What are the treatment options for lung cancer?

Treatment Options for Lung Cancer

The treatment of lung cancer is fundamentally determined by histologic subtype (non-small cell vs. small cell), stage at presentation, and molecular characteristics, with surgery being the cornerstone for early-stage disease, combined modality therapy for locally advanced disease, and systemic therapy (including chemotherapy, targeted agents, and immunotherapy) for metastatic disease. 1, 2

Early-Stage Non-Small Cell Lung Cancer (Stage I-II)

Surgical Management

• Complete surgical resection with ipsilateral mediastinal lymph node dissection is the standard treatment for stage I (T1-2N0) and stage II (T1-2N1, T3N0) NSCLC. 3, 1, 2
• Lobectomy or pneumonectomy with lymph node dissection forms the foundation of surgical treatment, with lobectomy preferred when feasible due to lower operative mortality (<2% vs. <6% for pneumonectomy). 3, 1
• Pneumonectomy carries higher surgical risk but achieves better oncologic outcomes in appropriately selected patients. 1
• For elderly patients or those with respiratory dysfunction, conservative resection techniques (segmentectomy or atypical resection) may be considered as exceptions. 3, 1
• Pulmonary function should be evaluated by VO2 max determination, with an operability threshold of approximately 15 ml/kg/min. 3, 2
• Age alone is not an absolute contraindication for surgical resection in carefully selected patients. 3, 2

Adjuvant Therapy

• Postoperative radiotherapy is NOT indicated for stage I and II N0-N1 tumors if complete resection was achieved. 3, 1, 2
• Adjuvant chemotherapy efficacy has not been clearly demonstrated in early-stage disease and should only be performed in randomized clinical trials. 3, 2
• For resected stage IB (T2a ≥4 cm), II, or IIIA NSCLC, single-agent pembrolizumab is FDA-approved as adjuvant treatment following platinum-based chemotherapy. 4

Radiotherapy as Alternative

• For patients with medical contraindications to surgery or who refuse surgery, curative external-beam radiotherapy with classical fractionation is an alternative. 3
• A total dose exceeding 60 Gy to the tumor mass is advantageous if the technique accounts for respiratory function without increasing severe complications. 3

Locally Advanced Non-Small Cell Lung Cancer (Stage III)

Stage IIIA Disease

For resectable stage IIIA NSCLC, complete excision with wide lymph node dissection is an option, while unresectable disease requires combined modality therapy. 3, 1

Resectable Stage IIIA

• Neoadjuvant chemotherapy containing cisplatin and at least one other drug can be administered to stage IB, II, and IIIA tumors. 3, 1, 2
• For resectable tumors ≥4 cm or node-positive disease, pembrolizumab combined with platinum-containing chemotherapy as neoadjuvant treatment, followed by single-agent pembrolizumab as adjuvant treatment after surgery, is FDA-approved. 4
• Nivolumab in combination with platinum-doublet chemotherapy is also FDA-approved for neoadjuvant treatment of resectable NSCLC (tumors ≥4 cm or node positive). 5

Unresectable Stage IIIA

• Short-term induction chemotherapy containing cisplatin and at least one other drug, combined with external-beam radiotherapy at optimal dose (minimum 60 Gy with classical fractionation), is the standard treatment. 3, 1
• Sequential combination of induction chemotherapy with conventional radiotherapy can reduce metastases and improve short-term survival, particularly in patients with good prognosis. 3

Stage IIIB Disease

• Radiotherapy aimed at local control and/or improved survival is the treatment of choice. 3
• External-beam radiotherapy should deliver a minimum dose of 60 Gy with classical fractionation using high-energy photons (9 MV) with individualized lead shielding and computerized dosimetry. 3
• For patients with good performance status and unresectable stage III disease, concurrent chemoradiotherapy is preferred. 1
• Surgical excision can be undertaken in carefully selected patients, particularly those with T4N0 tumors, though operative mortality is approximately 10%. 3

Special Considerations for Stage III

• Stage N3 tumors remain a contraindication for classical surgery. 3
• Induction treatment can increase the risk of acute respiratory distress syndrome (ARDS) after pneumonectomy. 3
• Hypofractionated radiotherapy provides better quality of life for patients with less than 3 months life expectancy. 3

Metastatic Non-Small Cell Lung Cancer (Stage IV)

First-Line Systemic Therapy

Platinum-based doublet chemotherapy prolongs survival, improves quality of life, and controls symptoms in patients with good performance status (0-1). 3, 1

Chemotherapy Regimens

• Chemotherapy containing cisplatin should be offered to patients with stage IV NSCLC and performance status of 0 or 1. 3
• Platinum combined with vinorelbine, gemcitabine, or taxane are standard doublet regimens. 1
• For nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations, pembrolizumab combined with pemetrexed and platinum chemotherapy is FDA-approved as first-line treatment. 4
• For squamous NSCLC, pembrolizumab combined with carboplatin and either paclitaxel or paclitaxel protein-bound is FDA-approved as first-line treatment. 4

