Lung Cancer Management

Staging of NSCLC  

Clinical staging is established initially from history, physical examination, pathologic findings, chest, upper abdomen, and adrenal CT scan, CBC with platelet count, and chemistry profile of the patient. Pathologic lymph node evaluation may be done through mediastinoscopy, mediastinotomy, EBUS, EUS, EBUS-FNA, EUS-FNA, or CT-guided biopsy.  

Supraclavicular lymph node metastasis in NSCLC may be staged using CT, PET/CT scan, or neck ultrasound FNA. Brain MRI with or without contrast and FDG PET/CT scanning are recommended for the detection of distant metastases in NSCLC.   

Revised Tumor, Nodes, and Metastases (TNM) System (Eighth Edition)  

The revised TNM system is proposed by the IASLC and adopted by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC). It determines if the patient would benefit from surgical resection and may predict the patient’s survival. It is currently recommended to classify both NSCLC and SCLC.   

Primary Tumor Evaluation  

Evaluates the degree of spread of the primary tumor.  

TX	Primary tumor cannot be assessed, or tumor is present in malignant cells in sputum or bronchial washings but not seen in imaging or bronchoscopy
T0	No evidence of primary tumor
Tis	Carcinoma in situ; squamous cell carcinoma in situ; adenocarcinoma in situ (adenocarcinoma with pure lepidic pattern, ≤3 cm greatest dimension)
T1	Tumor size ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without invasion that is more proximal than the lobar bronchus in bronchoscopy
T1mi	Minimally invasive adenocarcinoma (adenocarcinoma ≤3 cm greatest dimension with predominantly lepidic pattern and ≤5 mm invasion in greatest diameter)
T1a	Tumor size is ≤1 cm in greatest dimension; superficial spreading tumor with invasion limited to the bronchial wall and with possible proximal extension to the main bronchus
T1b	Tumor size >1 cm but ≤2 cm in greatest dimension
T1c	Tumor size >2 cm but ≤3 cm in greatest dimension
T2	Tumor size >3 cm but ≤5 cm or tumor with any of the following features: Involves main bronchus without involvement of the carina; with atelectasis or obstructive pneumonitis extending to the hilar region; Invades the visceral pleura
T2a	Tumor size >3 cm but ≤4 cm in greatest dimension
T2b	Tumor size >4 cm but ≤5 cm in greatest dimension
T3	Tumor size is >5 cm but ≤7 cm in greatest dimension or tumor directly involving any of the following: Chest wall, pericardium, phrenic nerve or separate nodules in the same lobe
T4	Tumor size is >7 cm in greatest dimension with invasion of these relevant structures: Mediastinum, heart, great vessels, trachea, diaphragm, recurrent laryngeal nerve, esophagus, vertebral body and carina, or separate tumor nodules in different ipsilateral lobe

Regional Lymph Node (LN) Evaluation  

This is an evaluation of the extent of nodal involvement. Mediastinal lymph node involvement usually makes surgical resection inappropriate.

NX	Regional LN cannot be assessed
N0	No regional LN metastasis
N1	Metastases in ipsilateral peribronchial and/or hilar LN and intrapulmonary nodes, including involvement by direct extension
N2	Metastases in ipsilateral mediastinal and/or subcarinal lymph node
N3	Metastasis in contralateral mediastinal or hilar or ipsilateral or contralateral scalene, or supraclavicular LN

Evaluation of Distant Metastasis

M0	No distant metastasis
M1	Distant metastasis
M1a	Malignant pleural or pericardial effusion or tumor with pleural or pericardial nodules or presence of separate nodules in the contralateral lobe
M1b	Single extrathoracic metastasis in a single organ
M1c	Multiple extrathoracic metastasis in ≥1 organ

Staging

Occult carcinoma	TX N0 M0
Stage 0	Tis N0 M0
Stage IA1	T1mi N0 M0; T1a N0 M0
Stage IA2	T1b N0 M0
Stage IA3	T1c N0 M0
Stage IB	T2a N0 M0
Stage IIA	T2b N0 M0
Stage IIB	T1a N1 M0 T1b N1 M0 T1c N1 M0 T2a N1 M0 T2b N1 M0 T3 N0 M0
Stage IIIA	T1a N2 M0 T1b N2 M0 T1c N2 M0 T2a N2 M0 T2b N2 M0 T3 N1 M0 T4 N0 M0 T4 N1 M0
Stage IIIB	T1a N3 M0 T1b N3 M0 T1c N3 M0 T2a N3 M0 T2b N3 M0 T3 N2 M0 T4 N2 M0
Stage IIIC	T3 N3 M0; T4 N3 M0
Stage IVA	Any T Any N M1a; Any T Any N M1b
Stage IVB	Any T Any N M1c

Residual Tumor After Treatment

R0	Complete resection with negative margins
R1	Microscopically positive margins but without visible tumor remaining
R2	Gross unresected tumor

Patient Assessment  

During the assessment of patients with NSCLC, it is important to identify comorbidities (ie heart, kidney, and liver problems), and assess the performance status (PS).  

