2025+ACCP临床实践指南：早期非小细胞肺癌患者的管理

指南肿瘤内科· 肺癌 · 2025

Extent of Resection

3. In medically fit patients with a peripheral ≤ 2 cm clinical stage I NSCLC with a ground-glass/lepidic(GG/L) component, we suggest lobectomy,segmentectomy, or sublobar non-anatomic(wedge)resection as equivalent alternatives.(Conditional Recommendation; Moderate Certainty of Evidence).

Remarks:

A peripheral tumor has an epicenter that falls within the outer one-third of the lung(from the hilum to the ribcage or diaphragm).

Size is the maximal dimension of the solid component(on axial CT images using lung window settings and≤1.25 mm slice thickness).

A segmentectomy or wedge should include at a minimum a systematic lobe-specific lymph node

(L.H.S.),Smithville, ON, Canada; Department of Medicine(D. A.),University of Michigan, Ann Arbor, MI; Yale University School of Medicine(J. B. and F. D.), New Haven, CT; Department of Surgery(F.F.), University of Washington, Seattle, WA; Division of Thoracic Surgery(M. L.), Massachusetts General Hospital, Boston, MA; Princess Margaret Hospital(N. L.), Toronto, ON, Canada; and the Departments of Radiation Oncology(G. M. V.) and Thoracic and Cardiovascular Surgery(S. M.), Cleveland Clinic, Cleveland, OH.

DISCLAIMER: CHEST guidelines are intended for general information,are not medical advice, and do not replace professional medical care and physician advice, which should always be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://www.chestnet.org/Guidelines-and-Resources.

CORRESPONDENCE TO: John Howington, MD, MBA, FCCP, FACS;email: john.howington@commonspirit.org

DOI:https://doi.org/10.1016/j.chest.2025.06.023

sampling with thorough assessment of lack of node involvement.

A segmentectomy or wedge should involve a margin of either≥ 2 cm or a margin/tumor size ratio of≥1, which should be confirmed at the time of resection.

4. In medically fit patients with a peripheral≤ 2 cm solid or mostly solid clinical stage I NSCLC, we suggest lobectomy, segmentectomy, or sublobar non-anatomic(wedge) resection as equivalent alternatives.(Conditional Recommendation; Moderate Certainty of Evidence).

Remarks:

A peripheral tumor has an epicenter that falls within the outer one-third of the lung(from the hilum to the ribcage or diaphragm).

Size is the maximal dimension of the solid component(on axial computed CT images using lung window settings and≤1.25 mm slice thickness).

A sublobar resection should include at a minimum a systematic lobe-specific lymph node sampling with thorough assessment of lack of node involvement.

A sublobar resection should involve a margin of either≥2 cm or a margin/tumor size ratio of≥1,which should be confirmed at the time of resection.

5. In medically fit patients with clinical stage I NSCLC tumors that are either centrally located or> 2 cm, we recommend lobectomy over sublobar resection(segmentectomy or wedge resection).(Strong Recommendation; Low Certainty of Evidence).

Remarks:

Central tumors have an epicenter that is within the inner two-thirds of the lung(from the hilum to the ribcage or diaphragm).

Size is the maximal dimension of the solid component(on axial CT images using lung window settings and≤1.25 mm slice thickness).

This size definition applies to both completely solid and part-solid(ground glass) tumors.

6.In medically fit patients with clinical stage II NSCLC, we recommend lobectomy over sublobar resection(segmentectomy or wedge resection).(Strong Recommendation; Low Certainty of Evidence).

7. In patients with clinical stage I NSCLC considered high risk for lobectomy, we suggest sublobar resection(segmentectomy or wedge resection) over lobectomy.(Conditional Recommendation; Low Certainty of Evidence).

Surgical Settings

8. For patients with clinical stage I/II NSCLC, we suggest treatment by a board-certified thoracic surgeon.(Conditional Recommendation; Low Certainty of Evidence).

Remarks:

Surgeon volume should not be the sole consideration for referring patients with stage I/II NSCLC for surgical care.

Hospital volume should not be the sole consideration for referring patients with stage I/II NSCLC for surgical care.

Surgeons who were not trained in the United States or through Accreditation Council for Graduate Medical Education-approved thoracic fellowships, but who did undertake programs with curricula and case requirements like those offered by organizations such as the American Board of Thoracic Surgery, could be considered board-certified thoracic surgeons.

Lymph Node Evaluation

9. For patients undergoing resection of known or suspected clinical stage I and II NSCLC, we recommend intraoperative systematic mediastinal and hilar lymph node sampling or dissection over selective or no sampling for accurate pathologic staging.

(Strong Recommendation; Low Certainty of Evidence).

Remarks:

Node stations that have been invasively evaluated prior to resection(eg, mediastinoscopy) can be counted together with the intraoperative evaluation.

It is unclear whether a complete mediastinal node dissection has benefit over a lobe-specific systematic dissection.

Whether systematic sampling is essential in predominantly GG/L tumors remains questionable.

10. For patients undergoing surgical resection of known or suspected clinical stage I and II NSCLC, we suggest systematic lymph node sampling or dissection including sampling from at least 3 mediastinal stations and at least 1 hilar station.(Conditional Recommendation; Using Certainty of Evidence).

Remarks:

Node stations that have been invasively evaluated prior to resection(eg, mediastinoscopy) can be counted together with the intraoperative evaluation.

It is unclear whether a complete mediastinal node dissection has benefit over a lobe-specific systematic dissection.

Whether systematic sampling is essential in predominantly GG/L tumors remains questionable.

