What is the recommended diagnostic workup and stage‑specific management for non‑small cell lung cancer, including surgery, adjuvant therapy, chemoradiation, targeted therapy, and immunotherapy?

Non-Small Cell Lung Cancer: Diagnostic Workup and Stage-Specific Management

Diagnostic Workup

All patients with suspected NSCLC require pathological confirmation according to WHO classification, comprehensive staging with CT chest/upper abdomen, and PET-CT to rule out metastatic disease before treatment planning. 1

Initial Diagnostic Steps

• Obtain tissue diagnosis via bronchoscopy with multiple biopsies for central lesions, or CT-guided transthoracic needle biopsy for peripheral nodules <2 cm 1
• Perform molecular testing immediately on all specimens, including EGFR mutation analysis, ALK rearrangement testing, and PD-L1 expression—this is mandatory before initiating any treatment as it fundamentally changes the therapeutic approach 2, 3
• Complete staging with PET-CT within 4 weeks of planned treatment initiation to assess mediastinal nodes and exclude distant metastases 1
• Obtain contrast-enhanced brain MRI (not CT) for all stage III patients and those being considered for curative treatment, as MRI is more sensitive for detecting occult CNS involvement 1, 2

Mediastinal Staging

• For peripheral tumors without CT/PET evidence of nodal disease: proceed directly to surgery without invasive mediastinal staging 1
• For suspected mediastinal lymph node involvement on imaging: obtain pathological confirmation via EBUS/EUS-guided fine-needle aspiration as the first-line technique 1
• If EBUS/EUS is negative but clinical suspicion remains high: perform mediastinoscopy, which has the highest negative predictive value for ruling out N2 disease 1

Preoperative Assessment

• Measure FEV1 and DLCO: patients with both >80% and no major comorbidities can proceed to surgery; those with lower values require additional cardiopulmonary exercise testing 1
• Calculate perioperative risk using validated risk-specific models to estimate postoperative morbidity and mortality 1

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Stage I-II NSCLC: Early-Stage Disease

Anatomical resection (lobectomy) with systematic mediastinal lymph node dissection is the standard treatment for all medically operable patients with stage I-II NSCLC. 1

Surgical Management

• Perform lobectomy as the standard resection for tumors ≥2 cm with solid appearance on CT; anatomical segmentectomy is acceptable only for pure ground-glass opacities or minimally invasive adenocarcinomas 1
• Use VATS approach for stage I tumors when surgeon expertise permits, as it is the preferred access method 1
• Complete systematic mediastinal lymph node dissection conforming to IASLC specifications—this is critical for accurate pathological staging and directing adjuvant therapy 1

Adjuvant Chemotherapy

• Administer platinum-based doublet chemotherapy to all patients with completely resected stage II-III disease (cumulative cisplatin dose up to 300 mg/m² over 3-4 cycles, with cisplatin-vinorelbine being the most studied regimen) 1
• Consider adjuvant chemotherapy for stage IB tumors >4 cm, though pre-existing comorbidity and postoperative recovery must factor into this decision 1
• Do not use molecular analyses (ERCC1, mutation testing) to guide adjuvant therapy selection—current evidence does not support this approach 1
• Do not use targeted agents in the adjuvant setting outside of clinical trials 1

Non-Surgical Treatment for Medically Inoperable Patients

• Deliver stereotactic ablative radiotherapy (SABR) with biologically equivalent tumor dose ≥100 Gy for stage I peripheral tumors—this is the non-surgical treatment of choice 1
• Use conventional fractionated radiotherapy (60-66 Gy) for tumors >5 cm or centrally located lesions where SABR carries excessive toxicity risk 1

Critical Caveat

• Never administer postoperative radiotherapy for completely resected early-stage NSCLC—this worsens survival and is contraindicated except in R1 resection (positive margins) 1

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Stage III NSCLC: Locally Advanced Disease

All stage III patients must be discussed in a multidisciplinary tumor board including thoracic surgeon, medical oncologist, and radiation oncologist to determine the optimal treatment sequence before initiating any therapy. 1, 4

Discrete N2 Disease (Stage IIIA with Resectable Nodes)

Either definitive concurrent chemoradiation (60-66 Gy with platinum-based chemotherapy) or induction therapy followed by surgical resection are both acceptable approaches—patient values and preferences should guide the choice as neither demonstrates clear superiority. 1

• Do not perform primary surgical resection followed by adjuvant therapy for preoperatively identified N2 disease—this approach is inferior and not recommended outside clinical trials 1
• If trimodality approach is chosen, the entire treatment plan including surgery must be decided upfront before starting induction therapy, and should only be performed at centers with experienced teams tracking their outcomes 1
• For incidental (occult) N2 discovered during surgery after thorough preoperative staging: complete the planned resection and mediastinal lymphadenectomy if R0 resection is achievable, then administer adjuvant platinum-based chemotherapy 1

