Curative intent therapy of stage I–III non-small cell lung cancer: a patient-centered precision approach to assess, measure, and interpret benefits and harms

Introduction

Historically, most lung cancers were diagnosed at a distant metastatic stage (IV) (1). Consequently, the treatment of such advanced disease was aimed primarily at controlling tumor burden but not with curative intent. However, following the 2011 National Lung Screening Trial (2), the proportion of lung cancers diagnosed in the United States (U.S.) at a localized stage (I–II) increased by 5% annually between 2014 and 2018, while those diagnosed at stage IV decreased by 6%, representing a stage shift at a national level (3). By 2020, the number of patients with stage I–III lung cancers had overtaken those with stage IV disease (4). The number of stage I–III lung cancers is expected to increase (3), most of which are eligible for curative intent therapy through a combination of definitive treatment (i.e., surgical resection, radiation, or chemoradiation) to resect or eradicate lung cancer, and additional adjunctive therapies that are either preoperative (aka neoadjuvant); postoperative (aka adjuvant); perioperative (aka neoadjuvant followed by adjuvant); or consolidative (following chemoradiation) to reduce recurrence and improve survival. In addition, a key ethical principle of medical practice is beneficence—to achieve and produce net benefit over harm (5). This principle has been historically difficult in lung cancer, in part due to a lack of safe treatment options, poor prognosis, and excessive risks taken in attempts for cure (6).

As surgical and radiation techniques advance, definitive lung cancer treatment has become safer and better tolerated. In parallel, advances in radiologic, histopathologic, and molecular characterization—the lattermost a form of endotyping, have substantially increased our understanding of the natural history of non-small cell lung cancer (NSCLC) and informed us of the substantial heterogeneity of lung cancer (7). Furthermore, molecular endotyping has led to the development of host-directed therapy in the case of immune checkpoint inhibitors (ICIs) and more targeted therapy with receptor tyrosine kinase inhibitors (rTKIs). One radiologic-biologic advance, derived largely from lung cancer screening with chest computed tomography (CT), is that lesions with ground glass opacities are associated with higher risk of adenocarcinomas but usually follows an indolent course (8) and portend excellent prognosis (9). If these non-malignant or indolent lung cancers that are unlikely to cause harm are resected, a 2024 International Association for the Study of Lung Cancer (IASLC) Early Detection and Screening Committee (10) raised concerns on overdiagnosis and overtreatment (11-13). In addition, surgical treatment has advanced beyond lobectomy, with calls for precision surgery to completely resect cancer while avoiding resection of normal lung to prevent long-term harms (14). Alongside molecular endotyping, ICIs and targeted therapies (e.g., rTKI) are increasingly incorporated in the treatment of stage IB-IIIB NSCLC. In neoadjuvant and perioperative therapy, controversies exist regarding the subjectivity of resectable disease (15,16), effects of delays to definitive surgery incurred by neoadjuvant therapy (17), and consideration of patients subsequently not receiving surgical treatment (16). Due to these controversies, another 2024 IASLC Expert Panel recommended clinical equipoise in deciding between neoadjuvant chemo-ICI followed by surgery vs. upfront surgery followed by chemo-ICI therapy, to weigh benefits vs. harms, as well as incorporation of the patient’s perspectives in decision making, particularly for stage II NSCLC (18).

Therefore, as precision medicine advances, it is essential to characterize the benefits and harms in curative intent therapy of stage I–III NSCLC. In this project, we reviewed advances in stage I–III NSCLC informed by phase III randomized controlled trials (RCTs) designed to determine treatment efficacy in the past 15 years or individual participant data meta-analyses of RCTs. To facilitate decision-making and arrive at beneficent care, we incorporated a precision medicine model to assess and measure benefits and harms, referred to international and transdisciplinary guidelines, and interpreted the results from the perspective of a hypothetical patient faced with choosing between different treatment options.

Methods

Precision medicine model

To evaluate benefits and harms of the various treatment options of NSCLC, we incorporated a precision medicine model used in chronic lung disease (19). This model emphasizes the importance of accounting for person and disease heterogeneity and stratifying them appropriately, with four possible outcomes illustrated among a population with the same disease and treatment: (I) positive effect and no toxicity; (II) positive effect and toxicity; (III) no positive effect and no toxicity; or (IV) no positive effect but presence of toxicity (19). We anchored outcomes on survival—favoring overall survival (OS), a critical patient-centered outcome in translating oncology RCTs (20)—over disease-specific [e.g., disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), or event-free survival (EFS; composite of disease progression, recurrence, or death)] survival. Where combined treatments have no demonstrated superior effect on survival compared to a less intensive strategy, we considered the more intensive strategy as having no survival benefit and potentially toxic (scenarios 3 and 4).

Statistical analyses

To consider trade-offs between treatment benefits and harms, we followed standard recommendations to use absolute instead of relative statistics (21). We calculated the number needed-to-treat (NNT) for beneficial effect (NNTB) or NNT for harmful effect (NNTH) as: 1/absolute risk reduction (ARR) or absolute risk increase (ARI) (%), and as recommended—with specified follow-up time (22). To facilitate communication and decision-making, where pertinent, we incorporated a novel metric to combine benefits and harms—the NNT for net effect (NNTnet), calculated as: 1/(ARR − ARI), or 1/(1/NNTB − 1/NNTH) (23). The NNTnet is interpreted similarly to that of NNT—i.e., on average, the number of patients needed to be treated (compared to another strategy) to confer one net effect. A positive NNTnet is interpreted similarly to the NNTB, as the average number needed to be treated to see the benefit exceeding the harm by one outcome event. A negative NNTnet is interpreted similarly to the NNTH—i.e., the average number needed to be treated to see the harm exceeding the benefit by one event (23). Among patients with atrial fibrillation (24), the NNTnet has been applied to evaluate the benefit (stroke prevention) and harm (bleeding) of anticoagulation and, in another study, antibiotic therapy for lower respiratory tract infections (25). An online NNTnet calculator is available for use and illustration (26).

Patient-centered interpretation

We categorized treatment effects on OS as small (≤2%), medium (3–5%), large (6–10%), or very large (>10%), informed by: (I) what most patients with early-stage lung cancer have reported as acceptable mortality risk to gain 1 year of life (≤2%) (27); (II) the maximal postoperative mortality risk endorsed by the 2022 American Society of Clinical Oncology (ASCO) guideline on multi-modality therapy (≤5%) (28); and (III) the largest 5-year OS benefit observed with adjunctive chemotherapy (4%) (29), ICI (10%) (30), and rTKI (10%) (31) therapy in stage II–III NSCLC. We interpreted results from the perspective of a hypothetical patient faced with choosing between treatment options—an important aspect of shared decision-making, communication of statistics (32), and translation (33). We expanded upon the concepts of overdiagnosis, overtreatment, and undertreatment endorsed by a 2024 IASLC Early Detection and Screening Committee (10). We further defined overtreatment as added or combined treatments with a demonstrated net negative or zero balance on survival or a 90-day treatment-associated mortality risk of >2–5%, informed by what patients have reported as acceptable (2%) and the maximal risk endorsed by contemporary clinical guidelines (5%) (27,28). In addition, we assessed benefits and harms of neoadjuvant or preoperative therapy for patients with resectable stage II–IIIB NSCLC, noting potential imbalances in benefits and harms that could be conceptualized as undertreatment or overtreatment.

Synthesis of results

We synthesized findings first on diagnosis, then definitive treatment, followed by adjunctive (adjuvant, consolidative, neoadjuvant) therapies. We noted important prognostic characteristics among participants across RCTs and countries: age- or disease-related performance status (PS), effects of combustible cigarette smoking [i.e., chronic obstructive pulmonary disease (COPD), lung function], and tumor biology [e.g., programmed death-ligand 1 (PD-L1) expression levels]. We referenced guidelines or statements from the IASLC (10,18), other international groups (34), the American Society of Therapeutic Radiation Oncology (35,36), the American Association of Thoracic Surgery (37), ASCO (28,38-40), the European Society of Medical Oncology (41), and the National Comprehensive Cancer Network (NCCN) (42)—arguably the most commonly regarded clinical oncology guideline in the U.S. We used the term “recommended” to refer exclusively to guideline or statement recommendations, noting consensus or non-consensus among panel members and/or across guidelines. We defined good PS as World Health Organization or Eastern Cooperative Oncology Group (ECOG) PS 0–1 or Karnofsky performance scale 80–100. Unless specified, we used the 8^th edition of the tumor-node-metastasis (TNM) staging system (43); disease-specific and toxicity measures were as standardly assessed across RCTs—by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (44) and the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events, respectively (45).

