What is the treatment approach for adenocarcinoma (a type of non-small cell lung cancer) of the lung?

Treatment of Adenocarcinoma of the Lung

For adenocarcinoma of the lung, treatment is determined by stage and molecular profile: early-stage disease (I-II) requires surgical resection with lobectomy and mediastinal lymph node dissection; locally advanced disease (III) needs multimodality therapy with chemotherapy and radiation; and metastatic disease demands molecular testing for actionable mutations (EGFR, ALK) to guide targeted therapy, with platinum-based chemotherapy for those without targetable alterations. 1, 2

Initial Evaluation and Molecular Testing

• Obtain adequate tissue sampling for both histological diagnosis and comprehensive molecular testing before initiating treatment 1
• Test all adenocarcinomas for EGFR mutations and ALK rearrangements, as these guide first-line therapy decisions 1, 2
• Additional molecular targets include ROS1 rearrangements, MET amplification, RET rearrangements, and BRAF mutations 2
• Complete staging with contrast-enhanced CT chest/upper abdomen, brain imaging, and PET-CT scan for mediastinal and distant metastasis assessment 1
• Perform invasive mediastinal staging for radiographically normal mediastinum with central tumors or N1 lymph node enlargement 1

Stage I and II Disease (Early-Stage)

Surgical resection is the definitive treatment and offers the best chance for cure 2, 1

• Lobectomy with ipsilateral mediastinal lymph node dissection is the standard surgical approach 2
• Pneumonectomy should be reserved for tumors that cannot be completely resected by lobectomy, though it carries higher operative risk (mortality <6% vs <2% for lobectomy) 2
• Surgery should be performed by a board-certified thoracic surgeon performing ≥4 anatomic resections monthly 2
• Systematic mediastinal lymph node sampling or complete lymphadenectomy must be performed at resection 2

Special Surgical Considerations

• For elderly patients or those with respiratory compromise, segmentectomy may be considered for T1a tumors, though this remains under investigation 2
• Age alone is not a contraindication if the patient is carefully selected 2, 3
• Evaluate pulmonary function with VO2 max; operability threshold is approximately 15 ml/kg/min 2, 3
• Treat severe vascular disease before proceeding with lung surgery 2, 3

Adjuvant Therapy for Early-Stage Disease

• Adjuvant chemotherapy is recommended for stage II disease and has demonstrated survival benefit 2
• Adjuvant chemotherapy or radiation for stage I disease is of unproven benefit and should not be routinely administered 2, 3
• Postoperative radiotherapy is not indicated for completely resected stage I-II N0-N1 tumors 3, 4

Stage III Disease (Locally Advanced)

Treatment requires a multimodality approach tailored to resectability 1, 3

Resectable Stage IIIA

• Complete surgical resection with extensive lymph node dissection is an option for carefully selected patients 3, 4
• Neoadjuvant chemotherapy with cisplatin-based regimen can be administered before surgery 3, 4
• For resectable tumors ≥4 cm or node-positive disease, neoadjuvant platinum-based chemotherapy followed by surgery, then adjuvant pembrolizumab is FDA-approved 5

Unresectable Stage IIIA and IIIB

• Concurrent chemoradiotherapy with platinum-based doublet chemotherapy is the standard treatment 3, 4
• Short-term induction chemotherapy containing cisplatin plus at least one other drug combined with external-beam radiotherapy 3, 4
• For stage III patients not candidates for surgery or definitive chemoradiation, pembrolizumab monotherapy is approved if PD-L1 TPS ≥1% without EGFR/ALK alterations 5

Stage IV Disease (Metastatic)

Molecular testing results dictate first-line therapy selection 1

Patients WITH Actionable Mutations

• EGFR mutations: First-line EGFR tyrosine kinase inhibitors (osimertinib, erlotinib, gefitinib, afatinib) are superior to chemotherapy 2, 1
• ALK rearrangements: ALK inhibitors (alectinib, brigatinib, crizotinib) are first-line therapy 2, 1
• Test for additional targetable alterations (ROS1, RET, MET, BRAF) as specific inhibitors exist 2

Patients WITHOUT Actionable Mutations

• For PD-L1 TPS ≥1%: Pembrolizumab monotherapy is first-line treatment 5
• For PD-L1 TPS ≥50%: Pembrolizumab monotherapy provides superior outcomes to chemotherapy 5
• For any PD-L1 level: Pembrolizumab plus pemetrexed and platinum chemotherapy is first-line for non-squamous histology 5
• Platinum-based doublet chemotherapy (cisplatin or carboplatin with pemetrexed, gemcitabine, or taxane) for good performance status patients 1, 3
• Docetaxel monotherapy 75 mg/m² every 3 weeks for disease progression after platinum-based therapy 6

Oligometastatic Disease

• Solitary brain metastasis with resectable primary tumor: surgical resection of both sites followed by whole brain radiotherapy or stereotactic radiosurgery 1, 3
• Solitary adrenal metastasis with resectable lung tumor: surgical resection has achieved long-term survival in selected cases 1, 3

Radiation Therapy Options

• Stereotactic body radiotherapy (SBRT) provides superior local control compared to conventional radiation for medically inoperable stage I patients 2
• SBRT is the primary curative-intent approach for patients refusing surgery or deemed inoperable by multidisciplinary team 2
• Thoracic radiotherapy should use high-energy linear photon accelerator with weekly dose not exceeding 10 Gy 2
• Radiofrequency ablation can be used for medically inoperable patients with peripheral tumors <3 cm 2

Follow-Up and Surveillance

• Post-surgical surveillance: spiral chest CT every 6-12 months for 2 years, then annually 3, 4
• During chemotherapy: assess response after 2-3 cycles by repeating baseline imaging 3, 4
• Measure and report response using RECIST 1.1 criteria 3, 4
• Close follow-up every 6 weeks after first-line therapy for metastatic disease 1
• Consider radiological follow-up every 6-12 weeks to allow early initiation of second-line therapy 1

Critical Pitfalls to Avoid

• Inadequate tissue sampling preventing molecular testing—obtain sufficient tissue upfront 1
• Delaying molecular testing—results must be available before treatment initiation 1
• Using docetaxel 100 mg/m² in previously treated patients—this dose increases mortality; use 75 mg/m² 6
• Administering docetaxel to patients with bilirubin >ULN or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN—severe toxicity and death risk 6
• Not considering re-biopsy at progression—transformation or new molecular targets may emerge 1
• Administering adjuvant radiation for completely resected stage I-II N0-N1 disease—no benefit demonstrated 3, 4