Infiltrative Stage III (N2/N3) or Unresectable Disease

Concurrent platinum-based chemotherapy with radiotherapy (60-66 Gy) is the standard treatment for patients with performance status 0-1 and minimal weight loss (<10%). 1

• Use once-daily thoracic radiotherapy with total dose 60-66 Gy—dose escalation beyond this is not recommended and worsens outcomes 1
• Deliver chemotherapy concurrently with radiotherapy rather than sequentially, as concurrent administration improves survival 1
• Use platinum-based doublet regimens such as cisplatin-etoposide or cisplatin-vinorelbine delivered concurrently with RT (2-4 cycles) 1
• Do not administer prophylactic cranial irradiation after complete response to concurrent chemoradiation—this is not supported outside clinical trials 1

For Patients with Performance Status 2 or Substantial Weight Loss

• Tailor treatment intensity downward: consider sequential chemoradiation or radiotherapy alone rather than aggressive concurrent approaches 1
• Assess patient values regarding treatment toxicity versus potential benefit before proceeding with curative-intent therapy 1

Special Consideration: T4N0-1 Disease

Surgery is the treatment of choice for resectable T4N0-1 tumors when complete R0 resection is technically achievable and cardiopulmonary fitness is adequate. 5

• Administer induction chemotherapy followed by surgical resection as the optimal sequence for stage III T4N0-1 disease 5
• Confirm N0 or N1 nodal status—presence of N2/N3 disease shifts treatment toward definitive chemoradiation rather than surgery 5

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Stage IV NSCLC: Metastatic Disease

Molecular profiling is mandatory before initiating any systemic therapy—treatment selection depends entirely on the presence of actionable mutations (EGFR, ALK, ROS1, etc.) and PD-L1 expression. 2, 3

Treatment Selection Algorithm

For EGFR-Mutated Disease

Osimertinib is the preferred first-line EGFR-TKI due to superior progression-free survival, overall survival, and CNS penetration (>60% CNS response rate). 3

• Never use immune checkpoint inhibitors in EGFR-mutated NSCLC—response rates are only 3.6% compared to 23% in EGFR wild-type disease, regardless of PD-L1 expression 3
• Never combine EGFR-TKIs with immunotherapy—this causes excessive toxicity, particularly pneumonitis 3
• If T790M resistance mutation develops: switch to osimertinib (if not already on it), which achieves 71% response rate 3
• Continue EGFR-TKI even after resistance develops when adding subsequent treatments—discontinuation leads to accelerated disease progression 3

For ALK-Rearranged or Other Actionable Drivers

First-line targeted therapy is strongly preferred over chemotherapy due to higher response rates and improved outcomes 2

For Patients Without Actionable Mutations

Platinum-based doublet chemotherapy is the standard first-line treatment using regimens such as carboplatin/paclitaxel, cisplatin/pemetrexed (for non-squamous), or cisplatin/vinorelbine 1, 2

• Limit chemotherapy to 4-6 cycles maximum with response evaluation after 2-3 cycles 1, 2
• For elderly patients or performance status 2: single-agent chemotherapy is recommended, though fit elderly patients without comorbidity can receive standard doublet therapy 1

Oligometastatic Disease

For isolated metastases (single brain, adrenal, contralateral lung, or internal mammary node), treat with curative intent using definitive local therapy combined with systemic therapy. 2

• Confirm truly isolated disease with PET-CT and brain MRI before proceeding with aggressive local therapy 2
• Deliver stereotactic body radiotherapy to the metastatic site after 2-3 cycles of systemic therapy if chemotherapy is urgently needed 2

Second-Line Treatment

Second-line systemic treatment with docetaxel, pemetrexed, or erlotinib improves disease-related symptoms and survival. 1

• Erlotinib achieves higher response rates in non-smokers, women, adenocarcinomas, Asians, and patients with EGFR mutations 1

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Critical Pitfalls to Avoid

• Never delay molecular testing results before treatment planning—EGFR/ALK status fundamentally changes the treatment paradigm away from immunotherapy toward targeted therapy 2, 3
• Never give osimertinib within 3 months of immune checkpoint inhibitors—this significantly increases pneumonitis risk 3
• Never assume internal mammary node involvement is N2 disease—isolated IMN metastasis represents M1a (stage IV) disease requiring systemic therapy, not locoregional chemoradiation 2
• Never perform postoperative radiotherapy for completely resected stage I-II disease—this is contraindicated and worsens survival 1
• Never use immune checkpoint inhibitors as monotherapy in EGFR-mutant disease before exhausting standard therapeutic options—efficacy is markedly inferior 3