Stereotactic Body Radiotherapy(SBRT) and Ablative Techniques

11. For patients who have clinical stage I NSCLC and are considered medically appropriate for a form of surgical resection after assessment of their operative risk, we suggest resection over SBRT.(Conditional Recommendation; Low Certainty of Evidence).

12. For patients who have clinical stage I NSCLC and are considered medically appropriate for a form of surgical reactions medically appropriate for a form of surgical reactions.LW cancerors.

13. For patients NOT considered to be appropriate candidates for surgical resection by assessment of their operative risk and who have clinical stage I NSCLC, we suggest SBRT over ablative procedures.(Conditional Recommendation; Very Low Certainty of Evidence).

Remarks:

Ablation is a reasonable approach if the radiation oncologist deems SBRT to be associated with a high risk of complications or limited effectiveness.

Adjuvant Therapy

14. For patients with completely resected stage I NSCLC, we do NOT recommend routine treatment with adjuvant chemotherapy or immunotherapy outside of a clinical trial.(Strong Recommendation;Moderate Certainty of Evidence).

15. For patients with resected stage IB NSCLC and epidermal growth factor receptor(EGFR) ex19del/L858R mutations, we recommend treatment with adjuvant targeted therapy.(Strong Recommendation;Moderate Certainty of Evidence).

16. For patients with completely resected stage II NSCLC, we recommend treatment with adjuvant chemotherapy.(Strong Recommendation; Moderate certainty of Evidence).

17a. For patients with completely resected stage II NSCLC and alterations in EGFR or anaplastic lymphoma kinase, we recommend adjuvant targeted therapy following chemotherapy.(Strong Recommendation; Moderate Certainty of Evidence).

17b. For patients with completely resected stage II NSCLC without EGFR or anaplastic lymphoma kinase alterations, we suggest adjuvant immunotherapy following chemotherapy.(Conditional Recommendation; Moderate Certainty of Evidence).

Background

Lung cancer remains the number 1 cause of cancer death in men and women in the United States and much of the world.1 The primary treatment of stage I non-small cell lung cancer(NSCLC) in patients with acceptable surgical risk has been lobectomy.2 However, this paradigm has become subject to increasing scrutiny as smaller tumors are being identified because of expansion of lung cancer screening and more liberal use of CT scanning for medical care. The American Joint Committee on Cancer staging system for lung cancer now segregates T subclassifications by size because of independent impact on survival, optimal surgical treatment of cancers<2 cm(cT1a1-T1a2) has been reexamined.

To this end, randomized trials have shown equivalent survival of sublobar resection and lobectomy for peripheral stage I lung cancers< 2 cm in size.3,4 Minimally invasive surgery(MIS) for stage I lung cancer has become the dominant approach in the United States based on established benefits of reduced pain, shorter length of stay, and faster return of functional status. Yet,questions remain around the oncologic efficacy of MIS approaches compared to thoracotomy for lobectomy in stage I NSCLC.

The continued discovery and refinement of targetable tumor mutations as well as clear impact of immunotherapy now mandate comprehensive standardized biomarker testing for every patient with NSCLC. Moreover, improved response rates and progression-free survival from targeted and immune therapies has positioned these elements in emerging neoadjuvant and adjuvant strategies for select patients with stage IB and II disease.

Finally, for those deemed medically unfit for more aggressive therapies for early-stage cancers,alternative therapies continue to evolve. Specifically,less morbid ablative options are now routinely offered if conventional therapy is thought too risky.As treatment options for patients with early-stage lung cancers become more numerous, and algorithms more complex, multidisciplinary discussions will be required to match a given patient with the optimal treatment options.

Study Design and Methods

A multidisciplinary expert panel was formed and con-ducted a systematic review to answer 6 key clinical ques-tions developed using the Population, Intervention,Comparator, and Outcome format(e-Table 1). The final systematic search was conducted in May 2024 for Key Question 1 and April 2023 for Key Questions 2-6. The Grading of Recommendations, Assessment, Develop-ment, and Evaluation10 approach was employed to

formulate recommendation statements and to assess the certainty of evidence informing statements. Certainty of evidence ratings represent the confidence in the estimated effects for an outcome and are defined in e-Table 2.

Full details of the methodology employed are contained in e-Appendix 1, e-Appendix 3, and e-Figure 1. Based on 578 studies, the panel developed 17 recommendations.See Figures 1-3 for sample algorithms for guideline implementation.

Minimally Invasive Approaches

Evidence and Evidence-to-Decision

The 2 recommendations on invasiveness of resected procedure were informed by 21 studies. 11-31 When comparing MIS to thoracotomy, the balance of effects favored MIS for patients with both clinical stage I and

stage II disease, although the certainty of evidence was low for both patient populations(e-Tables 3A and 3B).For patients with stage I disease, the panel drafted a strong recommendation despite low certainty of evidence for an association with survival when using MIS approaches. The panel paired the survival benefit with the clinical judgment that patients recover faster

with an MIS approach to support strong guidance in this patient population. For patients with stage II disease, a conditional recommendation for MIS was favored based on survival equivalence paired with patient-reported quality of life improvement. For both recommendations,the guidance is anticipated to be acceptable to all key stakeholders. However, the feasibility of implementing the guidance was judged as probably yes based upon the fact that not all institutions have access to MIS technology.