Results

Screening & diagnosis

Lung cancer screening with low-dose CT (LDCT) has been accepted as a standard of care for high-risk individuals with significant tobacco exposure (46-48). A 2022 Cochrane systematic review and meta-analysis of 11 RCTs—involving 94,445 participants undergoing LDCT screening—demonstrated that LDCT screening for 6 to 9 years reduced the relative risk of lung cancer-related mortality by 19% (49). This meta-analysis further demonstrated that 296 participants needed to be screened to prevent one lung cancer-related death (moderate-certainty evidence) (49).

In this context, overdiagnosis can occur if an individual is diagnosed with a lung cancer that has no clinical significance, i.e., that would not have caused any harm if left undiscovered, particularly if the individual subsequently dies of a competing, non-lung cancer death (e.g., due to comorbidity) (10,50). This scenario is most common with lesions subsequently diagnosed as pre-invasive adenocarcinoma (i.e., atypical adenomatous hyperplasia; adenocarcinoma in situ) (10) but can also occur with minimally invasive adenocarcinoma and lepidic adenocarcinoma (9). On chest CT, they are associated with ground glass opacities and can appear as a pure ground-glass nodule (GGN) or part-solid (aka mixed ground glass and solid) GGN (51-53). While such pure and part-solid GGNs are associated with a greater likelihood of malignancy compared to solid lesions (54), they tend to have a more indolent course and better long-term prognosis (9). Thus, one could argue that in some patients, overtreatment can occur if these lesions are resected, particularly among the elderly and/or those with serious co-morbid conditions that are expected to substantially reduce their lifespan (10,55).

However, a challenge in the clinical application of these concepts is that the information needed to determine true cases of overdiagnosis and overtreatment can only be applied in retrospect (56). Furthermore, guidelines on the management of GGNs vary substantially. For example, for pure GGNs measuring 5 to 20 mm or greater or part-solid GGNs measuring 5 to 8 mm or greater, the recommendations include performing invasive diagnostic testing followed by resection or empiric resection if highly suspicious for malignancy. Moreover, the definitions of concerning features on follow-up CT scans vary—if they persist, enlarge in size, and/or, for pure GGNs, develop a new solid component. In addition, the recommended timing of the follow-up chest CT is broad—ranging from 3 to 12 months (Table 1) (37,47,57-60). Not surprisingly, estimates of overdiagnosis with LDCT screening also vary substantially—0 to 36% (average 18%) at ≥10 years (low-certainty evidence) (49), and up to 67% at shorter 6.5 years follow-up (61).

In addition to overdiagnosis and overtreatment, another harm is the incurrence of an invasive diagnostic procedure that can cause complications, notably pneumothorax. The rate of incurring invasive diagnostic procedures following baseline LDCT screening is 363 per 10,000 participants, with the number needed-to-screen to incur an invasive procedure determined to be 44 (harm) (11 RCTs, moderate-certainty evidence) (49). Also, to diagnose peripheral lung lesions, another 2023 meta-analysis of four RCTs involving 325 participants demonstrated that, compared to radial endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TNBA), interventional radiology-guided transthoracic needle aspiration or biopsy (TTNA) resulted in better diagnostic yield (83% vs. 69%; ARR, 14%) but higher pneumothorax rate (21% vs. 3%; ARI, 18%) (62).

Incorporated into a summary statistic that combines the benefit (averted lung cancer-related death) and harm (incurrence of an invasive procedure), the NNTnet of LDCT screening, compared to no LDCT screening, is 1/(1/296 − 1/44), or −52; in other words, 52 patients are needed to be screened with LDCT to incur a net additional invasive diagnostic procedure (harm) to prevent one lung cancer-related death (benefit). A negative NNTnet raises a red flag for potential net harm over benefit; however, the benefit of averted lung cancer-related death is more valuable to prospective patients than the risk of incurring a diagnostic procedure (Figure 1A). Additionally, to diagnose peripheral lung lesions, the NNTnet to measure the net benefit (diagnostic yield) and harm (pneumothorax) of TTNA, compared to radial EBUS-TBNA, is 1/(0.14 − 0.18), or −25; in other words, 25 patients are needed to undergo TTNA to incur one additional pneumothorax (harm) to yield a diagnosis (benefit) of a peripheral lung lesion. The negative NNTnet raises a red flag for potential net harm over benefit if TTNA is selected (Figure 1B). This information may be particularly important for patients with significant COPD or emphysema, in whom the risk of pneumothorax is substantially greater than the average patient, weighed against a potential for serious adverse events associated with sedation or general anesthesia for diagnostic bronchoscopy [1% among research participants (63); 7% needed interventions (64)]. Such information can be used in shared decision-making with prospective patients regarding the American College of Chest Physicians (ACCP) (57,65), British Thoracic Society (BTS) (58), and NCCN (42) guidelines—all of which recommend radial EBUS-TBNA or TTNA in diagnosing peripheral lung nodules. The weighing of benefits and harms could also be incorporated into the NNTnet to balance them better (23); however, such analyses are not clinically established, in part due to the lack of studies on patient preferences and values.

Figure 1 Illustration of the NNTnet to Measure Benefits and Harms of Lung Cancer Screening and Diagnosis. (A) NNTnet on averted lung cancer-related death (benefit) and incurring of invasive procedure (harm) with LDCT screening vs. no LDCT screening. The red human figure denotes the individual in whom harm can occur within a sample population. Explanation: the number needed-to-screen to prevent a lung cancer-related death is 296 (benefit), as derived from meta-analyses of 11 RCTs (49), and the number needed-to-screen to incur an invasive diagnostic procedure is 44 (harm). Combined into a single summary statistic to measure net benefit and harm, the NNTnet = 1/(1/296 − 1/44), or −52; interpreted as: on average, 52 patients are needed-to-screen with LDCT, compared to no LDCT, to have a net one additional invasive diagnostic procedure to prevent one lung cancer-related death. The negative NNTnet raises a red flag for potential net harm over benefit; however, the benefit of averted lung cancer-related death is more valuable to prospective patients than the risk of incurring a diagnostic procedure. Illustration obtained from the NNTnet online calculator using respective NNTB and NNTH statistics (25,26). (B) NNTnet on diagnostic yield (benefit) and pneumothorax (harm) with TTNA vs. radial EBUS-TBNA. The red human figure denotes the individual in whom harm can occur within a sample population. Explanation: a meta-analysis of 4 RCTs demonstrated that, compared to radial EBUS-TNBA, TTNA resulted in an absolute 14% higher diagnostic yield (benefit), weighed against an absolute 18% higher risk of pneumothorax (harm) (62). Therefore, the NNTnet for TTNA is 1/(0.14 − 0.18), or −25; interpreted as, on average, 25 patients are needed to undergo TTNA, compared to radial EBUS-TBNA, to incur one additional pneumothorax (harm) to yield a diagnosis (benefit) of a peripheral lung lesion. The negative NNTnet raises a red flag for potential net harm over benefit if TTNA is selected. This information can be used in shared decision-making with prospective patients, particularly among those with COPD/emphysema, with regard to the ACCP (57), BTS (58), and NCCN (42) guidelines—all of which recommend either radial EBUS-TBNA or TTNA in diagnosing peripheral lung nodules. Illustration obtained from the NNTnet online calculator using respective NNTB (7.14) and NNTH (5.56) statistics (25,26). ACCP, American College of Chest Physicians; BTS, British Thoracic Society; COPD, chronic obstructive pulmonary disease; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; LDCT, low-dose computed tomography; NCCN, National Comprehensive Cancer Network; NNTB, number needed-to-treat for beneficial effect; NNTH, number needed-to-treat for harmful effect; NNTnet, number needed-to-treat for net effect; RCT, randomized controlled trial; TTNA, transthoracic needle aspiration or biopsy.

