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Early-stage and perioperative therapy

TL;DR

  • Curative-intent management is an integrated sequence: confirm histology, complete mediastinal and distant staging, judge physiological operability, and then choose local plus systemic therapy in a multidisciplinary conference.
  • Surgery remains the reference local treatment for operable stage I disease. Carefully selected peripheral tumours no larger than 2 cm can be treated by an anatomic segmentectomy or another protocol-defined sublobar resection; this does not justify indiscriminate wedge resection.
  • Adjuvant cisplatin-based chemotherapy produces a modest but real survival gain after complete resection, concentrated in stage II–III disease. Squamous histology changes the partner drug and toxicity calculus more than the underlying indication.
  • Neoadjuvant or perioperative chemo-immunotherapy has changed resectable stage II–III NSCLC: randomized trials consistently improve event-free survival and pathological response. The trials enroll NSCLC, so the squamous result is a subgroup inference unless explicitly reported.
  • Unresectable stage III disease belongs on a different pathway: concurrent chemoradiation when tolerable, followed by consolidation immunotherapy for patients without progression. Resectability must be decided before treatment, not inferred from stage alone.
  • Pathological complete response and circulating-tumour-DNA clearance are promising intermediate measures, but neither should replace mature survival evidence or a complete surgical specimen in routine decisions.

The curative-intent pathway

An early clinical stage is not yet a treatment plan. The same apparent tumour can lead to lobectomy, segmentectomy, stereotactic ablative radiotherapy (SABR), chemoradiation, or multimodality perioperative therapy depending on nodal status, anatomical resectability, cardiopulmonary reserve, molecular findings, and patient preference. Modern TNM stage groups also changed with the ninth edition, so the edition must be recorded explicitly ([PMID 38447919](https://pubmed.ncbi.nlm.nih.gov/38447919/){target="_blank" rel="noopener"}; [PMID 38885896](https://pubmed.ncbi.nlm.nih.gov/38885896/){target="_blank" rel="noopener"}).

Decision point Minimum question Why it changes care
Tissue Is this definitively squamous NSCLC? Excludes small-cell carcinoma, metastasis, and non-pulmonary squamous primaries
Anatomy Can an R0 resection be achieved without prohibitive loss of lung or critical structures? Separates surgical from definitive-radiation pathways
Nodes Has suspicious mediastinal disease been invasively sampled where indicated? Occult N2/N3 disease can overturn a surgery-first plan
Physiology What are spirometry, diffusing capacity, predicted postoperative function, exercise capacity, frailty, and cardiac risk? Technical resectability is not physiological operability
Biology Are actionable drivers excluded where this affects perioperative immunotherapy eligibility? Some pivotal trials excluded EGFR- or ALK-altered disease
Sequence Is the best systemic treatment neoadjuvant, adjuvant, or both? Postoperative delivery is less certain after complications; perioperative exposure adds time and immune toxicity
Values What trade-off does the patient make between recurrence risk, operative risk, pulmonary reserve, treatment duration, and uncertainty? Several reasonable paths may exist near stage and fitness boundaries

Surgery: extent is a selection problem

Lobectomy with systematic nodal assessment remains the benchmark operation for a fit patient with a resectable tumour. Pneumonectomy carries materially different risk and should trigger a particularly rigorous review of alternatives, predicted postoperative function, and whether induction therapy may increase operative complexity. Physiological assessment should integrate FEV1, diffusing capacity, calculated postoperative reserve, exercise testing when indicated, and comorbidity rather than using age alone ([PMID 19477657](https://pubmed.ncbi.nlm.nih.gov/19477657/){target="_blank" rel="noopener"}).