The benefits of a minimally invasive surgery(video-assisted thoracic surgery[VATS]/robotic-assisted thoracic surgery) over open(thoracotomy) for stage I lung cancer treatment initially centered on the reduced morbidity and pain, which collectively translated into an expedited return of functional status for patients.32 Over the past 10 years, however, numerous studies have provided essentially no evidence of harms associated with MIS approaches, leading to widespread adoption of MIS approaches for stage I lung cancer to the degree that VATS/robotic-assisted thoracic surgery are now collectively the most common approaches for lobectomy in the United States.33

Perhaps most importantly is that a meta-analysis of MIS compared to thoracotomy as treatment of stage I NSCLC suggests MIS is associated with higher survival rates(hazard ratio[HR], 0.83; 95% CI, 0.78-0.89)(e-Table 3A). This analysis represents a 30,000-patient cohort called from over 25 studies from the past approximately 20 years. This advantage is observed over several metrics, including pain, earlier hospital discharge, and quality of life questionnaires. ${}^{11,32}$

There is a paucity of studies that assess this comparison in patients with stage II NSCLC(e-Table 3B).Nonetheless, it is evident that there is oncologic equivalence between MIS lobectomy and thoracotomy for nodal upstaging, and overall survival(OS), and MIS superiority if self-reporting of pain and physical function are to be considered.

Extent of Resection

Evidence and Evidence-to-Decision

When selecting the extent of appropriate resection, the procedure favored by the balance of effects was affected by the location, size, and composition of the tumor, as well as the health of the patient. The certainty of evidence ranged from low through moderate for these 5 recommendations and was greatly impacted by a lack of randomized trials

(e-Tables 3C-3F). Additionally, although the harms of recommended interventions were judged as trivial or small across recommendations, the benefits of the recommended procedure ranged from trivial through large and led to 2 recommendations of equivalency and 3 where a procedure was favored. In 2 recommendations,lobectomy has been strongly recommended over sublobar resection despite an overall paucity of evidence and low certainty of survival benefit. Although the surgical limitations of sublobar resection for centrally located,>2 cm, and stage II tumors, are described in detail below, in brief, strong recommendations have been drafted based on the potential for harms to patients if sublobar resection was used in place of lobectomy. All 5 recommendations are expected to be feasible to implement and acceptable to stakeholders.

Randomized data from 30 years ago demonstrated that lobectomy was the preferred surgical treatment over sublobar resection(segmentectomy/wedge) for patients with operable stage I NSCLC.34

There are several critical elements when comparing sublobar resection to lobectomy that challenges evidence interpretation, including size≤ 2 cm, histopathologic constituency(and/or radiographic characterization),location, and margin status. Unfortunately, each of these elements importantly contributes to subsequent specific recommendations by way of inference more so than absolute or unequivocal evidence, and this is highlighted in each specific recommendation.

The concept of lepidic-type or lepidic-predominant NSCLC was brought forward in 2011 and refers to a subset of cancers where the expected disease-specific survival from complete resection approaches 100%.35 This classification includes adenocarcinoma in situ(pure lepidic growth) and minimally invasive adenocarcinoma(≤5mm) for lepidic predominant cancers with a consolidation tumor ratio much less than 0.5. This terminology has replaced bronchoalveolar cancer and is often considered to have a radiographic corelate, ground-glass opacity, noted on chest CT.36 Interestingly, the presence of a pure ground-glass opacity lesion on a chest CT scan, even when compared to lepidic histopathology,predicts disease-specific survival more accurately.36

There appears to be no survival advantage of lobectomy over sublobarreion correction for this presentation of cancer with the caveat being that a≥ 2 cm margin or a margin:tumor ratio≥ 1 is obtained. ${}^{37}$ Moreover, it is expected that regardless of lung resection, systematic lymph node sampling be performed and confirmed as

negative. Finally, to be considered peripheral, the target lesion should be confined to the outer one-third of the pulmonary parenchyma, thus rendering sublobar resection justifiable. ${}^{4}$

Some important modern retrospective data have helped inform the recommended paradigm shift to now recommend equivalence of sublobar resection and lobectomy for clinical stage I NSCLC that is beyond adenocarcinoma in situ or minimally invasive cancer.These comparative studies demonstrated that for smaller solid and part solid lung cancers, although collectively continuing to support a higher local recurrence rate for sublobar resection, this no longer seems to translate into lower OS(e-Table 3D). Moreover, in 1 of these studies,resected pure solid lesions, regardless of lobectomy or segmentectomy, demonstrate similar OS at a mean follow-up approaching 4 years.38

The real driver of change has been the publication of 3 well-designed multi-institutional randomized trials comparing sublobar and lobectomy as surgical treatment for T1a/T1b(≤ 2 cm) clinical stage I NSCLC(e-Table 3D). ${}^{3,4,39}$ Common among them are intraoperative confirmation of pathologic stage I disease(meticulous hilar and mediastinal intraoperative lymph node sampling), negative parenchymal margins assessed intraoperatively, and that lesions had consolidation to tumor ratio> 0.5. Two surprising findings, aside from disease-specific survival, were revealed. The first is that although greater local recurrence with sublobar resection was evident, this did not seem to translate to a survival disadvantage in this modern cohort; in fact,segmentectomy was associated with OS in the Japan Clinical Oncology Group(JCOG) 0802 study.4 In addition, the difference in postoperative pulmonary function between the 2 arms was quite small, especially in light of the fact that Cancer and Leukemia Group B(CALGB) 140503 was composed of 60% of wedge resections in the sublobar arm.

Central tumors can be defined as having an epicenter within the inner two-thirds of the lung as measured from hilum to ipsilateral chest wall. This location often precludes wedge resection because of depth and geometry issues. Segmentectomy also becomes disfavored given the limited margins that can be obtained, the low likelihood that straightforward segmental boundaries could be identified to make the resection technically feasible, and perhaps more complicated lymphatic drainage pathways that are engaged for more central lesions vs peripheral ones.