Definitive lobectomy vs. sub-lobar resections

Lung resection is the recommended definitive treatment of stage I–IIIA/B NSCLC for medically-appropriate patients (37,42,66). Surgical options include anatomic resections (i.e., segmentectomy or greater resections) or non-anatomic wedge resections, the latter reserved for those with peripheral stage IA1–2 NSCLC without nodal involvement (37,42). The sub-lobar resection options are based on the results of two contemporary, non-inferiority RCTs that evaluated the extent of resection for peripheral stage IA1–2 NSCLC.

A 2022 non-inferior RCT—designed with an equivalence threshold of ≤5% in 5-year OS (small-to-medium effect) involving 1,106 participants from Japan (44% never-smoked; 95% without respiratory disease) with peripheral stage ≤ IA1–2 NSCLC—demonstrated that, compared to lobectomy, segmentectomy resulted in statistically better 5-year OS (94.3% vs. 91.1%; ARR, 3.2%) (67). Compared to lobectomy, participants in the segmentectomy group had less decrement in forced expiratory volume in 1 second (FEV₁) % predicted at 1 year (mean difference, 3.5%), 1 or more normal lung segment saved (benefits), with no difference in 5-year RFS (88%, inclusive of distant recurrence and second primary lung cancers) between groups (67). After a median follow-up of 7.3 years, the segmentectomy group had higher local-regional recurrence (ARI, 5.1%) but lower non-lung cancer deaths (ARR, 4.5%) and deaths from subsequent cancers (ARR, 3.4%) (67).

In contrast, another RCT [2023], designed with a between-group difference-threshold of <8% in 5-year DFS to suggest equivalence, found that—among 697 international participants (9% never-smoked; prevalence of respiratory disease not reported) with peripheral stage IA1–2 NSCLC—sub-lobar resections (59% wedge resections; 38% segmentectomy) were non-inferior to lobectomy in 5-year OS (80% sub-lobar vs. 79% lobectomy) and DFS (64%) (68). At 6 months following surgery, decrements in FEV₁ % predicted were less following sub-lobar resection compared to lobectomy (mean difference, 2.0%) (68). Participants in the sub-lobar resection group had higher local-regional recurrence after a medium follow-up of 7 years compared to the lobectomy group (ARI, 3.4%) (68).

Therefore, there was consistent evidence across these two RCTs that, compared to lobectomy—sub-lobar resections for stage IA1–2 NSCLC resulted in absolute benefits of 2.0–3.5% less decrements in FEV₁ % predicted at 6–12 months and, by definition of the differences between lobectomy vs. segmentectomy or wedge resections—one or more segment of normal (or non-cancerous) lung saved; weighed against an absolute harm of 3.4–5.1% increased risk of local-regional recurrence after a median follow-up of 7–7.3 years. In addition, there was a differential effect of the extent of resection on OS, with the larger 2022 RCT involving predominantly patients without respiratory disease (95%) demonstrating statistically superior 5-year OS benefit following segmentectomy (ARR, 3.2%, medium effect; NNTB, 32) while the other smaller 2023 RCT—involving a more heterogenous population—demonstrating statistically equivalence in a disease-specific outcome (5-year DFS, inclusive of distant recurrence) between sub-lobar resections and lobectomy (68). The 12.5% difference in 5-year OS rates between these RCTs (a large effect) despite all participants having peripheral stage IA1–2 NSCLC was likely due, at least in part, to participant/patient heterogeneity—i.e., the differences in the proportion of those who never smoked and without comorbid respiratory disease (67,68). The superiority of segmentectomy over lobectomy in one RCT could have been mediated by a 3.5% less decrement in FEV₁ % predicted and prevention of subsequent non-lung cancer deaths, including from cardiopulmonary disease and subsequent cancers (67). The treatment effects on OS and DFS across these RCTs favor OS as the more patient-centered outcome.

Interpreted from the perspective of a hypothetical patient faced with choosing between resections for peripheral stage IA1–2 NSCLC (if offered), segmentectomy preserves more normal lung and could improve 5-year OS by preventing subsequent deaths from other causes, at the expense of living with a potential increased risk of local-regional recurrence. Therefore, compared to segmentectomy among patients with peripheral stage IA1–2 NSCLC, lobectomy could be conceptualized as overtreatment, as endorsed by a 2024 IASLC Committee (10) (ARI, 3.2%, medium effect; NNTH, 32). These findings have impetus for future studies, including subgroup analyses of existing RCTs, to evaluate the effect of wedge resection and segmentectomy among patients with comorbid respiratory disease—prevalent among 40–70% of patients with lung cancer in the U.S. (69,70) and European countries (71)—in whom the potential benefits of preserving non-cancerous lung could be even greater. Trials are ongoing to evaluate wedge resection vs. segmentectomy for stage IA2 NSCLC (72).

Definitive radiation—stereotactic body radiotherapy (SBRT) vs. conventionally-fractionated or hypo-fractionated external beam radiotherapy (XRT)

Among patients with stage I–IIA-(N₀) NSCLC deemed medically inoperable, SBRT is the recommended treatment (36,42,73). Three RCTs evaluated SBRT vs. XRT on OS and disease-specific outcomes. A 2016 RCT from European countries involving 102 participants with stage I–IIB-N₀ [tumor size (T) ≤6 cm] NSCLC (75% with good PS; 68% with COPD) reported that—compared with conventionally-fractionated XRT—SBRT resulted in no statistically significant differences in 3-year PFS or OS (54% SBRT vs. 59% XRT) (74). This RCT was closed prematurely due to changes in standard of care—reaching approximately 50% of the intended sample size to detect an absolute 20% difference in 3-year RFS between groups. Another RCT [2019]—from Australia and New Zealand involving 101 participants with stage I–IIA-N₀ (T ≤5 cm) NSCLC (100% with good PS) demonstrated that—compared with more modern, three-dimensional conformal XRT—SBRT resulted in better 2-year OS (ARR, 18%, very large effect; NNTB, 6), local disease control, lower treatment failure, and no difference in health-related quality of life (HRQL) between groups (75). This RCT reached 100% of the intended sample size to detect a 20% difference in 2-year local control rates between groups. In both RCTs, grade 3–4 toxicity appeared similar or higher with SBRT, with no treatment-related grade 5 (fatal) toxicity (74,75) (Table 2).

In contrast, a third RCT [2024], largest to date—from Canada involving 233 participants with medically-inoperable stage I–IIA-N₀ (T ≤5 cm) NSCLC—reported no statistically significant difference between groups in 3-year local control (88% SBRT vs. 81% XRT), EFS (49% SBRT vs. 48% XRT), or OS (64% SBRT vs. 68% XRT) (79). Grade 3–5 (serious-fatal) toxicity occurred over 3–36 months appeared higher with SBRT (13% SBRT vs. 5% XRT) and even higher with central tumors (11% central vs. 2% peripheral) (79), whereas XRT toxicity appeared less dependent on tumor location (5% central vs. 2% peripheral) (79). One SBRT-related fatality occurred in a participant with an ultra-central tumor (defined as target radiation field with overlap on the central bronchus), due to hemoptysis/pulmonary hemorrhage at 12 months. This RCT was closed prematurely under the advisement of an independent data safety and monitoring committee, reaching 72% of the intended sample size to detect a 12.5% difference in 3-year local control rates. A subsequent safety analysis—median follow-up of 2.9 (range, 0.7–5.2) years among 30 participants whose tumors were ultra-central—reported that grade 3–5 toxicity occurred among 17% SBRT vs. 0% XRT participants (ARI, 17%; NNTH, 6), with a dose-response relationship on higher volumetric dose being associated with increased toxicity (83).

Notable protocol differences across these RCTs include the 2016 and 2019 RCTs excluding centrally-located tumors—defined as those <1 cm from the mediastinum or <2 cm from the bifurcation of the lobar bronchus—while the 2024 RCT included all tumors regardless of centrality. Other notable differences include the 2019 RCT additionally excluding patients who had neoadjuvant chemotherapy or planned chemotherapy, and the 2024 RCT additionally excluding patients with comorbid interstitial lung disease/pulmonary fibrosis. Fractionation of XRT ranged 50–70 Gy across 20–35 fractions, delivered over 4–7 weeks (2016 and 2019 RCTs), and hypofractionation was 60 Gy delivered over 15 daily fractions (2024 RCT).

