therapy or extent of node assessment.

Many authors have reported systematic reviews and meta-analyses of non-randomized studies comparing lesser resection to lobectomy (69-75). However, no degree of systematic search rigor or meta-analytic proficiency in amalgamating reported results can overcome residual confounding in the source data. In fact, by combining studies the meta-analytic process obscures the weaknesses of each study. Thus, because of unaccounted (and obscured) confounders, drawing conclusions from meta-analyses of non-randomized studies is problematic.

Recurrence

Recurrence is a concern, especially because the LCSG821 RCT found a higher local recurrence rate after sublobar resection (8,31). However, assessment of this outcome is impacted by multiple factors (e.g., competing causes of death, length of follow-up, staging accuracy, tumor biology). The cleanest measure is FFR (or cumulative-incidence-of-recurrence). Recurrence-free or disease-free survival (RFS/DFS) is muddy because it mingles recurrence with competing causes of death. Simple comparison of the number (or type) of observed recurrences in cohorts is frequently reported but hard to interpret (no accounting for confounding factors or follow-up duration).

Few adjusted NRCs report recurrence by resection extent (Table 4) (39,43,45,46,53,57,60,64,76-80). The available evidence is unclear whether lesser resection increases recurrence risk. The confidence that confounders are accounted for is low. Variability in the incidence of recurrence is only partially potentially explained by tumor stage or follow-up duration. Most studies found a non-significant trend towards a higher recurrence rate after sublobar resection, rarely the opposite trend. Rates of locoregional recurrence are generally low (the outcome most likely affected by resection extent).

Pulmonary function tests (PFTs)

The impact of resection on PFTs serves as a surrogate for functional capacity (which hasn’t been studied). Segmentectomy doesn’t confer a meaningful benefit over lobectomy in healthy patients; studies reporting FEV1 ≥6 months postoperatively are shown in Table 5 (changes in diffusion capacity are seldom reported) (8,29,35,51,81-96) (it takes ~6 months following surgery for PFTs to reach a plateau; less after VATS resection) (95,97-99).

Lobectomy causes a ~14% long-term decrease in FEV1. Segmentectomy results in an FEV1 decrease of ~12% in studies involving many multi-segment resections (e.g., left upper tri-segmentectomy) and a decrease of ~5% in studies involving primarily single segment resections. Such decreases are not in a clinically relevant range for healthy patients. Indeed, exercise capacity is reported unchanged despite the FEV1 decrease (83,91). Available data shows an FEV1 decrease of 2–8% after wedge resection (89,95,100,101). The long-term impact of resection on FEV1 does not correlate with the time period or the approach (VATS/open).

Long-term QOL

In Table 6 (102-117) and Table 7 (11,24,118-130) postoperative QOL results are depicted reflecting no change, or small, moderate or large changes vs. baseline by generally accepted thresholds for clinically meaningful differences (128,131-136). Table 6 is mostly yellow (i.e., no change); these studies used the SF-36 tool (why this tool appears less sensitive is unclear; little change remains when using lower proposed thresholds for clinically meaningful differences). In Table 6 and Table 7, there is diminishing QOL impairment towards the right (i.e., increasing interval from surgery) and increasing impairment moving downward. The vertical gradient reflects increased VATS near the top and more extensive resections (e.g., pneumonectomy) towards the bottom (also generally older studies).

What conclusions can be drawn? The SF-36 tool seems less useful. VATS is associated with less QOL impairment vs. baseline, and this has mostly resolved by 6 months (except dyspnea). Whether sublobar resection has an impact is less clear—studies are limited and confounded by the use of VATS. Open lobectomy is associated with long-term QOL decreases in many domains. Older studies tend to show larger and more frequent QOL impairment, but often include larger resections.

The average doesn’t necessarily reflect an individual’s experience. Another measure is the proportion of patients that have improved, unchanged or worse QOL after surgery. Six months after thoracotomy, one study reported that 30–50% of patients experience meaningfully worse QOL vs. baseline (SF-36 instrument, included 9% pneumonectomy) (137). In another study, long-term QOL after thoracotomy was meaningfully worse in ~10–40% and improved in a similar proportion in various domains of the EORTC C-30 instrument in patients without recurrence (129). These authors reported that long-term symptoms were absent or meaningfully improved in ~60% and worse in ~10–20%—with the exception of dyspnea which was worse in ~40% vs. baseline. A prospective study involving primarily minimally invasive resections found that 20–40% were meaningfully worse and a similar proportion improved at 6 and 12 months in multiple EORTC domains (120). No data is available whether these proportions are influenced by sublobar resection.

Various predictors of worse QOL have been noted, mostly in single studies and measures of physical functioning. Worse long-term QOL has been associated with age (137) smoking (138), adjuvant chemotherapy (137), recurrence (129), higher baseline QOL (139), thoracotomy (vs. VATS) (111) and larger resection (i.e., pneumonectomy or lower ppoFEV1) (137,139). One study noted a non-significant trend to less impact on QOL with sublobar resection vs. lobectomy (137); another found physical QOL at ~11 months was unchanged after limited resection but decreased after lobectomy (likely confounded by use of VATS) (108,111). Conversely, variables that don’t correlate with QOL changes include gender (112,140), comorbidities, occurrence of postoperative complications, and stage (137). A case-matched study found no association between the presence of COPD and postoperative QOL (114).