Unfortunately, because stage II disease is the smallest component of disease presentation, there is a lack of clinical studies and trials to inform recommendations.Nonetheless, margin inadequacy and incomplete intraparenchymal and hilar lymph node assessment would no doubt be far more problematic for such patients offered sublobar resection, and this might lead to a lower chance of upstaging those patients with occult disease beyond stage II.

The limited data available do suggest that both disease-specific survival and OS are superior for lobectomy(over sublobar resection) for larger and more locally advanced lung cancers.40 This is not particularly surprising given trends of increased local recurrence rates that universally accompany lesser resections when compared to lobectomy for smaller, less advanced tumors. ${}^{34}$

It should also be appreciated that stage II disease does straddle the boundary of local and systemic disease recurrence, unlike stage I disease, and there is general concern that any surgery alone is inadequate treatment for stage II disease. This is supported by the survival advantage afforded patients receiving adjuvant therapy for stage II disease and does complicate the benefit of local therapy for this presentation(recommendations 16 and 17). Yet, the fact that patients with stage II cancers were included in the Checkmate 816 trial of induction immunotherapy and that lobectomy in the study arm represented almost 80% of all resections performed does suggest that the authors considered lobectomy the optimal surgery41 and not sublobar resection.

Until relatively recently, the term high operative risk when applied in this context has been considered by most arbitrary and ambiguous.42 Frailty indexes have not been developed specifically for lung surgery, and even when applied, are simply not granular enough to meaningfully guide treatment decisions. To standardize this very qualitative descriptor, the American Association for Thoracic Surgery developed a consensus statement guideline to help surgeons and physicians navigate this area of uncertainty.43 Several important preoperative factors should be considered.

Based on consensus, preoperative elements connoting the highest risk for lung surgery are: need for supplemental oxygen, low diffusion capacity(low diffusion capacity for carbon monoxide), poor functional status, presence of pulmonary artery hypertension, and severe perceived frailty. Next in line

were significantly decreased postoperatively predicted spirometry(predicted postoperative FEV1), liver cirrhosis, neurocognitive debility, and desaturation with limited activity. Finally, other factors to be used include inability to live independently, sarcopenia, and decreased oxygen utilization capacity(maximum oxygen consumption).

The decision to determine which patients are high risk still resides with the treating team and may very well end up being a composite of many of the factors listed above.Important in decision-making will also be patient perspectives, values, and preferences as well as quality of life considerations.

Surgical Settings

Evidence and Evidence-to-Decision

This recommendation was informed by 6 cohort studies and a low certainty of evidence(e-Table 3H).44-49 The benefits of receiving treatment by a board-certified thoracic surgeon were assessed as moderate while the harms were assessed as trivial, leading to a balance of effects strongly favoring the intervention. Although health equity may be reduced in some areas based on access to care by a board-certified surgeon, the

Surgical setting refers to the environment in which a patient receives care-typically described in terms of surgeon and hospital characteristics. Because of the heterogeneity of clinical practice, it is infeasible to conduct randomized trials. Information from observational studies limits the level of evidence supporting our recommendations. Although most studies evaluated the volume-outcome relationship,these investigations have significant methodologic challenges and have produced inconsistent or complex results that are difficult to implement(see e-Table 3).

Studies of the relationship between surgeon specialty and patient outcome have produced more consistent findings,although they too have their limitations. Investigators linked Medicare claims to the American Board of Thoracic Surgery(ABTS) Diplomates list and found that board certification and a general thoracic surgical practice were associated with a 23% lower associated risk of operative mortality compared to surgeons without ABTS certification-after accounting for patient characteristics,extent of resection, surgeon and hospital volume, and

hospital teaching status. ${}^{47}$ Another group of investigators interested in the relationship between specialization and long-term outcomes further linked Medicare claims and the ABTS Diplomates list to a national cancer registry to be able to adjust for cancer stage. They found that board certification and a general thoracic surgical practice was associated with an 11% lower risk of long-term death compared to surgeons without ABTS certification-after accounting for patient and cancer characteristics,preoperative management, surgeon and hospital volume,and hospital teaching status. Furthermore, specialists more frequently performed guideline-recommended staging, thoracoscopy, and resections after neoadjuvant therapy compared to surgeons without ABTS certification.44-46,48,49

Additional Comments/Implementation Recommendations

The body of evidence supporting specialization is limited by confounding, misclassification of specialty,and generalizability to all patients and geographic regions. Administrative data and cancer registries do not measure pulmonary function, functional status, or the severity of comorbid conditions. If specialists care for sicker patients, then studies may underestimate the true effect of specialty care. However, if specialists care for healthier patients, then studies may overestimate the true true effect of specialty care. Misclassification of specialization occurs when a surgeon pursues specialty training outside the United States. This type of bias may underestimate the true effect of specialty care. From an implementation perspective, surgeons with equivalent training to the ABTS should be considered specialists.Finally, specialists tend to work in more populated regions resulting in inequitable access to specialty care.While there is little evidence of sex- or race-based inequity, specialized care is less likely to be accessible to those without insurance, with lower education and income levels, or living in rural areas.45,48

Lymph Node Evaluation

Evidence and Evidence-to-Decision

The panel selected 33 studies to support recommendation statements for lymph node evaluation. ${}^{50-82}$ For both recommendations, the certainty of evidence was assessed as low(e-Tables 3I and 3J) based on serious and very serious risk of bias in studies reporting on outcome of interest plus downgrading for inconsistency and indirectness for multiple outcomes. The balance of effects strongly

favors systematic lymph node sampling or dissection and supports its use as standard clinical practice. A strong recommendation for systematic lymph node sampling or dissection over selective or no sampling has been presented despite low certainty or no sampling The panel opted for strong guidance here as performing selective or no sampling would lead to potential patient harms, including inaccurate staging and/or incomplete resection. Additionally, the recommendation indicates the guidance will lead to accurate pathological staging, which is tied to the survival outcomes reported in the identified studies. Both recommendations are expected to be acceptable to all stakeholders and feasible to implement and should probably increase health equity.