Therefore, there was inconsistent evidence across RCTs regarding the effects of SBRT vs. XRT on OS benefit and toxicity, with one RCT demonstrating a very large benefit of SBRT on 2-year OS (ARR, 18%; NNTB, 6) among those whose tumors are not centrally-located, while another RCT involving tumors regardless of centrality reported increased serious-fatal toxicity with SBRT compared to XRT (ARI, 17%; NNTH, 6), including fatality due to central tumor location. The effects of SBRT, therefore, can depend on central vs. peripheral tumor location, with a potential OS benefit that could be offset by late fatal toxicity with centrally or ultra-centrally located tumors.

RCTs comparing lobectomy vs. SBRT in medically operable stage I NSCLC have faced substantial accrual barriers, with two trials (NCT00840749; NCT00687986) enrolling a combined 4% of the accrual goal. Such RCTs may well need to further consider overtreatment with lobectomy for peripheral stage IA1–2 tumors, tumor proximity to central vital organs, and safety of surgical vs. non-surgical treatment options. Compared to sub-lobar resections with lymph node dissection, SBRT has the potential to undertreat occult nodal disease, weighed against the benefit of avoiding surgical complications.

Definitive concurrent chemoradiation vs. tri-modality treatment (Table 2)

In patients with resectable stage IIIA/B-(N₂) NSCLC, two RCTs compared definitive concurrent chemoradiation vs. tri-modality treatment (i.e., aka induction chemoradiation followed by surgical resection if there was no disease progression). A 2009 RCT involving 396 participants with stage IIIA/B-(N₂) NSCLC reported that—compared to concurrent chemoradiation—definitive tri-modality treatment resulted in no statistically significant difference in 5-year OS, but better PFS (ARR, 11%) (76). This RCT—designed to detect a between-group difference of 10% in 2-year OS (a large effect)—reached 70% of the intended accrual goal (76). Another RCT [2015], involving 161 participants, reported no statistically significant differences in 5-year OS or PFS between tri-modality treatment vs. concurrent chemoradiation, with a futility analysis suggesting equivalence on PFS for either strategy (77). This 2015 RCT was designed to detect a between-group difference of 15% in 5-year OS (very large effect) and did not reach the intended accrual also, reaching 54% (77). The postoperative mortality rates among the tri-modality treatment groups were 10% (76) and 7% (77), respectively.

Based on these RCTs, the 2023–2024 NCCN guideline recommends either definitive tri-modality treatment or concurrent chemoradiation for stage IIIA/B-N₂ NSCLC while cautioning against using induction therapy to change a tumor’s resectability (i.e., change unresectable to resectable disease) (42). The 2022 ASCO guideline recommends tri-modality treatment for stage IIIA/B-N₂ NSCLC only if complete resection is deemed possible and with an expected 90-day perioperative mortality risk ≤5% (28). The 2013 ACCP guideline, informed in part by the 2009 RCT, recommended either concurrent chemoradiation or induction therapy followed by surgery for discrete (single station)-N₂, stage IIIA/B NSCLC, while raising concerns on the subjectivity of resectable disease and high postoperative mortality with definitive tri-modality treatment (15). A 2022 analysis of the U.S. National Cancer Institute Surveillance, Epidemiology, and End Results Program involving 9,008 cases of stage III NSCLC identified that 25% were treated with tri-modality therapy while 75% were treated with concurrent chemoradiation (84).

However, in both RCTs, survival curves cross at approximately 1 year post-randomization (76,77)—suggesting survival trade-offs between groups before and after that period—i.e., possibly increased <1-year mortality and possibly better >2-year survival with definitive tri-modality treatment compared to concurrent chemoradiation. In addition, the postoperative mortality rates with definitive tri-modality treatment (7–10%) were excessively high if compared to rates reported in RCTs for stage IA NSCLC (0–2%) (67,68), upfront lobectomy (open or video-assisted) for stage I–IIIA NSCLC (1.5%) (78), and resections following neoadjuvant chemo-ICI therapies for stage IB–IIIA/B NSCLC (2–3%) (85,86). This increased mortality risk suggests higher operative risk following XRT. As well, most patients with early-stage lung cancer would accept a maximum mortality risk of 2% to gain 1 year of life (27). Therefore, from a hypothetical patient’s perspective, definitive tri-modality therapy, compared with concurrent chemoradiation, could be interpreted as overtreatment given the absence of demonstrated OS benefit weighed against a potential 7–10% postoperative mortality risk—i.e., if one dies within 1 year following resection, there could be no potential benefit (Figure 2).

Figure 2 Potential overtreatment of stage IIIA/B-(N2) NSCLC with definitive tri-modality treatment. Red arrow highlights crossing of OS curves at approximately 1 year follow-up (offsetting OS benefit and harm). Explanation: two RCTs [2009 (76) and 2015 (77)] evaluated the effects of tri-modality (i.e., neo-adjuvant/induction chemoradiation followed by surgery if there is no evidence of disease progression) vs. concurrent chemoradiation in stage IIIA/B-(N₂) NSCLC. Both RCTs—involving a total of 557 participants—reported no statistically significant difference on 5-year OS between groups. However, there was crossing of OS curves, with tri-modality therapy resulting in possibly lower survival within the first year and possibly higher survival beyond that period, suggesting potential early mortality for downstream OS benefit for the cohorts. This crossing of OS at approximately 1 year was present in both RCTs, which reported postoperative mortality rates of 7–10% (76,77). While non-parametric survival analyses can be used to better analyze these time-dependent varying effects, interpreted from the perspective of a prospective hypothetical patient facing treatment decisions on tri-modality therapy vs. concurrent chemoradiation (if offered), in the absence of demonstrated OS benefits—there is an imbalance of potential benefits weighed against potential harms with tri-modality therapy—i.e., if one dies within 1 year following surgery, there could be no potential downstream benefit. Additionally, most patients with early-stage lung cancer report that they would accept ≤2% treatment-related mortality to gain 1 year of life (27), and the 2022 ASCO guideline endorses a threshold ≤5% postoperative mortality risk for multi-modality therapy (28). Therefore, resection following chemoradiation could be interpreted as overtreatment. Figure adapted and reproduced from Albain et al. (76), with written permission from the publisher. ASCO, American Society of Clinical Oncology; NSCLC, non-small cell lung cancer; OS, overall survival; RCT, randomized controlled trial.

Adjunctive therapies (Table 2)—adjuvant chemotherapy and radiation

Adjuvant chemotherapy: following complete resection of stage IB/II–IIIA/B NSCLC, adjuvant chemotherapy is recommended for patients with good PS (15,28,38,40,66). A 2015 Cochrane individual participant data meta-analysis of 47 RCTs, involving 1,107 participants, demonstrated that survival was best with (I) surgery followed by adjuvant chemotherapy; (II) surgery only; (III) surgery followed by adjuvant chemotherapy and radiation; and (IV) surgery followed by adjuvant radiation (29). Compared to surgery only, surgery followed by adjuvant chemotherapy resulted in an absolute benefit in 5-year OS of 4% (medium effect; NNTB, 25) (Figure 3A) (29).