Two recent small RCTs deserve mention. A RCT of lobectomy (VATS vs. open) found a transient QOL impairment with return to baseline or higher; the return was faster after VATS (6 vs. 12 weeks) (24). A small RCT of segmentectomy vs. lobectomy found that global QOL returned to baseline by 3 months in both arms (11). Interpretation is difficult, however, because of the study size (n=108) and higher VATS use in the lobectomy arm (11).

Chronic pain

The incidence of chronic pain is reported variably. The impact of sublobar resection is unclear, confounded by VATS use. No differences were found in one study of 220 patients undergoing either VATS lobectomy, segmentectomy via mini-thoracotomy, or segmentectomy via thoracotomy with rib-spreading [2012–5]. At 1 month ~25% in each group were taking analgesics (of any kind), and by 3 months it was ≤5% (28). Moderate to severe pain persisted in 5–10% of patients at 1 year in a RCT of VATS vs. open lobectomy but was approximately half as frequent after VATS (24). In Table 6 and Table 7, pain at ≥6 months postoperatively is noted frequently after thoracotomy but infrequently after VATS.

Several studies addressing chronic pain report pain ≥1 year postoperatively in 30–60% of patients after thoracotomy (141-144) and 20–25% after VATS (141,144). The incidence of taking analgesics is much less (5% after VATS and 20% after thoracotomy) (141,142). Chronic pain has been associated with preoperative narcotic use, the intensity of early postoperative pain and intercostal nerve trauma (145).

The discrepancy between studies investigating QOL and chronic pain is probably due to semantic differences. An earlier review of chronic post-thoracotomy pain found that 50% had some discomfort/pain, ~10% used occasional narcotics, and <5% required more involved treatment (146). Taking this and the more recent studies on QOL and pain together, it appears these rates are still seen after thoracotomy, but approximately half as frequent after VATS.

Nuances and sources of ambiguity

Impact of resection margin

Guidelines recommend a resection margin of ≥2 cm (from tumor edge to cut lung parenchyma) or a margin to tumor size (M/T) ratio of ≥1) (147,148). Clinical practice, however, requires quantification of the risk of a narrow margin so it can be weighed against issues associated with additional resection. The ideal measure is actuarial locoregional recurrence (survival is muddied by unrelated deaths).

Variability in studies of margin distance and M/T ratio (Tables 8,9) (53,149-164) likely reflects multiple factors—e.g., adjustment for confounders, proportion of unfit patients or favorable tumors, follow-up duration, resection extent (average margin 15 mm for segment vs. 8 mm for wedge in a prospective study) (165). The data loosely suggest an inflection point around 1 cm, with ~25% recurrence with <1 cm margins. Why Maurizi et al. found no difference is unclear (150). The data regarding M/T ratio loosely suggests a locoregional recurrence rate of ~20% for M/T <1 vs. ~10% for ≥1. Margin distance appears to have little impact in primarily GG tumors (152,156).

Most studies have reported whole tumor size. Those reporting invasive size suggest the M/T (invasive) ratio is important (53,162). The discrepancy between the surgeon’s and pathologist’s margin assessment is another issue (not quantitatively defined). The pathologist typically removes the staple line, and measures the deflated, fixed lung. Studies mostly report the pathologic margin. Surgeons should aim for a surgical margin well beyond a M/T ratio of 1.

In conclusion, for solid tumors evidence loosely suggests a local recurrence rate of ~20–25% for a M/T ratio <1 or a margin <1 cm vs. ~10% for larger margins (recognizing that the pathologic measurement is likely ~3–5 mm less than the surgical assessment).

Impact of STAS

The term “spread through air spaces” (STAS) refers to a microscopic observation of tumor cells adjacent to a lung cancer; the median distance is 1–1.5 mm, but distances of 8–10 mm have been observed (166-169). STAS occurs in essentially all lung cancer types (adenocarcinoma, squamous, small cell, carcinoid, pleomorphic etc.) (169). The reported incidence is quite variable (15–80%) for each tumor type. STAS is rarely observed in adenocarcinoma in situ, minimally invasive adenocarcinoma or pure GG tumors (156,170-174) with some exceptions (29% STAS+ in pure GG, 34% among preinvasive tumors in one study) (175).

STAS is widely associated with worse long-term outcomes (169,176)—but also associated with multiple negative prognostic factors, e.g., aggressive adenocarcinoma subtypes (e.g., solid, micropapillary) (166,167,174,177-181), higher stage (174,175,180,182,183), larger tumors (169,174,175,180-183), and a greater solid component on imaging (172,175,181). No consistent correlation of STAS with genetic characteristics has emerged (169).