Studies comparing various degrees of completeness or“intensity” of lymph node removal at the time of curative-intent resection have used definitions that result in some overlap between groups. Most often studies have evaluated: selective lymph node biopsy, defined as sampling only selected suspicious or representative nodes; systematic sampling, consisting of exploration and biopsy of a standard set of lymph node stations based upon the involved lobe of the lung; or complete mediastinal lymph node dissection(MLND), where there is complete removal of all node-bearing tissue within defined anatomic landmarks. Overlap between study participants included in identified studies comparing outcomes of MLND and systematic sampling complicated comparison and meta-analysis of data comparing these strategies.

Survival benefits are associated with lymph node dissection when compared with lung resection alone for clinical stage I-II lung cancer. ${}^{52,71}$ This association persists in all age groups, including studies that specifically focused on older adults(> 80-year-old)patients. One study comparing lymph node dissection and lymph node sampling with no mediastinal lymph node evaluation found that the survival advantage(using no mediastinal node evaluation as comparator) was only seen with MLND.

For complete resection of NSCLC, the evidence supports at least a systematic nodal dissection as the standard approach. Favoring complete MLND over no intraoperative lymph node evaluation offers potential advantages that include greater likelihood of complete(R0) resection, more accurate nodal staging, and better local control by resected undetected micrometastases.Mitigating against this are the potentially increased

surgical morbidity, increased operative/anesthetic time,and scant evidence supporting improved OS for MLND.

For patients with clinical stage I NSCLC undergoing anatomic resection who have already undergone systematic hilar and mediastinal lymph node staging showing intraoperative N0 status, a meta-analysis of the available evidence demonstrated an association between better survival and MLND when compared with limited or single lymph node sampling(HR, 1.44; 95% CI, 1.27-1.63)(e-Table 3J). In the largest of these studies, a survival benefit was not observed following MLND. This multicenter study employed a very strict definition of“lymph node sampling” which was required of all participating investigators, and this standard was strictly enforced throughout the study. Similarly, in a randomized prospective study by Darling et al., ${}^{53}$ all patients underwent mediastinal sampling defined as 2R,4R, 7, and 10R for right-sided tumors and 5, 6, 7, and 10L for left-sided tumors, and if frozen sections were consistent with N0 disease, patients were randomized intraoperatively to receive either no further lymph node sampling or complete MLND. There were no differences in 5-year disease-free survival(DFS), local, regional, or distant metastasis between the 2 groups. Thus, using a strict definition of sampling may reduce clinically important differences in outcomes between systematic lymph node sampling and complete mediastinal node dissection. With that in mind, mediastinal lymph node sampling defined as pathologic evaluation of at least 5 nodal stations,≥1 hilar and≥ 3 mediastinal stations,may lead to outcomes comparable to complete MLND.

Additional Comments/Implementation Recommendations

Differences were not observed in DFS or OS between those undergoing lymph node dissection vs no lymph node assessment when considering only those with ground-glass lesions undergoing resection of clinical NO lung cancer.65

If upstaging after surgery is not occurring in approximately 5-15% of patients, that may be a signal that the operative mediastinal node sampling is inadequate. 53,82,83

SBRT and Ablative Techniques

Evidence and Evidence-to-Decision

The panel selected 42 studies to support recommendations on the use of SBRT and ablative techniques in patients with stage I disease. ${}^{14,84-124}$

Identified studies evaluated the following ablative techniques: thermal ablation, radiofrequency ablation,cryotherapy, and microwave ablation. When comparing resection to SBRT and ablative techniques in patients who are considered medically operable, the balance of effects favored resection with a low certainty of evidence(e-Tables 3K and 3L). For medically inoperable patients with stage I lung cancer, SBRT is favored over ablative techniques. This recommendation was based on very low certainty of evidence as evidence was downgraded for very serious risk of bias and indirectness. Identified studies that compared SBRT and ablative therapies enrolled both patients with stage I and stage II disease and only 1 study enrolling medically inoperable patients.The panel drafted the recommendation for only patients with stage I disease as the panel deemed stage II tumors inappropriate for SBRT and ablation due to either suspected N1 node involvement or a substantial incidence of occult node involvement based on size.Although these recommendations are expected to be acceptable to providers, it is anticipated that patients may prefer non-surgical therapy, and providers will need to fully detail the benefits and harms of these procedures.

In the absence of completed randomized phase III trials,the approach to comparing outcomes between surgery,SBRT(also known as stereotactic ablative radiotherapy or SABR), or ablative therapies by their efficacy or equivalence is complex and has been driven essentially by retrospective reviews and institutional reports. This does make conclusions from these studies subject to bias given the impact that patient, tumor, and treatment factors, such as imbalances in the burden of medical co-morbidity and lack of congruence in disease staging,may have when treatments are being selected. In acknowledging this reality, studies involving non-randomized studies become by necessity the primary source for evidence-based comparisons between surgical and non-surgical approaches in the management of early-stage lung cancer. Despite the presence of recognized confounding factors between studies,quantitative meta-analyses of such trials may still be carried out to develop predictive conclusions on treatment appropriateness. In making such comparisons, lung cancer-specific survival(LCSS) may offer the most appropriate end point to evaluate efficacy when comparing these treatment modalities.Recurrence-free survival(or DFS), OS, and treatment-related adverse events may provide further insights into

treatment benefits. Given the nature of the populations being compared when considering surgery vs SBRT or ablation, it is helpful to stratify patients by their operative risk.