Two randomized trials narrowed the operation for selected small peripheral NSCLC:

Trial Population and comparison Main result Boundary of inference
JCOG0802/WJOG4607L Peripheral clinical stage IA, tumour ≤2 cm, consolidation-to-tumour ratio >0.5; segmentectomy vs lobectomy Segmentectomy met and exceeded the prespecified overall-survival comparison but had more local relapse Japanese, highly selected peripheral tumours; not a general license for lesser resection ([PMID 35461558](https://pubmed.ncbi.nlm.nih.gov/35461558/){target="_blank" rel="noopener"})
CALGB/Alliance 140503 Peripheral clinical T1aN0 NSCLC ≤2 cm, pathologically node-negative; sublobar resection vs lobectomy Disease-free survival was noninferior and overall survival similar after intraoperative node confirmation Applies only to small peripheral, node-negative disease under trial-quality staging ([PMID 36780674](https://pubmed.ncbi.nlm.nih.gov/36780674/){target="_blank" rel="noopener"})

Segmentectomy is an anatomical oncologic resection; wedge resection is not interchangeable in every location. Margin adequacy, the ability to sample hilar and mediastinal nodes, tumour spread through air spaces, lesion depth, and the amount of actually preserved functional parenchyma all matter. Histology-specific randomized evidence is limited, and centrally arising LUSC is often anatomically unlike the peripheral lesions enrolled in these trials ([PMID 37374067](https://pubmed.ncbi.nlm.nih.gov/37374067/){target="_blank" rel="noopener"}).

SABR for medically inoperable stage I disease

SABR provides high local control without thoracotomy and is the standard curative local option for many medically inoperable stage I tumours. Operability should not be declared from one pulmonary-function number, and a patient who declines surgery is not biologically equivalent to a patient who cannot tolerate it. Comparative randomized evidence against surgery remains limited.

Squamous histology may carry a less favourable post-SABR pattern. In one institutional cohort, squamous histology was associated with local failure (hazard ratio [HR] 1.69), regional failure (HR 2.03), distant failure (HR 1.71), and death (HR 1.80) relative to non-squamous disease ([PMID 29571997](https://pubmed.ncbi.nlm.nih.gov/29571997/){target="_blank" rel="noopener"}). A National Cancer Database analysis reported median survival of 33 months for squamous versus 44 months for adenocarcinoma and five-year survival of 24% versus 36%, but selection and unmeasured confounding preclude a causal histology conclusion ([PMID 30642444](https://pubmed.ncbi.nlm.nih.gov/30642444/){target="_blank" rel="noopener"}). These data support surveillance vigilance, not dose escalation outside evidence.

Adjuvant platinum chemotherapy

The LACE individual-patient meta-analysis remains the clearest estimate of the conventional postoperative effect. Cisplatin-based chemotherapy reduced the hazard of death (HR 0.89, 95% confidence interval [CI] 0.82–0.96), corresponding to a 5.4 percentage-point absolute survival benefit at five years ([PMID 18506026](https://pubmed.ncbi.nlm.nih.gov/18506026/){target="_blank" rel="noopener"}). Benefit varied by stage: HR 1.40 in stage IA, 0.93 in IB, 0.83 in II, and 0.83 in III. There was no convincing interaction by histology.

For LUSC, cisplatin plus vinorelbine is a historically well-supported adjuvant regimen; alternatives depend on kidney function, hearing, neuropathy, performance status, and local guidance. Pemetrexed is not an appropriate squamous partner. A postoperative recommendation should state the absolute recurrence risk, likely absolute benefit, uncertainty around stage IB/high-risk features, and probability that toxicity or postoperative recovery prevents completion.

Neoadjuvant and perioperative chemo-immunotherapy

The pivotal trials used different stage editions, tumour-size thresholds, immunotherapy duration, and definitions of event-free survival. Their hazard ratios should not be treated as if they compare the regimens head to head.