Figure 3 Benefit of adjuvant chemotherapy and harm of radiotherapy in resected stage I–IIIA/B NSCLC. (A) Benefit of adjuvant chemotherapy on OS. Explanation: a 2015 individual participant data meta-analysis of 26 RCTs (n=8,447)—evaluating surgery followed by adjuvant chemotherapy vs. surgery alone in stage I–IIIA/B NSCLC—determined that there was clear evidence of OS benefit with adjuvant chemotherapy (5-year OS: 64% vs. 60%, P<0.01; ARR, 4%—medium effect; NNTB, 25) (comparison 1) (29). In 12 RCTs that evaluated surgery followed by adjuvant chemotherapy and radiation vs. surgery followed by adjuvant radiation alone, there was also evidence of OS benefit with adjuvant chemotherapy (5-year OS: 33% vs. 29%, P<0.01; ARR, 4%, medium effect; NNTB, 25) (comparison 2) (29). Figure adapted and reproduced from Burdett et al. (29) with written permission from the publisher. (B) Harmful effect of adjuvant radiation on OS. Explanation: a subsequent 2016 individual participant data meta-analysis of 14 RCTs—evaluating surgery followed by adjuvant radiation vs. surgery—determined that there was a significant detrimental effect of adjuvant radiation on 2-year OS [58% vs. 53%, P<0.01; ARI, 5%, medium effect; NNTH, 20 (87)]. This difference diverged beginning around 4 months and remained proportionally diverged for the 5 years to which OS data were reasonably reliable. Therefore, the 5-year OS detriment is also 5%. Combined into a summary statistic to measure benefit and harm on 5-year OS, compared to surgery alone (without any adjuvant treatment), the NNTnet for surgery + adjuvant chemotherapy + radiotherapy is 1/(1/25 − 1/20), or −100, interpreted as, on average, 100 patients treated with surgery + adjuvant chemotherapy + adjuvant radiation would result in a net one additional death by 2–5 years (i.e., overtreatment). Additionally, two subsequent RCTs (2021 and 2022) involving 865 participants with stage IIIA/B-(N₂) NSCLC—traditionally considered high-risk for recurrence due to N₂ involvement—with and without additional high-risk features such as visceral pleural involvement or extracapsular extension—demonstrated that following surgery and adjuvant chemotherapy, adjuvant radiation, compared to observation only, had no statistically-significant effect on OS or DFS in neither RCT, but with increased cardiopulmonary toxicity (88,89). Taken together, the harm of adjuvant radiation can more than offset the benefit of adjuvant chemotherapy following resection of stage I–IIIA/B NSCLC, including those with N₂ disease, with or without additional high-risk features for recurrence. Arrows drawn near the referenced follow-up time (i.e., 2- or 5-year). Figure adapted and reproduced from Burdett et al. (87) with written permission from the publisher. ARI, absolute risk increase; ARR, absolute risk reduction; DFS, disease-free survival; NNTB, number needed-to-treat for beneficial effect; NNTH, number needed-to-treat for harmful effect; NNTnet, number needed-to-treat for net effect; NSCLC, non-small cell lung cancer; RCT, randomized controlled trial; OS, overall survival.

Adjuvant radiation: following complete resection of stage IB/II–IIIA/B NSCLC, adjuvant postoperative radiotherapy (PORT) is harmful and not recommended (40,42,90) and not recommended for routine use in completely resected stage IIIA/B-N₂ NSCLC (40,90)—traditionally considered high risk for recurrence due to N₂ (ipsilateral mediastinal and subcarinal) nodal involvement.

A 2016 Cochrane meta-analysis of 11 RCTs, involving 2,343 individual participants following completely resected stage IB–IIIA/B NSCLC, demonstrated that—compared to surgery only—PORT resulted in increased mortality, with a detriment on 5-year OS of 5% (medium effect; NNTH, 20) (Figure 3B) (87). There was no statistically significant trend to suggest differential effects among stage groups. Subgroup analyses did not identify differential effects by radiation techniques, dosage, histologic subtypes, nodal status, or age groups (87).

In addition, two contemporary RCTs evaluated modern PORT [three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT)] exclusively in patients with completely resected stage IIIA/B-N₂ NSCLC. A 2022 RCT—involving 501 European participants randomized to PORT (89% via 3D-CRT and 11% IMRT radiotherapy) or no PORT—found that 3-year OS and DFS were not different between groups (88). There were no differential effects by the presence of additional high-risk features such as extracapsular extension or greater extent of N₂ involvement (88). Compared to no PORT, PORT participants experienced higher grade 3–4 pneumonitis (ARI, 4%) and cardiopulmonary toxicity (ARI, 6%) (harms). After a median follow-up of 4.8 years, mediastinal recurrence was lower following PORT (ARR, 14%), but deaths due to cardiopulmonary disease were also higher (ARI, 6%) (88). Similarly, another 2021 RCT—involving 394 participants from China randomized to PORT (11% via 3D-CRT and 89% IMRT) or no PORT—demonstrated no statistically significant difference between groups in 3-year OS or DFS (89). Additional high-risk features of visceral pleural involvement were present in 66% of participants, and 58% had ≥4 lymph nodes involved. Again, 3-year local-regional recurrence was lower (ARR, 9%), but grade 1–3 pneumonitis or esophagitis was higher (ARI, 24%), with 3% of deaths due to cardiopulmonary disease (89). Critically, the authors of both RCTs concluded that PORT cannot be routinely recommended for completely resected stage IIIA/B-N₂ NSCLC (88,89). Interestingly, despite unfavorable results with PORT, including in stage up to IIIB-N₂, the 2023–2024 NCCN guideline recommends that PORT could be considered for subgroups of patients with high-risk features in N₂ disease (e.g., extracapsular extension or multi-station nodal involvement) following complete (R₀) resections (42). In contrast, thoracic oncologists from European countries and ESMO endorse adjuvant radiation only for incomplete (R_1,2) resections, citing harmful toxicity with PORT (91,92).

From the perspective of a hypothetical patient following complete resection of stage I–IIIA/B NSCLC, adjuvant radiation would be considered overtreatment, with demonstrated fatal effects or no OS benefit among those with high-risk N₂ disease, regardless of other additional high-risk features. In addition, the detrimental effect of PORT on 5-year OS (NNTH, 20) more than offsets the benefit of adjuvant chemotherapy (NNTB, 25). Compared to surgery only (without any adjuvant therapy), the NNTnet of adjuvant chemotherapy and adjuvant radiation following complete resection of stage I–IIIA/B NSCLC is −100 [1/(1/25 − 1/20)], or on average, 100 patients treated with surgery followed by adjuvant chemotherapy and radiation would result in one additional death (Figure 3A,3B). Among the group with high-risk stage IIIA/B-N₂ disease, PORT, compared to no PORT, can confer a 9–14% absolute benefit in reduced local-regional recurrence, but at the expense of increased 4–24% cardiopulmonary/esophageal toxicity and 3–6% subsequent deaths from cardiopulmonary disease. These benefits and harms measures are imbalanced, since death from any cause would preclude any potential benefit.

Adjunctive therapies—adjuvant ICIs or rTKI

Adjuvant ICI or rTKI therapies: following resection of stage IB–IIIA/B NSCLC, adjuvant ICI or rTKI therapy is recommended across guidelines (28,38,42): ICI therapy for tumors with PD-L1 expression levels ≥1%, or osimertinib for tumors with sensitizing epidermal growth factor receptor (EGFR) mutations [prevalent among 15% internationally (93); 10% among white; 6% among U.S. Veterans (94)]. These recommendations were based on three RCTs.

With adjuvant ICI therapy, a 2021 RCT of 1,005 participants (54% with PD-L1 ≥1%) with resected stage IB–IIIA NSCLC (7^th edition) following adjuvant chemotherapy reported in an interim analysis that—compared to best supportive care—the addition of atezolizumab (PD-L1 inhibitor) over 1 year resulted in better 3-year DFS (56% vs. 49%; ARR 7%) (95) but no difference in 4-year OS (75% in both groups) (96). This analysis also stratified participants by baseline PD-L1 expression levels and found that those with PD-L1 ≥50% but not PD-L1 ≥1% had statistically better OS (96). Atezolizumab-related grade 3–4 toxicity occurred in 11% and fatal (grade 5) events in 1% (95,96).

Another RCT [2022]—involving 1,177 participants (60% with PD-L1 ≥1%) with resected stage IB–IIIA NSCLC (7^th edition) with and without adjuvant chemotherapy—reported in an interim analysis that, compared with placebo, adjuvant pembrolizumab (PD-1 inhibitor) over 1 year resulted in better 3-year DFS (58% vs. 50%; ARR, 8%) but not OS (82% vs. 80%) (97). There were no differential trends by baseline PD-L1 expression levels <1%, 1–49%, and ≥50% (97). Grade ≥3 toxicity increased by 8% (34% pembrolizumab vs. 26% placebo). Pembrolizumab-associated fatality occurred among 1%. Mature 5-year OS data from these two RCTs are not yet available.

With adjuvant rTKI therapy, a 2020 RCT of 682 participants from Japan and Taiwan demonstrated that, compared to placebo, 1 year of osimertinib following resected EGFR-mutated stage IB–IIIA NSCLC (7^th edition) resulted in better 5-year OS (ARR, 10%, large effect; NNTB, 10) (31) and DFS (98). Serious toxicity increased by 4% but time to HRQL deterioration was not different between groups (82).

