Non-Small Cell Lung Carcinoma

Non-small cell lung carcinoma makes up about 85% of lung cancers.

Subtypes are adenocarcinoma (about 40%, the commonest and the type found in never-smokers), squamous cell carcinoma (25 to 30%, central, with cavitation and hypercalcemia from parathyroid hormone-related peptide) and large cell carcinoma.

Lung cancer is the leading cause of cancer death worldwide. Risk factors are tobacco smoking (80 to 85%), radon, asbestos, air pollution, prior chest radiotherapy and a family history.

Never-smokers (more often women of East Asian origin) frequently have EGFR mutations or ALK fusions.

Staging by tumor size and extent (T), nodes (N) and metastasis (M): stage I (small node-negative tumor), II (larger tumor or hilar nodes), IIIA to IIIC (mediastinal nodes or local invasion) and IV (distant metastasis, pleural or pericardial effusion). Five-year survival is about 70 to 90% for stage I, 50 to 60% for stage II, 15 to 35% for stage III and under 10% for stage IV, though targeted treatment and immunotherapy have lengthened survival.

Biomarkers that decide treatment: EGFR, ALK, ROS1, BRAF V600E, KRAS G12C, MET exon 14 skipping, RET and NTRK fusions, HER2 mutation, and PD-L1 tumor proportion score. Complications: bronchial obstruction, post-obstructive pneumonia, pleural effusion, superior vena cava syndrome, Pancoast syndrome, brain, bone and adrenal metastases, hypercalcemia and thromboembolism.

• Persistent cough, hemoptysis, dyspnea, chest pain and weight loss, or an incidental nodule on imaging
• Recurrent pneumonia, hoarseness (left recurrent laryngeal nerve), dysphagia, superior vena cava obstruction
• Pancoast tumor: shoulder and arm pain, Horner syndrome, hand weakness
• Clubbing, hypertrophic pulmonary osteoarthropathy, hypercalcemia, hyponatremia, neurological paraneoplastic syndromes
• Red flags: hemoptysis, stridor, facial swelling, new bone pain, headache or focal deficit, and confusion

1. Chest radiograph, then CT of chest and upper abdomen with contrast.
2. Fluorodeoxyglucose PET-CT for staging and to guide biopsy.
3. MRI of the brain for stage II and above and for symptoms.
4. Tissue diagnosis: bronchoscopic biopsy, CT-guided core biopsy, or biopsy of the most accessible metastasis. Mediastinal staging by endobronchial ultrasound-guided needle aspiration for nodes over 1 cm or PET-avid nodes, and for central tumors.
5. Molecular testing on all non-squamous tumors, and on squamous tumors in never-smokers and young patients, by next-generation sequencing, with PD-L1 immunohistochemistry. Plasma circulating tumor DNA when tissue is inadequate.
6. Fitness assessment: spirometry and diffusing capacity (predicted postoperative FEV1 and DLCO should exceed 40%), exercise testing when borderline, cardiac assessment, and performance status.

Differentials: small cell carcinoma, metastasis from another primary, lymphoma, carcinoid tumor, tuberculoma, organizing pneumonia and fungal infection.

1. Stage I and II (operable): lobectomy with systematic nodal dissection by video-assisted or robotic surgery. Segmentectomy for peripheral tumors of 2 cm or less. Cefazolin 2 g IV before incision (3 g if over 120 kg) and enoxaparin 40 mg SC daily for 7 days.
2. Stereotactic body radiotherapy for inoperable stage I: 54 Gy in 3 fractions for peripheral tumors, 48 to 50 Gy in 4 to 5 fractions for tumors near the chest wall, and 60 Gy in 8 fractions for central tumors.
3. Adjuvant and neoadjuvant therapy:
   • Cisplatin 75 mg/m2 IV on day 1 with vinorelbine 30 mg/m2 IV on days 1 and 8, every 21 days for 4 cycles, for stage II and IIIA after surgery.
   • Osimertinib 80 mg orally once daily for 3 years after resection of EGFR-mutant stage IB to IIIA.
   • Atezolizumab 1200 mg IV every 3 weeks for 1 year after chemotherapy for PD-L1 of 1% or more.
   • Neoadjuvant nivolumab 360 mg IV with platinum doublet chemotherapy every 3 weeks for 3 cycles before surgery in resectable stage IB to IIIA.
4. Unresectable stage III: concurrent chemoradiotherapy 60 Gy in 30 fractions with cisplatin 50 mg/m2 on days 1 and 8 and etoposide 50 mg/m2 on days 1 to 5 every 28 days for 2 cycles (or carboplatin AUC 2 with paclitaxel 45 to 50 mg/m2 weekly), then durvalumab 10 mg/kg IV every 2 weeks for up to 12 months in the absence of progression.
5. Stage IV with a driver mutation:
   • EGFR: osimertinib 80 mg orally once daily.
   • ALK: alectinib 600 mg orally twice daily with food.
   • ROS1: entrectinib 600 mg orally once daily.
   • BRAF V600E: dabrafenib 150 mg twice daily with trametinib 2 mg once daily.
   • MET exon 14: capmatinib 400 mg orally twice daily.
   • RET: selpercatinib 160 mg orally twice daily.
   • KRAS G12C (after first-line therapy): sotorasib 960 mg orally once daily.
   • Monitor for interstitial lung disease, liver tests, QT interval, rash, diarrhea, and left ventricular function.
6. Stage IV without a driver mutation:
   • PD-L1 of 50% or more: pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles.
   • Non-squamous: pembrolizumab 200 mg with carboplatin AUC 5 and pemetrexed 500 mg/m2 every 3 weeks for 4 cycles, then maintenance pembrolizumab and pemetrexed. Give folic acid 400 to 1000 micrograms daily and vitamin B12 1000 micrograms IM every 9 weeks, with dexamethasone 4 mg orally twice daily for 3 days around each dose.
   • Squamous: pembrolizumab with carboplatin AUC 5 and paclitaxel 200 mg/m2 every 3 weeks for 4 cycles, then pembrolizumab.
   • Second line: docetaxel 75 mg/m2 IV every 3 weeks with filgrastim as needed.
7. Metastases: stereotactic radiosurgery 18 to 24 Gy in 1 fraction for 1 to 4 brain metastases, palliative radiotherapy 20 Gy in 5 fractions for bone, and zoledronic acid 4 mg IV every 4 weeks for bone disease.
8. Supportive care: antiemetics (ondansetron 8 mg with dexamethasone 8 mg), monitoring of thyroid, liver, glucose and cortisol on immunotherapy with prednisolone 1 mg/kg orally for grade 2 or higher events, early palliative care, and smoking cessation (varenicline 0.5 mg orally daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks).
9. Prevention: annual low-dose chest CT in people aged 50 to 80 years with at least 20 pack-years who currently smoke or quit within 15 years.

Follow-up: CT every 3 to 6 months for 2 years after radical treatment, then yearly. Counsel on smoking cessation and prognosis.