Trial Design Efficacy result Safety or interpretive point
CheckMate 816 Three cycles nivolumab plus platinum-doublet chemotherapy vs chemotherapy before surgery Median event-free survival (EFS) 31.6 vs 20.8 months; HR 0.63 (97.38% CI 0.43–0.91). Pathological complete response (pCR) 24.0% vs 2.2% Surgery occurred in 83.2% vs 75.4%; grade 3–4 treatment-related adverse events 33.5% vs 36.9% ([PMID 35403841](https://pubmed.ncbi.nlm.nih.gov/35403841/){target="_blank" rel="noopener"})
CheckMate 816 final OS Long-term follow-up of the same neoadjuvant-only strategy Death HR 0.72 (95% CI 0.523–0.998); estimated five-year OS 65.4% vs 55.0% Five-year OS was 95.3% among patients with pCR versus 55.7% without, a landmark association rather than randomized validation of pCR ([PMID 40454642](https://pubmed.ncbi.nlm.nih.gov/40454642/){target="_blank" rel="noopener"})
KEYNOTE-671 Neoadjuvant pembrolizumab plus chemotherapy, surgery, then adjuvant pembrolizumab vs matched placebo pathway At first report, 24-month EFS 62.4% vs 40.6%; HR 0.58. pCR 18.1% vs 4.0% Grade ≥3 treatment-related adverse events 44.9% vs 37.3% ([PMID 37272513](https://pubmed.ncbi.nlm.nih.gov/37272513/){target="_blank" rel="noopener"})
KEYNOTE-671 OS update Later analysis 36-month OS 71% vs 64%; death HR 0.72 (95% CI 0.56–0.93). Median EFS 47.2 vs 18.3 months; HR 0.59 The design cannot isolate how much benefit came from the postoperative component ([PMID 39288781](https://pubmed.ncbi.nlm.nih.gov/39288781/){target="_blank" rel="noopener"})
AEGEAN Perioperative durvalumab plus neoadjuvant chemotherapy vs placebo pathway EFS HR 0.68 (95% CI 0.53–0.88); pCR 17.2% vs 4.3% Grade 3–4 adverse events 42.4% vs 43.2%; efficacy analysis excluded known EGFR/ALK alterations ([PMID 37870974](https://pubmed.ncbi.nlm.nih.gov/37870974/){target="_blank" rel="noopener"})
CheckMate 77T Neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab vs chemotherapy/placebo pathway Significantly improved EFS and pathological response Perioperative design again does not isolate the marginal value of adjuvant immunotherapy ([PMID 38749033](https://pubmed.ncbi.nlm.nih.gov/38749033/){target="_blank" rel="noopener"})

These studies establish a class-changing treatment principle, but several questions remain open: the minimum effective immune exposure; whether a patient with pCR needs postoperative treatment; how to act on persistent circulating tumour DNA; and whether immune-resistant KEAP1/NFE2L2-altered LUSC requires a different strategy. Treatment before surgery also creates a small but consequential possibility of progression, immune toxicity, or declining fitness before resection.

Adjuvant immunotherapy after resection and chemotherapy

IMpower010 tested atezolizumab after adjuvant platinum chemotherapy. In stage II–IIIA disease with tumour-cell PD-L1 expression of at least 1%, disease-free survival improved with HR 0.66 (95% CI 0.50–0.88); the HR was 0.79 in all stage II–IIIA disease and 0.81 in the intention-to-treat population ([PMID 34555333](https://pubmed.ncbi.nlm.nih.gov/34555333/){target="_blank" rel="noopener"}). Treatment-related grade 3–4 events occurred in 11%, and grade 5 events in 1%.

PEARLS/KEYNOTE-091 tested adjuvant pembrolizumab after complete resection, with chemotherapy strongly recommended by stage. Median disease-free survival was 53.6 versus 42.0 months in the overall population (HR 0.76, 95% CI 0.63–0.91), but the prespecified PD-L1 ≥50% population did not cross significance at that analysis (HR 0.82, 95% CI 0.57–1.18) ([PMID 36108662](https://pubmed.ncbi.nlm.nih.gov/36108662/){target="_blank" rel="noopener"}). The discordant biomarker patterns warn against importing metastatic PD-L1 logic unchanged into the postoperative setting.

Stage III: resectable and unresectable are different questions

Stage III is heterogeneous. Single-station, potentially resectable N2 disease is not equivalent to bulky multistation N2, N3, or invasive T4 disease. The label “resectable” should be a prospective multidisciplinary judgement including thoracic surgery and radiation oncology. Guideline synthesis supports concurrent chemoradiation for fit patients with unresectable stage III NSCLC ([PMID 34936470](https://pubmed.ncbi.nlm.nih.gov/34936470/){target="_blank" rel="noopener"}).