Adjunctive therapies—consolidation (post-chemoradiation) ICIs or rTKI

Among patients with unresectable stage III NSCLC, the addition of durvalumab is recommended following concurrent chemoradiation (aka consolidation therapy) (28,38,42). A 2018 RCT of 713 international participants (22% with PD-L1 ≥25%) with unresectable stage III NSCLC demonstrated that, compared with placebo, consolidation durvalumab resulted in better 5-year OS (ARR, 10%, large effect; NNT, 10) (30). Analyses did not stratify PD-L1 expression levels by ≥1%. Serious toxicity was higher by 6% with durvalumab, with no meaningful differences in HRQL between groups (99). In addition, a 2024 RCT—involving 216 participants from Japan following chemoradiation for stage III EGFR-mutated NSCLC—reported in an interim analysis that, compared with placebo—osimertinib administered until disease progression resulted in better 1-year PFS (74% vs. 22%, ARR, 52%) and higher grade ≥3 toxicity (ARI, 23%) (100). Mature 5-year OS from this latter RCT is not yet available.

The NCCN comments that the role of adjuvant ICI therapy following resection of stage IB/II–IIIA/B is unclear among those with PD-L1 <1% while recommending durvalumab following chemoradiation for stage III NSCLC regardless of baseline PD-L1 expression levels (42). However, across the three RCTs evaluating adjuvant or consolidation ICI therapy, patients with any PD-L1 expression levels were enrolled (30,95,97). Yet, there was no clear effect of adjuvant atezolizumab or pembrolizumab on OS at 3–4 years: 0–2% (96,97) compared to a large 5-year OS benefit (10%) with durvalumab following concurrent chemoradiation for stage III NSCLC. Therefore, the effect of adjuvant ICI therapy following adjuvant chemotherapy on 5-year OS, if any, is likely small or medium, possibly related to timing following definitive treatment and baseline risk of disease recurrence after adjuvant chemotherapy. In addition, the assays used to determine PD-L1 expression levels vary substantially, depending on immunohistochemistry platforms, PD-L1 antibodies used, and scoring systems (101). The cut-off thresholds to indicate test positivity also vary widely: ≥1% to ≥50% in PD-L1 expression levels, and test positivity among participants range 20–80% (101). In other words, 20–80% may not derive any biological benefit with ICI therapy.

Taken together, the largest 5-year OS benefit across these five RCTs that evaluated adjunctive (adjuvant or consolidation) ICI or rTKI therapy was 10% (large effect; NNTB, 10), with: (I) 1-year of durvalumab following concurrent chemoradiation of unresectable stage III NSCLC (30); or (II) 1-year of osimertinib for resected, EGFR-mutated stage IB–III A/B NSCLC (31). In addition, adjuvant ICI therapy (following adjuvant chemotherapy) increases grade 3–4 toxicities by 6–11%, fatality by 1%, with unclear effects on 5-year OS (95-97). Following resection of EGFR-mutated NSCLC, osimertinib can increase serious or grade ≥3 toxicity by 4% (82), and following chemoradiation, by 23% (100). These benefits and harms can be discussed with prospective patients in treatment decision-making.

Adjunctive therapy—neoadjuvant therapies

In the neoadjuvant setting, a 2022 RCT involving 358 international participants with resectable IB–IIIA NSCLC (7^th edition)—comparing neoadjuvant chemotherapy followed by surgery vs. neoadjuvant chemotherapy-nivolumab followed by surgery (aka neoadjuvant chemo-ICI therapy)—reported higher rates of complete pathological response and better 2-year EFS with chemo-ICI therapy (85). Additionally, a 2023 RCT of 797 international participants resectable II–IIIB NSCLC—comparing neoadjuvant chemotherapy followed by surgery vs. neoadjuvant chemotherapy-pembrolizumab followed by surgery and adjuvant pembrolizumab (aka perioperative chemo-ICI therapy)—reported better 2-year EFS with perioperative chemo-ICI therapy (86). Similar benefits on EFS were observed with other RCTs (2023 and 2024) evaluating perioperative durvalumab-chemotherapy (102) and nivolumab-chemotherapy (103). In interim reports, neoadjuvant or perioperative chemo-ICI therapy, compared with neoadjuvant chemotherapy only, resulted in absolute 2-year EFS benefits of 9–11%. Participants in the investigative groups received neoadjuvant chemo-ICI therapy over ≥3–4 months preoperatively and adjuvant ICI therapy over 1 year postoperatively. The prevalence of PD-L1 <1% was 33–44%. No RCT has reported data on 5-year OS (Table 3).

The optimal treatment approach for resectable stage II–IIIA/B NSCLC is highly debated. A 2024 IASLC panel reported 55% agreement (non-consensus) among members in recommending upfront surgery followed by adjuvant chemo-ICI therapy vs. neoadjuvant chemo-ICI therapy followed by surgery and adjuvant ICI therapy for resectable stage II NSCLC (18). The 2023–2024 NCCN guideline recommends that all patients with stage IB–IIIB NSCLC be evaluated for neoadjuvant chemo-ICI therapy while cautioning against using this approach to change a tumor’s resectability (42). A 2022 international consensus statement recommends either (suggesting equivalence) neoadjuvant chemo-ICI therapy followed surgery and adjuvant ICI therapy or upfront surgery followed by adjuvant chemo-ICI therapy for patients with resectable stage II–IIIA/B NSCLC (34). Across guidelines or consensus statements, if selected, 3–4 cycles of neoadjuvant chemo-ICI therapy (delivered over 9–12 weeks) are recommended (18,34,42), as evaluated across RCTs.

However, across these RCTs, a combined 20%—473 of 2,418—participants whose disease initially was deemed resectable through multidisciplinary discussions subsequently did not receive surgical treatment, for reasons that included disease progression, tumor subsequently deemed unresectable, adverse events, patient declination, or surgeon refusal (85,86,102,103). A smaller proportion also underwent surgery but had surgery aborted due to intraoperative findings precluding safe resection (85,86,102,103). In addition, 100% of participants had surgery postponed longer than the recommended ≤8 weeks from diagnosis to surgery (albeit not made specific to the neoadjuvant setting) (107-109). In fact, surgery was likely postponed much longer—up to 5 months or more (85,102,103), particularly if neoadjuvant chemo-ICI were administered sequentially (85), with additional unknown delays from diagnosis to initiation of neoadjuvant therapy, all of which could result in disease progression (110,112). Moreover, among those who underwent resection, the combined complete resection (R₀) rate was 91% (85,86,102,103), substantially lower than 98% rate reported in another 2022 RCT involving upfront lobectomy for stage I–IIIA NSCLC (open and video-assisted) (78), and the 97% rate reported in a 2020 IASLC staging project (111). Furthermore, the pneumonectomy rate was 13% (85,86,102,103), higher than 5–8% reported in prior series (113,114), possibly due to a need to increase the extent of resection to achieve complete resection. Following resection, 20–45% of participants also received additional therapies, including 6–19% adjuvant radiation [a proportion of which for incomplete (R_1,2) but some for complete (R₀) resections, depending on local practice] (85,86,102,103)—the harms of which include cardiopulmonary/esophageal toxicity and detrimental effects on OS as identified above (87-89). In one RCT, there was also evidence of disease upstaging, among 6% of participants (85), and a high rate of recurrence postoperatively—35% at 3-year (104).

To date, no RCT has directly compared neoadjuvant systemic therapy followed by surgery vs. upfront (or minimally postponed) surgery followed by adjuvant therapy on OS among patients with resectable stage II–III NSCLC (18). A 2014 individual participant data meta-analysis of 15 RCTs involving 2,385 participants with resectable NSCLC identified a benefit of 5% in 5-year OS associated with neoadjuvant chemotherapy (115). However, 10 of these RCTs evaluated neoadjuvant chemotherapy followed by surgery vs. surgery alone, while five RCTs evaluated neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy vs. surgery; therefore, direct comparison of neoadjuvant therapy followed by surgery vs. surgery followed by adjuvant therapy was not possible (115).