In most studies STAS portends worse RFS and higher recurrence rates after sublobar resection (Tables 10,11) (156,166-168,170,173,174,178,181-186). This is generally maintained after multivariable adjustment (only limited confounders accounted for). There is less data after lobectomy—STAS portends worse RFS but this is generally not maintained after multivariable adjustment. STAS is associated with a higher distant recurrence rate after sublobar resection in some studies (181,184) but not in others (170,174,186). A greater proportion of favorable tumors doesn’t mitigate the negative prognostic impact of STAS.

A simplistic assumption is that STAS represents a mechanism by which metastasis occurs. This creates a focus on intraoperative detection (frozen-section sensitivity), resection extent and defining a safe margin. However, decades of evidence demonstrate that metastasis is determined by complex cellular transformations, signaling and host-tumor interactions (187-189). STAS may reflect microenvironment evidence of these processes. In other cancers microenvironment evidence of immune recognition of cancer cells and activation of tumor-host interaction predicts long-term outcomes (190). This mental construct suggests that surgical interventions would not affect the impact of STAS.

The available data is inconclusive whether a negative prognostic impact of STAS can be altered by a more extensive resection. Few studies have addressed this with conflicting results (Table 11) (53,178,185). In an extensively adjusted retrospective analysis Eguchi et al. found that if STAS is present, lobectomy is associated with better RFS and fewer recurrences than sublobar resection (53). Eguchi et al. also observed that recurrences after sublobar resection in STAS + tumors were associated with an M/T ratio of <1 (this margin/STAS analysis was unadjusted for any confounders) (53). The observation invited speculation that a wider margin might mitigate the negative prognostic impact of STAS. Another unadjusted analysis of sublobar resection found that STAS was associated with a similar increase in loco-regional recurrence for M/T ≥1 as for M/T <1 (174).

Single vs. multi-segmentectomy

A right upper lobectomy is arguably the same as a left upper tri-segmentectomy, and a right middle lobectomy the same as lingulectomy. In database studies the proportion of such “lobe-like” segmentectomies is unavailable. In single-institution series, the proportion is 20–40% (43,46,51,191,192), and 30–55% of segmentectomies involve ≥3 segments (43,46,51,191,192). Studies involving many multi-segmentectomies found no OS or LCSS difference between segmentectomy vs. lobectomy (43,46,51).

Anatomic location

Whether the tumor size and anatomic location confidently permit an adequate margin is important in deciding the resection extent in an individual patient. Wedge resection is only feasible for tumors in the outer third of the lung (from the pleural space to the hilum). Achieving an adequate margin is difficult even for segmentectomy when tumors are central or near an intersegmental boundary. A simulation model estimated that ~25–33% of 1–2 cm tumors would be amenable to segmentectomy (defined as ≥2 cm from an intersegmental plane); for bi-segmentectomy ~50% would meet this criterion (assuming uniform tumor distribution throughout the lungs) (193).

Summary of outcomes in healthy patients

In healthy patients contemporary RCTs demonstrate equivalent perioperative mortality for segmentectomy or wedge vs. lobectomy (1–4% 90-day mortality). The incidence of major complications is also low (5–15% grade ≥3) and not improved by sublobar resection. A significant benefit to VATS over thoracotomy has been demonstrated extensively for lobectomy; this also appears true for segmentectomy. Pain and impaired QOL is generally resolved by 3 months after VATS resection.

Adjusted NRCs with high confidence that results reflect the treatment demonstrate worse OS for segmentectomy or wedge resection than lobectomy. Multiple additional NRCs with greater residual confounding mostly favor lobectomy; statistical significance is fairly consistent for OS and LCSS for wedge but less so for segmentectomy vs. lobectomy. While we await mature results from RCTs, the aggregate evidence indicates meaningfully worse long-term outcomes after segmentectomy or wedge resection than lobectomy in healthy patients with cI NSCLC.

VATS resection has little long-term impact on QOL, but open resection results in persistently worse QOL. A QOL benefit to sublobar resection is unclear due to confounding by VATS/open approach. Sublobar resection may attenuate an increase in dyspnea that is commonly noted after lobectomy. However, PFTs demonstrate no meaningful advantage for segmentectomy over lobectomy in healthy patients, particularly when including multi-segmentectomies.

Evidence suggests no meaningful difference in short-, intermediate- or long-term outcomes for a “lobe-like” multi-segmentectomy vs. lobectomy. The risk of an inadequate margin given an individual tumor’s anatomic location is an important consideration. Locoregional recurrence rates of ~20–25% for margins of <1 cm or a margin/tumor ratio of <1 are half as frequent with larger margins for solid tumors; margin appears to have less impact in primarily GG tumors. Worse long-term outcomes are reported when STAS is present (especially after sublobar resection); this is confounded because STAS is associated with many negative prognostic factors. It is unclear whether the impact of STAS can be mitigated by converting to a lobectomy.

Short-term and long-term outcomes for segmentectomy or wedge resection vs. lobectomy are summarized in Table S2-2. 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

Choosing which type of resection is best for a particular patient demands balancing various factors and outcomes. This analysis of the relevant evidence in generally healthy patients provides a foundation for a framework to facilitate individualized decision-making across the spectrum of lung cancer patients.

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.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-21-1824/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. 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/.

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