PACIFIC established durvalumab after definitive platinum-based chemoradiation in patients without progression. Initial median progression-free survival was 16.8 versus 5.6 months (HR 0.52) ([PMID 28885881](https://pubmed.ncbi.nlm.nih.gov/28885881/){target="_blank" rel="noopener"}); overall-survival analysis gave a death HR of 0.68 and 24-month survival of 66.3% versus 55.6% ([PMID 30280658](https://pubmed.ncbi.nlm.nih.gov/30280658/){target="_blank" rel="noopener"}). At five years, estimated OS was 42.9% versus 33.4% and PFS 33.1% versus 19.0% ([PMID 35108059](https://pubmed.ncbi.nlm.nih.gov/35108059/){target="_blank" rel="noopener"}). These results do not make consolidation durvalumab interchangeable with perioperative therapy for resectable disease.

Optimizing the person, not only the tumour

Postoperative pulmonary complications occurred in 18.4% across 34 studies comprising 31,696 patients in a 2024 meta-analysis. Reported risk associations included more advanced TNM stage (odds ratio [OR] 4.29), COPD (OR 2.47), smoking (OR 2.37), poor rehabilitation compliance (OR 1.64), male sex (OR 1.62), diabetes (OR 1.56), and ECOG performance status above 1 (OR 1.37) ([PMID 38975138](https://pubmed.ncbi.nlm.nih.gov/38975138/){target="_blank" rel="noopener"}). Associations are not necessarily intervention effects, but they identify modifiable preparation targets.

Smoking cessation at or around diagnosis was associated with better overall survival in a systematic review (summary relative risk 0.71 across lung cancers; 0.77 in NSCLC) ([PMID 34995798](https://pubmed.ncbi.nlm.nih.gov/34995798/){target="_blank" rel="noopener"}). Earlier observational work in early-stage NSCLC associated continued smoking with mortality HR 2.94 and recurrence HR 1.86 ([PMID 20093278](https://pubmed.ncbi.nlm.nih.gov/20093278/){target="_blank" rel="noopener"}). Cessation support should therefore be delivered as cancer treatment, without blame.

Prehabilitation usually combines aerobic and resistance exercise, respiratory training, nutrition, and behavioural support. A multicentre randomized trial reported that multimodal prehabilitation before lung resection was feasible and evaluated functional and postoperative outcomes, adding higher-quality evidence to a previously heterogeneous literature ([PMID 40374400](https://pubmed.ncbi.nlm.nih.gov/40374400/){target="_blank" rel="noopener"}). It should complement—not delay—time-sensitive definitive treatment.

What is specifically different in LUSC?

Feature Practical consequence
Central airway origin is common Bronchoscopy, sleeve resection expertise, pneumonectomy avoidance, and bleeding/obstruction planning may be especially relevant
Actionable classic drivers are uncommon but not absent Broad molecular work-up still matters where it changes perioperative eligibility or reveals a non-squamous biology
Pemetrexed is histology-inappropriate Choose a squamous-compatible platinum partner
Smoking-related COPD and cardiovascular disease are frequent Competing risk and postoperative reserve need explicit quantification
Cavitation and necrosis occur Imaging response may be difficult to interpret; infection and haemorrhage remain clinical differentials
Perioperative trials are NSCLC-wide Histology subgroup consistency supports use, but LUSC-specific absolute benefits are less certain

Follow-up and recurrence logic

After curative-intent treatment, surveillance must distinguish recurrence, a second primary lung cancer, treatment toxicity, and non-cancer respiratory disease. Symptoms override a routine imaging calendar. New haemoptysis, focal neurological change, rapidly worsening dyspnoea, stridor, fever with obstruction, or features of pulmonary embolism require urgent evaluation. A continuing smoker should receive repeated cessation help, not exclusion from surveillance or therapy.

Open questions

  1. Can postoperative immunotherapy be safely omitted after pCR or durable circulating-tumour-DNA clearance?
  2. Which LUSC genomic states predict failure of perioperative chemo-immunotherapy despite radiographic response?
  3. Is neoadjuvant-only immunotherapy sufficient for selected patients, and which trial can isolate that question?
  4. How should centrally located small LUSC be represented in surgery-versus-SABR comparative trials?
  5. What prehabilitation components improve complications and recovery without delaying resection?

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