Compared with neoadjuvant chemotherapy, traditionally used to debulk tumors (116), a unique biological rationale for neoadjuvant ICI therapy is priming of the immune system to recognize tumor antigens while the tumor is still present (117). However, the optimal treatment duration to achieve this priming effect is not well-established (18), observed to occur within days and peak at 1 week following the first dose in melanoma, and may not occur at all among those without pre-existing anti-tumor immunity (118). Genomic biomarkers, such as tumor aneuploidy (119), can predict therapeutic response. However, prospective RCTs are lacking. As such, a 2024 IASLC statement recommended equipoise to weigh benefits against harms and incorporating patients’ perspectives in decision making, particularly for stage II NSCLC (18).

Taken together, from the perspective of a hypothetical prospective individual patient diagnosed with resectable stage II–IIIA/B NSCLC, the risks associated with neoadjuvant systemic therapy—on disease progression, upstaging, subsequent non-surgical treatment, intraoperative incomplete resection, need for more extensive resection, adjuvant radiation, and postoperative recurrence—seem to substantially outweigh the benefits of pathological or radiographical tumor response, particularly among those with PD-L1 expression levels <1%. Notably, the combined 20% rate of subsequent non-surgical treatment among patients with disease initially deemed resectable could be interpreted as undertreatment, given that surgery is more likely to render cure. In other words, one in five patients treated with neoadjuvant chemo-ICI therapy would not receive surgery at all, with a NNT to incur non-surgical treatment of 5 (1/0.20) (harm; NNTH, 5). If given the choice, timely (or minimally postponed) resection would more likely maximize benefits and minimize harms.

Discussion

With greater implementation of LDCT lung cancer screening, the number of individuals diagnosed with stage I–III NSCLC is increasing. In this study, we incorporated a precision medicine model and analyzed the benefits and harms of curative intent therapy of stage I–III NSCLC informed by data from phase III RCTs or individual participant data meta-analyses of RCTs. In addition, we applied a novel metric known as the NNTnet to combine benefits and harms into a single summary statistic to measure the net effect. We regarded international and transdisciplinary guidelines and interpreted the results in a quasi-prospective fashion—by modeling a hypothetical patient diagnosed with stage I–III NSCLC faced with choosing between treatment options. The results we identified through our patient-centered precision approach to evaluate benefit and harms results have important implications in clinical decision-making to avoid over- or undertreatment, maximize benefits, and minimize harms in beneficent care for this growing population.

In the context of screening and diagnosis, we discussed potential overdiagnosis of pre-malignant or indolent lung cancers presenting as GGNs and potential overtreatment with surgical resection. We also illustrated the use of the NNTnet metric to facilitate communication and shared decision-making. In addition, we identified inconsistencies between guidelines on the management of GGNs, including indications for surgical treatment, partly due to a lack of an accepted definition of pre-malignant, indolent, and invasive lung cancer.

In definitive treatment, we identified the following scenarios of overtreatment with potential detrimental effects on OS: (I) lobectomy compared to segmentectomy for peripheral NSCLC lesions (stage IA1–2), with the former surgical approach associated with greater lung function loss and worse 5-year OS due to subsequent non-lung cancer deaths (67); (II) definitive tri-modality treatment (i.e., chemoradiation followed by surgery if no disease progression) compared to concurrent chemoradiation in stage III A/B NSCLC, due to excessively high postoperative mortality rates and potentially higher risk of death within 1 year following tri-modality treatment; and (III) PORT compared to no PORT following complete resections of stage II–IIIA/B NSCLC, due to increased cardiopulmonary toxicity and subsequent deaths. A side benefit of segmentectomy compared to lobectomy was better preservation of lung function—on average, 3.5% FEV₁ % predicted more saved—likely a clinically meaningful amount as anchored to the 5-year OS benefit of 3.2% (67). These results have implications in clinical translation and future trials to prevent overtreatment, particularly for those with co-morbid COPD/emphysema (120,121), present among 50% of U.S. patients with lung cancer (69,70) and 60–80% of U.S. Veterans (105,106). In addition, serious-to-fatal toxicity incurred by irradiation to the lungs and central mediastinum can present months to years following radiation completion (79,83,88,89,122) and may not be adequately recognized or captured using standard methods of toxicity assessment (45) (Table 4). These results have implications to avoid intense radiation to treat ultra-central tumors and/or adjuvant radiation to the mediastinum following lung cancer resectional surgery.

Moreover, we found incongruent definitions of superiority and non-inferiority of treatment effects, with an absolute difference in 5-year OS of 4% considered superior for adjuvant chemotherapy (29) and concurrent chemoradiation (80) compared to <5% in 5-year OS considered as non-inferior in the design of a contemporary RCT evaluating segmentectomy vs. lobectomy (67). Similarly, we identified overly optimistic estimates of OS benefits with definitive tri-modality treatment, with RCTs justifying 5-year OS benefits of 10–15% over concurrent chemoradiation but subsequently interpreted as equivalent despite insufficient accrual, with excessively high postoperative mortality rates following tri-modality treatment (76,77). Moreover, the ≤5% postoperative mortality threshold endorsed by a 2022 ASCO guideline panel for the treatment of stage III NSCLC (28)—while lower than an older 2013 ACCP guideline (≤10%) (125)—does not seem congruent with what most patients with early-stage lung cancer would accept to gain 1 additional year of life in choosing between surgery or SBRT (≤2%) (27). These findings have important implications for clinical guidelines to justify the endorsement of treatment-mortality thresholds and future trials to more reasonably justify effect estimates that may well need to include patients’ perspectives (126).

With neoadjuvant and preoperative therapy, we identified potential pitfalls in clinical translation of previously defined RCT protocols, with greater potential harms than benefits that could be conceptualized as undertreatment of resectable stage II–III A/B-(N₂) NSCLC. Neoadjuvant therapy is an accepted standard treatment of solid cancers, including early-stage breast cancer (127). However, this neoadjuvant approach may not translate well to NSCLC, possibly due to: (I) higher tumor aggressiveness and/or lower response rates to systemic therapy in NSCLC [whereas neoadjuvant therapy in breast cancer may lower the stage of the disease and change inoperable to operable disease (127)]; (II) higher clinical significance of nodal involvement in NSCLC that may render complete resections technically more challenging, with no valid sentinel lymph node to guide dissections (whereas sentinel lymph node dissections are performed routinely in breast cancer to evaluate and guide the extent of surgery); (III) adjuvant radiation to the mediastinum following lung cancer resection demonstrating detrimental effects [as opposed to demonstrated survival benefit following breast cancer surgery (128,129)]; and (IV) potentially higher risk for occult distant metastasis at the time of diagnosis and hematogenous metastasis incurred during the neoadjuvant period.

Modeling studies have reported that, on average, 40% of metastatic distribution patterns of solid cancers can be attributed to blood flow, and this association was highest in lung cancer (82%) (130). Therefore, the unique dual supply of blood to the lungs—the bronchial and pulmonary artery circulations—with the latter receiving 100% of the cardiac output, may render a higher risk of hematogenous spread in lung cancer than, for example, breast cancer which receives a much smaller fraction of blood. An additional physiological characteristic is that blood flow to the lower lung zones (West zone 3) is up to 10-fold higher than the apical regions (West zone 1) in the upright human (131). Therefore, the risk for occult or subsequent metastases from stage I–III NSCLC located in the lower lung zones (West zone 3) may be greater than those located in the upper lung zones (West zone 1) (132). Indeed, series of patients with SBRT-treated stage I–II NSCLC report 2–3 times increased risk of subsequent distant metastasis and worse OS among those with lower or middle compared to upper lobe disease (133,134). Furthermore, a 2018 systematic review of surgically treated stage I–III NSCLC also reported lower OS among those with lower lobe compared to upper lobe NSCLC (135), possibly due to distant metastases. These findings have implications to assess the risk of occult or escape metastasis at time of diagnosis, time elapsed from diagnosis and staging to definitive treatment, and assessment of post-definitive treatment recurrence, separated by distant from loco-regional recurrence—and accurate accounting of cases subsequently diagnosed as second primary lung cancers, oligometastatic disease, or multi-focal adenocarcinomas—stratified by upper vs. lower lobe disease. These elements can then guide clinical decisions on upfront vs. postponed definitive surgery, neoadjuvant vs. adjuvant therapies depending on risk (Figure 4).