Operable Patients: Stereotactic Body Radiotherapy:Twenty-one studies of SBRT compared to resection for patients with stage I/II NSCLC judged to have acceptable operative risk were considered in the aggregate for a meta-analysis(e-Table 3K). Twenty of these studies were retrospective cohort studies. The remaining study92 analyzed outcomes for a combined population derived from 2 incomplete prospective randomized controlled trials comparing SBRT to resection in operable patients that all closed for failure to accrue. With respect to OS,the meta-analysis involved 25,855 SBRT and 28,988 resection patients. Results suggested that SBRT is associated with a higher risk of death over time when compared to resection(HR,1.58; 95% CI, CI 1.45-1.72;P<.00001)(e-Table 3K). Fewer studies were available for LCSS or recurrence-free survival analyses, but the HRs from each demonstrated association between survival and resection over SBRT. A limited number of these studies(8 in total) provided data for adverse event analysis. For both SBRT and resection, the rate of grade 3 events or higher was generally< 10%. One study showed that treatment-related mortality favored SBRT over resection(3.7% vs 0%, respectively).

Quality of life studies involving SBRT and resection patients have been reported in 3 publications. 86,107,118 Overall, these studies have found no clinically significant differences in quality of life following either SBRT or surgery for patients with early-stage NSCLC.

SBRT: Special Populations: Octogenarians: Three studies ${}^{88,102,108}$ analyzed outcomes for patients 80 years of age and older as they represent a population with a recognized increased operative risk based on advanced age. For those octogenarians considered operable, data analysis demonstrated an association between SBRT and a higher risk of death over time when comparing the total number of patients from these 3 studies(216 SBRT vs 163 resection), with an HR of 1.45(95% CI, 1.05-2.01)(e-Table 3K).

High Operative Risk: A retrospective cohort study of 538(76 SBRT and 462 surgical) patients compared outcomes between high and low operative risk patients with stage I NSCLC undergoing either surgical resection or SBRT, with risk defined by impaired pulmonary

function and other pre-treatment co-morbidities.94 In this study, surgical resection was associated with higher 5-year LCSS(76.1% vs 56.3%) and OS(46.6% vs 23.6%)rates than SBRT, respectively.

Ablative Therapies: Due to the limited numbers of studies available, ablation studies(radiofrequency,microwave, or cryoablation) were combined as a single category of procedures rather than by individual technologies when evaluating comparisons to surgery outcomes. Looking at 7 studies involving a total of 1,311 ablation and 2,341 resection patients, there was a trend toward ablation with a higher risk of death averaged over time when compared to resection(HR, 1.43;95% CI, 0.96-2.11; P=.08)(e-Table 3L). ${}^{87,101,103,113,119,120,124}$ The caveat to interpreting these studies is that patients offered percutaneous thermal ablation for early-stage NSCLC were were medically inoperable due to comorbidities or limitations in performance.

Inoperable Patients: SBRT vs Ablative Therapies: For the inoperable population, 5 propensity-matched retrospective publications in the last 6 years have provided the data available for analysis. ${}^{84,89,104,105,119}$ 2 studies(30%-31% vs 26%-27%), ${}^{84,89}$ with the remaining 3 studies demonstrating a non-statistical difference between SBRT and ablative therapies.Notably, the 5-year OS realized in these studies was lower than expected for patients with stage I and II NSCLC from surgical series or healthy SBRT patients. In cases where tumor size is< 2 cm, the survival advantage of SBRT over ablation appears to disappear. Although ablation is associated with small changes in pulmonary function and quality of life in the short term, the long-term impact is more variable and difficult to predict based on patient-specific factors.

Additional Comments/Implementation Recommendations

Appropriate choice of SBRT vs ablation should consider tumor size and location, expertise of physicians providing these local treatment options, patient's risk and tolerance of procedure related complications, and underlying lung disease that might preclude the use of radiation(eg, interstitial lung disease or previous radiated tissue). Long-term outcomes are associated with specific tumor characteristics, including tumor size,change in pulmonary function associated with treatment, and size of the ablation zone which

correlates directly with risk for recurrence(> 8-10 mm of ablation“margin” is associated with a lower recurrence risk).

Adjuvant Therapy

Evidence and Evidence-to-Decision

Recommendations for adjuvant therapy in patients with early-stage NSCLC were informed by 18 randomized controlled trials(e-Tables 3N-3Q)evaluating the efficacy and morbidity of adjuvant platinum-based chemotherapy,125-137 EGFR tyrosine kinase inhibitors(TKIs),6,8 ALK TKIs, and immune checkpoint inhibitors.5,7 Across patients with stage I NSCLC, the benefits of adjuvant chemotherapy and immunotherapy therapy were deemed to be trivial while the harms of therapy were defined as moderate,resulting in balance of effects favoring no therapy. In patients with stage IB NSCLC, the small benefits of TKIs outweighed the trivial harms. In comparison,for resected patients with stage II disease, the moderate benefits of adjuvant chemotherapy outweighed the samples with stage II disease, the TKI therapy and immunotherapy demonstrated small benefits in patients with stage II disease that offset the associated harms. For all 4 recommendations, the certainty of evidence was assessed as moderate, and recommendations are expected to be acceptable to all stakeholders and feasible to implement.

