What are the treatment options for metastatic lung cancer?

Treatment Options for Metastatic Lung Cancer

Systemic therapy should be offered to all metastatic (stage IV) non-small cell lung cancer (NSCLC) patients with performance status (PS) 0-2, with treatment selection based on histology, molecular pathology, age, performance status, comorbidities, and patient preferences. 1

Initial Diagnostic Workup

• Complete history including smoking history, weight loss assessment, performance status evaluation, and physical examination 1
• Pathological diagnosis according to WHO classification with specific subtyping of all NSCLCs for therapeutic decision-making 1
• Molecular testing for driver mutations, particularly EGFR mutation status in non-squamous histology 1
• ALK rearrangement testing should be performed, especially in younger patients 1
• Contrast-enhanced CT scan of chest and upper abdomen, with brain imaging for patients eligible for loco-regional treatment 1
• PET-CT scan for highest sensitivity in assessing mediastinal lymph nodes and distant metastases 1

First-Line Treatment Options

For Patients with Driver Mutations:

• First-line treatment with tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib should be prescribed to patients with tumors bearing activating EGFR mutations 1
• Patients with EGFR mutations and poor performance status (PS 3-4) may also benefit from EGFR TKIs 1
• ALK-positive patients can be efficiently targeted with ALK inhibitors 1

For Patients Without Driver Mutations:

Non-Squamous NSCLC:

• Cisplatin-based chemotherapy is the treatment of choice for non-squamous tumors 1
• Pemetrexed is preferred to gemcitabine in patients with non-squamous tumors 1
• Bevacizumab combined with paclitaxel-carboplatin regimen may be offered to patients with non-squamous histology NSCLC and PS 0-1 after exclusion of contraindications 1
• Pembrolizumab in combination with pemetrexed and platinum chemotherapy is indicated as first-line treatment for metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations 2

Squamous NSCLC:

• Pembrolizumab in combination with carboplatin and either paclitaxel or paclitaxel protein-bound is indicated as first-line treatment 2
• Single-agent pembrolizumab is indicated for first-line treatment of patients with NSCLC expressing PD-L1 (TPS ≥1%) with no EGFR or ALK genomic tumor aberrations 2

Special Patient Populations

Poor Performance Status (PS ≥2) Patients:

• Chemotherapy prolongs survival and possibly improves quality of life compared to best supportive care 1
• Single-agent chemotherapy with gemcitabine, vinorelbine, or taxanes is recommended 1, 3
• Platinum-based combinations may be considered as an alternative 1
• Poor PS (3-4) patients should be offered best supportive care in the absence of tumors with activating EGFR mutations 1

Elderly Patients:

• Single-agent chemotherapy is standard first-line therapy for clinically unselected elderly advanced NSCLC patients 1
• Platinum-based chemotherapy is preferred for elderly patients with PS 0-1 and adequate organ function 1
• A single-agent approach remains recommended for elderly unfit or comorbid patients 1

Treatment Duration

• For most patients, four cycles of chemotherapy are recommended, with a maximum of six cycles 1
• For patients in palliative care settings, limiting treatment to 2-4 cycles of single-agent chemotherapy is recommended to balance potential benefit with quality of life 3

Treatment of Oligometastatic NSCLC

Patients with solitary metastases in specific locations can be treated with curative intent:

Brain Metastases:

• For solitary brain metastasis, surgical resection followed by whole-brain radiation therapy (WBRT) or alternatively radiosurgery ± WBRT 1
• WBRT after surgery prolongs overall survival 1
• Radiosurgery combined with WBRT is superior to WBRT alone in patients with up to three brain metastases 1

Adrenal Metastases:

• For solitary histologically-proven adrenal metastasis, resection of both adrenal and primary tumor has shown prolonged survival in selected patients 1

Lung Metastases:

• Solitary lesions in the contralateral lung should be considered as synchronous secondary primary tumors and treated with surgery and adjuvant chemotherapy if indicated, or definitive radiotherapy/chemoradiotherapy 1

Second-Line Treatment

• Docetaxel is indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy 4
• Pembrolizumab is indicated for metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) with disease progression on or after platinum-containing chemotherapy 2

Supportive Care Measures

• Early palliative care intervention is recommended in parallel with standard oncologic care, showing improvement in quality of life, mood, reduction in aggressive treatment, and improvement in median survival 1
• Radiotherapy plays a major role in symptom control for bone and brain metastases and pain related to chest wall, soft tissue, or neural invasion 1
• Zoledronic acid or denosumab is recommended for patients with bone metastases to reduce skeletal-related events 1

Response Evaluation and Follow-Up

• Response evaluation is recommended after two to three cycles of chemotherapy using the same initial radiographic investigation 1
• Close follow-up at least every 6 weeks after first-line therapy is advised 1
• Radiological follow-up should be considered every 6-12 weeks to allow for early initiation of second-line therapy 1

Common Pitfalls to Avoid

• Avoid full-dose regimens in elderly or frail patients; consider dose modifications 3
• Follow-up with PET is not routinely recommended due to its high sensitivity and relatively low specificity 1
• Do not administer docetaxel to patients with abnormal liver function or neutrophil counts <1500 cells/mm³ 4
• Avoid delaying early palliative care intervention, which has been shown to improve outcomes 1