Immunotherapy Options

• For NSCLC expressing PD-L1 (TPS ≥1%) with no EGFR or ALK genomic tumor aberrations, single-agent pembrolizumab is FDA-approved as first-line treatment for stage III disease (not candidates for surgery/chemoradiation) or metastatic disease. 4
• Nivolumab combined with ipilimumab is FDA-approved for first-line treatment of metastatic NSCLC expressing PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations. 5
• Nivolumab combined with ipilimumab and 2 cycles of platinum-doublet chemotherapy is FDA-approved for first-line treatment of metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations. 5

Second-Line and Beyond

• For metastatic NSCLC with disease progression on or after platinum-containing chemotherapy, single-agent pembrolizumab (for tumors expressing PD-L1 TPS ≥1%) or nivolumab is FDA-approved. 4, 5
• Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving immunotherapy. 4, 5

Oligometastatic Disease

Surgical resection of both the primary tumor and metastasis can be undertaken in carefully selected patients with operable NSCLC and solitary metastases. 3

Solitary Brain Metastasis

• Resection or stereotactic radiosurgery (SRS) are the primary alternatives. 3
• Addition of whole brain radiotherapy (WBRT) to surgery or SRS improves local control but not overall survival, requiring individual assessment. 3
• If the primary tumor is resectable (T1-3 N0-1), surgery with or without chemotherapy is an option in highly selected, fit patients. 3
• Excision of primary tumor and brain metastasis is standard in patients with operable NSCLC and single brain metastasis. 3

Solitary Adrenal Metastasis

• Systemic chemotherapy is recommended. 3
• In selected fit patients, adrenalectomy can be considered if lung disease is also resectable. 3
• Excision of primary tumor and adrenal metastasis is standard in patients with operable NSCLC and single adrenal gland metastasis. 3

Palliative Interventions

Pleural Effusion Management

• Thoracoscopy with talc pleurodesis is the standard treatment for malignant pleural effusion recurring in a non-trapped lung. 3
• When thoracoscopy with talc pleurodesis cannot be performed, alternatives include intrapleural instillation of talc suspension, bleomycin, or tetracyclines. 3
• Pleural effusion should be investigated via cytology or histological sampling to determine neoplastic vs. benign origin. 3

Palliative Radiotherapy

Radiotherapy provides rapid symptom control for multiple indications. 3

• Pain due to chest mass, bone metastases, or neural compression 3
• Hemoptysis 3
• Cough and dyspnea due to local airway obstruction 3
• Superior vena cava syndrome 3
• Spinal cord compression 3
• Pathologic bone fractures (or risk thereof) should be considered for postoperative radiotherapy after stabilization 3

Surgical and Endoscopic Palliation

• Major airway stenosis with dyspnea or post-obstructive infection may benefit from endoscopic debulking by Nd-YAG laser, cryotherapy, or stent placement. 3
• Uncontrolled intrapulmonary infection precluding systemic antitumor therapy may require surgical intervention. 3

Response Evaluation and Follow-Up

During Treatment

• Response evaluation is recommended after 2-3 cycles of chemotherapy by repeating initial radiographic tests showing tumor lesions. 3, 1, 2
• Measurement and reporting must follow RECIST 1.1 criteria. 1, 2

Post-Treatment Surveillance

• Spiral chest CT with or without contrast every 6-12 months for 2 years after surgery, then annually. 1, 2
• Due to the aggressive nature of the disease, generally close follow-up is advised, with modalities depending on individual retreatment options. 3

Multidisciplinary Approach

Multidisciplinary consultation is the standard in this rapidly changing field of lung cancer treatment. 3, 1, 2

• Early involvement of a multidisciplinary team including pulmonary medicine, thoracic surgery, medical oncology, radiation oncology, palliative care, radiology, and pathology expedites evaluation and reduces unnecessary testing. 2
• Complex and toxic treatments should be undertaken whenever possible in the setting of randomized clinical trials. 3

Key Pitfalls and Caveats

• Severe vascular disease must be treated before lung surgery. 3, 2
• Induction treatment increases the risk of ARDS after pneumonectomy. 3
• Stage N3 tumors are a contraindication for surgery outside of clinical trials. 3
• Patients with EGFR or ALK genomic tumor aberrations must have disease progression on FDA-approved targeted therapy before receiving immunotherapy. 4, 5
• Hyperfractionated radiotherapy does not appear more efficacious and has higher toxicity. 3
• Accelerated radiotherapy improves local control but results in greater toxicity, excluding combination with chemotherapy. 3