The use of adjuvant cisplatin-based chemotherapy for 4 cycles improves overall survival in patients with resected stage II NSCLC, including those with≥ 4 cm, node-negative tumors(stage IIA eighth edition American Joint Committee on Cancer).126-129,131-134,136,137 patients unable to tolerate cisplatin, carboplatin may be used. The second chemotherapy agent should be histology appropriate(eg. pemetrexed for non-squamous but not squamous). Although randomized trials have not demonstrated improvement in survival outcomes following adjuvant cisplatin-based therapy in patients with resected stage I NSCLC,125,126,128,130,134,137 we recognize that TNM staging is an imperfect predictor of recurrence risk in patients with smaller tumors and high-risk features such as visceral pleural invasion,spread through airspaces and lymphovascular invasion,and detection of circulating tumor DNA. Some multidisciplinary tumor boards recommend adjuvant chemotherapy to patients with such high-risk tumors,although high-level evidence is lacking. This is an

Figure 1- Sample management algorithm for average-risk patients. a"Resection sug-gested over stereotactic body radiotherapy or ablative techniques. bRection by a board-certified thoracic surgeon suggested.ALK= anaplastic lymphoma kinase;EGFR= epidermal growth factor receptor;GG/L= ground-glass/lepidic.

![Average-Risk Patients\nStage II\nMinimally invasive resection\na,b\nPeripheral\n≤ 2 cm solid or mostly solid\nLobectomy OR segmentectomy OR sublobar nonanatomical resection\nLobectomy\nIntraoperative systematic mediastinal and hilar lymph node sampling/dissection (≥ 3 mediastinal stations, ≥ 1 hilar station)\nStage IB with EGFR ex19del/L858R mutation\nStage II\nTargeted therapy\nChemotherapy\nBomarker alterations\nTargeted\n](2/aj0YEe4oUhYkBdfpda0fYP/figureabd10d4779b044f290f1134993bfe948_0_1.png) important gap in the evidence which should be addressed by dedicated randomized trials.

Adjuvant checkpoint inhibition with atezolizumab for up to 16 cycles(every 3 weeks for 1 year) in patients with resected stage II NSCLC(T≥5 cm or N1),with programmed death-ligand 1(PD-L1) tumor cell(TC) expression≥ 1% and EGFR/ALK negative,improves DFS after at least 1 dose of cisplatin-based chemotherapy(HR DFS, 0.66; 95% CI, 0.50-0.88).5 In a previous publication, a trend to improved OS was seen, particularly in those with PD-L1 TC≥50%(HR OS, 0.42; 95% CI, 0.23-0.78). 138 Treatment discontinuation for adverse events occurred in

18.2% of patients. In a separate study, adjuvant checkpoint inhibition with pembrolizumab for up to 1 year in patients with resected stage II NSCLC(T≥4 cm or N1) improved DFS(HR DFS, 0.76; 95% CI 0.63-0.91). Although 14% of patients did not receive adjuvant chemotherapy, the US Food and Drug Administration approval is after adjuvant chemotherapy. Benefit was seen irrespective of PD-L1 chemotherapy. Benefit was seen irrespective of PD-L13 current and EGFR genotype, although this is not recommended for patients with resected EGFR mutant lung cancer. No OS benefit has been observed to date. Treatment discontinuation for adverse events was seen in 19.8% of patients.

![High-Operative Risk Patients\nStage I\nMinimally invasive resection\nSublobar resection\n Intraoperative systematic mediastinal and hilar lymph node sampling/dissection (≥ 3 mediastinal stations, ≥ 1 hilar station)\nStage IB with EGFR ex19 del/L858R mutation\nTargeted therapy\nChemotherapy\nNo EGFR/ALK alteration\nTargeted therapy\nImmuno-teration\nTherapy\n](2/aj0YEe4oUhYkBdfpda0fYP/figure81dad4428d204b0a9498ab8d62a9de3a_0_0.png) Figure 2- Sample management algorithm for high-operative risk patients."Resection suggested over sterotic body radiotherapy or ablative techniques."Resection by a board-certified thoracic surgeon suggested."Based on upstaging. ALK= anaplastic lymphoma kinase; EGFR= epidermal growth factor receptor.

In patients with resected EGFR(exon19 deletion,L858R point mutation) mutant lung cancers, adjuvant osimertinib for up to 3 years improves OS(HR,0.49;95% CI, 0.34-0.70) ${ }^{139}$ and DFS(HR, 0.27; 95% CI,0.21-0.34) ${ }^{140}$ in patients with stage IB to IIIA disease,and central nervous system DFS in patients with stage II-III disease(HR, 0.24; 95% CI, 0.14-0.42).Most patients with resected stage II EGFR mutant

![Medically Inoperable Patients\nStage I\nSFRT\n](2/aj0YEe4oUhYkBdfpda0fYP/figure3ccdf6b2de6749839a2a5c8105b2208e_0_3.png) Figure 3- Sample management algorithm for medically inoperable patients. SBRT= stereotactic body radiotherapy.

lung cancer also received adjuvant chemotherapy prior to starting osimertinib, while those with stage IB did not. Thus, chemotherapy should still be recommended to appropriate patients(ie, stage II).Thirteen percent of patients discontinued treatment for adverse events.

Most recently, patients with resected stage II ALK rearranged lung cancer had improved DFS(HR DFS, 0.24;95% CI, 0.13-0.43) and central nervous system DFS(HR,0.22; 95% CI, 0.08-0.56) when receiving adjuvant alectinib 600 mg twice a day for 2 years compared to 4 cycles of adjuvant chemotherapy.9 Overall survival data have not been reported. Five percent of patients discontinued alectinib for adverse events. At this time, we do not believe that these trial data° provide sufficient long-term follow-up to withhold chemotherapy completely from patients with resected stage II and III NSCLC where it has been part of the standard of care to increase the chance of cure.

Alectinib should be offered to all high-risk patients, and chemotherapy should be discussed.