Figure 4 A proposed framework to evaluate benefits and harms of multi-modality curative intent therapy. Increasing toxicity with treatment intensity. Explanation: the magnitude of OS benefits (and follow-up time) as derived from RCTs or meta-analyses of RCTs, from lowest to highest are: 3% (5-year) with segmentectomy compared to lobectomy for peripheral stage IA1–2 NSCLC among patients without respiratory disease (67), 4% (5-year) with adjuvant chemotherapy following resection of stage I-IIIA/B NSCLC (29), 10% (5-year) with osimertinib following resected EGFR-mutated NSCLC (31), and 10% (5-year) with durvalumab following concurrent chemoradiation of unresectable stage III NSCLC (30); weighed against OS detriments: 0–2% (90-day) postoperative mortality following sub-lobar resection or lobectomy (67,68,78), 5% (2–5-year) with adjuvant radiation following complete resection of stage I–IIIA/B NSCLC (87), and 7–10% (90-day) postoperative mortality following concurrent chemoradiation (76,77); and what most patients with early-stage lung cancer have reported as an acceptable risk to gain 1 year of life (2%) (27). These OS benefits and harms can guide RCT design including power calculation of expected OS benefits, and interpret RCT results that evaluate preoperative therapy, combined adjuvant therapies, including combination ICIs. Deviations from magnitudes in expected OS effects could suggest offsetting or additive effects related to timing of treatments and/or baseline risks. EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; OS, overall survival; NSCLC, non-small cell lung cancer; RCT, randomized controlled trial.

It is also to be expected that combination ICIs (e.g., nivolumab + ipilimumab) (136) be increasingly utilized at the expense of increased toxicity (137), particularly among those with a cigarette smoking history (138) or interstitial lung disease/pulmonary fibrosis (139). Meta-analyses of RCTs have reported higher rates of fatal toxicity with combination ICIs (1.2%) compared to single ICI therapy (0.4–1.1%), most from pneumonitis (81). In addition, the dosing of ICI therapies evaluated in RCTs follows a maximalist approach similar to traditional cytotoxic chemotherapy—increasing dose to enhance efficacy (140). However, the pharmacokinetic and pharmacodynamic properties of ICIs differ substantially from cytotoxic chemotherapy: their immunobiological activity is optimally achieved when the targeted receptor is saturated and blocked; half-life can be as long as 20 days; and immunobiological activity can be maintained for 2 months after a single infusion (140). Also, their dose-response curves plateau, suggesting that increasing doses beyond a certain threshold do not improve efficacy (140). In patients with head and neck cancer, nivolumab delivered at doses 12-fold lower than those evaluated in RCTs can achieve similar OS benefits (140). Recently, a “less can be more” approach has been advocated in precision cancer treatment (141). There is also a documented history of aggressive cancer treatments resulting in increased morbidity and mortality (142), including in lung cancer (6,91). De-escalation strategies are being examined for ICIs in NSCLC (140). Therefore, decisions on added treatments can pay attention to the time horizon of effects—i.e., fatal harms with would be immediate and preclude any potential downstream benefits, while biological benefits on anti-tumor activities appear much less important if the lung cancer has been resected or eradicated. In addition, behavioral economic and psychological principles can enhance rational choices about risk, reward, time horizons, and trade-offs (143).

Our patient-centered precision approach to characterize benefits and harms can help interpret results within and across RCTs when: (I) robust results on OS are not yet available; (II) there is competing mortality at different follow-up times; (III) strategies are suggested to be equivalent on OS but with different harmful effects; or (IV) patients receive more than one treatment modality and their benefits and harms offset. Moreover, the U.S. National Academy of Medicine recommends that quality cancer care be safe—to avoid harm to patients from the care that is intended to help them; and that cancer care be patient-centered—providing care that is respectful of and responsive to individual patient preferences, needs, values, and ensuring that patient values guide all clinical decisions (144). Information of treatment benefits and harms should be discussed and weighed. The information derived from our approach can be used in patient-centered communication and guide shared decision-making in curative intent therapy of stage I–III NSCLC. For instance, the NNTnet can be incorporated to aggregate benefits and harms of lung cancer treatment within and across RCTs, particularly important when they are reported separately (23).

Moreover, the Consolidated Standards of Reporting Trials guideline recommends elements on quality reporting of harms (123). Systematic reviews have identified that reporting of harms are suboptimal in <50% of oncology RCTs (145,146). Our approach can help address some of these limitations by considering unique harms in curative intent therapy of stage I–III NSCLC: e.g., extent of lung resection, need for adjuvant radiotherapy, and perhaps most importantly—that OS be examined as both beneficial and harmful effect. Harm considerations can include composite toxic measures and better analyzed using time-to-event principles (Table 4) (124).

Finally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach recommends integrating patients’ values and preferences in clinical guideline development (33,147,148). In the GRADE approach, recommendations derived from high-quality evidence (typically from RCTs) on treatment benefit can be down-graded to “weak” or “conditional” recommendations if benefits and harms are closely balanced, if patients’ preferences are expected to vary substantially, or if no evidence on patient preference is available (149). A 2019 study identified that most oncology guidelines do not report benefits and harms and their probabilities to inform GRADE strength of recommendations, with none of the guidelines including patients’ preferences (150). Our approach can help assess whether benefits and harms are closely balanced using the NNTnet, and additionally, if there is no evidence available on patient preference—to interpret results from the perspective of a hypothetical patient faced with choosing between treatment options. To facilitate communication, GRADE also recommends that simple statements be used to summarize treatment effects, including language referring to “trivial”, “small”, “moderate”, or “large” effects (151). The categories of OS benefits and harms we identified can be helpful.

Strengths of our study include (I) a novel patient-centered precision approach to model to evaluate and measure benefit and harm in curative intent therapy for stage I–III NSCLC; (II) analysis of high-quality data obtained from phase III RCTs or meta-analyses of RCTs to enhance validity and clinical significance; (III) thorough regard of contemporary, international, transdisciplinary guidelines; (IV) specific clinical scenarios identified to avoid overtreatment, potential undertreatment, and maximize benefits and minimize harms; and (V) interpretation from the perspective of a hypothetical patient, using both subjective and objective assessments, to enhance rationality.

Study limitations include relatively few precedence of applying the NNTnet. However, this novel metric can be more commonly used in future studies. In addition, while definitive tri-modality therapy has been reported to treat 25% of stage III NSCLC in the U.S., tri-modality therapy may not be as commonly used in some healthcare systems and/or other countries. Last, our novel patient-centered precision approach incorporates a model endorsed in chronic lung disease, a novel summary statistic, thorough regard to clinical guidelines, and interpretation from the perspective of prospective hypothetical patients. To assess utility, other independent parties, including patients, clinicians/surgeons, clinical trialists, biostatisticians/researchers, and data safety and monitoring board/institutional review boards/regulatory agencies, can further examine its significance.

Future work can incorporate precision estimates (e.g., best-worst case scenario), assess other patient-centered beneficial and harmful measures [e.g., disability-adjusted life years (152); days outside of healthcare (153)], incorporate them into the NNTnet, and include patient perspectives to better inform decision-making. Additional work can extend upon the concepts of overdiagnosis, overtreatment, and undertreatment learned from RCTs to local health care systems (154).

Conclusions

We conclude that in curative intent therapy of stage I–III NSCLC, scenarios of imbalances between benefit and harm exist that point towards “less, and more precisely timed” treatments could be better, particularly in multi-modality therapy that incorporates biological, physiological, comorbid (lung) conditions, and mode of treatment (definitive resection or irradiation vs. adjunctive). Patient-centered and precise assessment of benefits and harms can help identify scenarios of overtreatment and undertreatment, particularly if interpreted from a patient’s perspective faced with choosing between treatment options. This approach can help patients, clinicians, and clinical trialists arrive at beneficent care.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-213/prf

Funding: This study was supported in part by the Career Development Award from the United States (U.S.) Department of Veterans Affairs, Rehabilitation Research Development and Translation Portfolio (No. 1IK2RX003661 to D.M.H.). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-213/coif). E.D.C. serves as an unpaid editorial board member of Journal of Thoracic Disease from February 2025 to January 2027. M.M.F. received funding from the VA Merit Award (No. I01BX003688-05A2) and Veterans Medical Research Foundation (VMRF). M.P.R. received funding from the NIH/NC; honoraria from the American Board of Internal Medicine and Physicians’ Education Resources; support from American Cancer Society National Lung Cancer Round Table; and has a leadership position at the American Thoracic Society. The other authors have no 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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