Additional Comments/Implementation Recommendations

With the emergence of targeted therapy and immunotherapy as recommended treatments for patients with resected NSCLC, biomarker testing for relevant alterations early in the patient's diagnostic workup is warranted. The evidence for treatment of patients with early-stage disease with biomarker alterations is rapidly evolving, and it is expected that comprehensive biomarker testing in this population will become increasingly important in the future. However,based on the exclusion of a Population, Intervention,Comparator, and Outcome question specific to comprehensive biomarker testing during project planning for this guideline, no evidence-based recommendation for testing can be provided at this time apart from the routine testing required for the recommended targeted therapies. Patients with resected stage II NSCLC should be referred for adjuvant systemic therapy discussion(irrespective of comprehensive biomarker testing results). Patients with resected stage IB EGFR mutant NSCLC should also be referred for adjuvant targeted therapy discussion.

An important evidence gap remains in our understanding of optimal adjuvant therapy for patients with resected NSCLC and less common EGFR sensitizing mutations. While patients with these tumor alterations were excluded from the AZD9291 Versus Placebo in Patients With Stage IB-IIIIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy(ADAURA) trial,8,140 it is important to understand that they still have TKI-sensitive disease. Until such evidence is generated addressing the benefit of adjuvant kinase inhibitors in this population, the use of adjuvant TKIs should be discussed on a case-by-case basis.

Recent data supporting survival benefit with perioperative chemo-immunotherapy ${}^{141}$ in patients with resectable stage II NSCLC support a multidisciplinary discussion of upfront surgery versus pre- or perioperative treatment prior to finalizing treatment decisions with the patient.

Summary

The best treatment for average or low operative risk patients with stage I NSCLC cell lung cancer remains surgical resection. For the first time, a meta-analysis

comparing OS for patients with stage I lung cancer reveals MIS is associated with better survival. This OS benefit, along with previously described reductions in pain and hospital length of stay, as well as improved quality of life, likely was the force behind the Society of Thoracic Surgeons setting MIS as a benchmark and reportable rate for the surgical treatment of patients with stage I NSCLC. New randomized trial evidence reveals equivalent OS of sublobar resection compared to lobectomy for patients with peripheral≤ 2 cm NSCLC.This subset of patients presents more frequently today with increased lung cancer screenings and incidental findings on ubiquitous CT body imaging. Both randomized controlled trials for sublobar resection highlighted the importance of intraoperative lymph node assessment and the ability to achieve a clear(R0)nocologic margin. Systematic lymph node sampling or lymphadenectomy remains the hallmark of a good oncologic operation for early-stage lung cancer. Studies of the relationship between surgeon specialty and short-and long-term patient outcomes show improved outcomes when a board-certified surgeon or a specialist in thoracic surgery performs the lung cancer surgery.Additionally, studies have shown that specialists demonstrate better adherence to guideline-recommended care when compared to surgeons without ABTS certification.44-46,48,49

Best practice dictates standardized comprehensive biomarker testing and mutation analysis for relevant tumor alterations early in the diagnostic workup of patients with NSCLC.

The use of adjuvant chemotherapy in patients with resected stage II NSCLC, including those patients with 4 cm, node-negative tumors, improves OS. In patients with resected stage IB(≥ 3 cm) and II EGFR mutant lung cancers, as well as stage II ALK mutant lung cancers, adjuvant targeted therapy improves OS. Recent data support the use of induction chemotherapy and immunotherapy in select patients with resectable stage IB and II NSCLC. These findings highlight the importance of a multidisciplinary discussion with patients with clinical stage IB or II NSCLC regarding upfront surgery vs preoperative treatment prior to finalizing treatment decisions with the patient.

For further review and discussion supporting these guideline statements, please see e-Appendix 4.

The improved survival rate of patients with NSCLC is a testament to the ongoing multidisciplinary approach to lung cancer detection, characterization, and treatment.

The diagnosis of lung cancer is undergoing a paradigm shift with more patients cured of their disease and for patients with recurrent or persistent disease a longer lifespan and potential for cure.

Funding/Support

The American College of Chest Physicians funded this guideline.

Financial/Nonfinancial Disclosures

Conflicts of interest are listed in e-Appendix 2.

Acknowledgments

Author contributions: J. H. and L. H. S. had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. D. A., J. B., F., J. H., M. L., N. L., L.H.S.,S.M.,and G.M.V. contributed substantially to the study design,data interpretation, and writing of the manuscript. F. D. contributed substantially to the data interpretation and review of the manuscript.

Role of sponsors: The sponsor had no role in the design of the study,the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The panel would like to thank Jessica Donington, MD, for her extensive efforts in the early development of the guideline.

Additional information: The e-Appendixes, e-Figure, and e-Tables are available online under“Supplementary Data.”

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图示：Average-Risk Patients Stage II Minimally invasive resection a,b Peripheral ≤ 2 cm solid or mostly solid Lobectomy OR segmentectomy OR sublobar nonanatomical resection Lobectomy Intraoperative systematic mediastinal and hilar lymph node sampling/dissection (≥ 3 mediastinal stations, ≥ 1 hilar station) Stage IB with EGFR ex19del/L858R mutation Stage II Targeted therapy Chemotherapy Bomarker alterations Targeted

图示：High-Operative Risk Patients Stage I Minimally invasive resection Sublobar resection Intraoperative systematic mediastinal and hilar lymph node sampling/dissection (≥ 3 mediastinal stations, ≥ 1 hilar station) Stage IB with EGFR ex19 del/L858R mutation Targeted therapy Chemotherapy No EGFR/ALK alteration Targeted therapy Immuno-teration Therapy

图示：Medically Inoperable Patients Stage I SFRT

引用 / 出处

2025+ACCP临床实践指南：早期非小细胞肺癌患者的管理. 2025.