To assess the performance status, the grading system developed by the Eastern Cooperative Oncology Group (ECOG) to determine disease progression, effect of disease on the patient, prognosis, and suitability of the treatment employed is usually utilized and is graded as follows: 

• Grade 0: Fully active with no restrictions
• Grade 1: With restrictions to strenuous activity but can do light work
• Grade 2: Capable of self-care but not any other activity
• Grade 3: Performs limited self-care and stays in bed or chair for >50% of waking hours 
• Grade 4: Disabled or restricted to bed or chair 
• Grade 5: Dead 

It is also vital to evaluate pulmonary function as it may indicate an increased risk of perioperative death and cardiopulmonary complication with standard lung surgery (ie FEV1 of <40%, carbon monoxide diffusion capacity of <40%, max O₂ uptake of <10 mL/kg/min, arterial O₂ saturation of <90%). Spirometry is recommended for patients being considered for lung surgery. Thoracentesis is recommended if pleural effusion is present. Thoracoscopy may be considered if thoracentesis is inconclusive.  

It is likewise important to identify the histologic subtypes and genetic alterations or mutations. Immunohistochemical staining is used to identify gene rearrangements, mutations and fusions, and to differentiate primary pulmonary adenocarcinoma from squamous cell carcinoma, large cell carcinoma, metastatic carcinoma, and malignant mesothelioma. 

It is also used to determine if there is neuroendocrine differentiation. Other assays being used include next-generation sequencing (NGS), real-time polymerase chain reaction (PCR), Sanger sequencing, and fluorescence in situ (FISH) analysis. Predictive biomarkers (eg EGFR, ALK, ROS1, BRAF V600E, KRAS, NTRK, PD-L1, c-MET, RET, ERBB2, NRG1, HER2, tumor mutational burden) are molecules that are indicative of genetic mutations and rearrangements, and protein overexpression that are used as therapeutic targets. T790M testing should be done in patients with EGFR mutation with possible resistance to initial treatment. Referral for genetic counseling is considered if there is suspicion of a germline alteration detected on somatic counseling. Other emerging biomarkers that may be used to identify novel therapies include genetic alteration, high-level MET amplification, and FGFR alterations.  

Staging of SCLC  

Full staging of SCLC should include history, physical examination, CT scan of the chest and/or abdomen, MRI or CT scan of the head, and a bone scan from the base of the skull to mid-thigh if PET scan is not obtained and limited stage is suspected. Bone marrow aspirate for biopsy is advised in patients with nucleated red blood cells on peripheral blood smear, neutropenia, thrombocytopenia, and no evidence of other metastasis.  

Chest X-ray and PET scan may be an optional part of the initial evaluation. The updated TNM system (8th edition) by the IASLC may be used for staging SCLC.  

Please see Staging of Non-Small Cell Lung Cancer under Evaluation: Small Cell Lung Cancer for more information.  

Staging should not delay the start of treatment for >1 week because SCLC is a very aggressive disease, with a faster doubling time, higher growth fraction, and earlier development of metastasis.  

Limited Disease (LD)  

Limited disease is confined to the primarily affected hemithorax, mediastinum, or supraclavicular nodes. It is equivalent to stages I-III of the TNM system except for T3-4 with multiple lung nodules that do not fit or are too extensive in a tolerable radiation field.  

Pulmonary function tests, bone imaging, and mediastinal staging via mediastinoscopy, mediastinotomy, endobronchial or esophageal USG-guided biopsy, and video-assisted thoracoscopy may be performed prior to initial treatment. Mediastinal staging may not be performed if the patient decides against surgical resection.  

Extensive Disease (ED)  

Extensive disease are metastases found beyond the supraclavicular areas, in the contralateral chest, or at distant sites. Same as stage IV of the TNM system or T3-4 with multiple lung nodules that do not fit in a tolerable radiation field. 

NSCLC: Perioperative Systemic Chemotherapy  

All patients should be evaluated for preoperative therapy, with strong consideration for Nivolumab plus platinum-doublet chemotherapy (Cisplatin or Carboplatin with Paclitaxel, Gemcitabine or Pemetrexed) for patients with tumors ≥4 cm or node positive and no contraindications to immune checkpoint inhibitors. Patients positive for EGFR mutations and ALK gene fusions should be identified and excluded from this regimen. Perioperative chemotherapy, given concurrently with radiation therapy, depending on the disease stage, is recommended for high-risk patients with stage IIA-IIIB.  

Cisplatin-based regimens (Cisplatin plus either Vinorelbine, Etoposide, Gemcitabine, Docetaxel, or Pemetrexed) are recommended for patients with contraindications to immune checkpoint inhibitors. Cisplatin plus Pemetrexed combination is preferred in patients with nonsquamous NSCLC and combination with Gembitabine or Docetaxel is preferred in patients with squamous NSCLC. Carboplatin-based regimens (Carboplatin plus either Paclitaxel, Gemcitabine, or Pemetrexed) are recommended for patients with comorbidities or with contraindications to Cisplatin therapy or immune checkpoint inhibitors.  

Alectinib may be considered in patients with ALK-positive NSCLC. Based on the phase 3 result of the ALINA study, adjuvant Alectinib treatment significantly improves disease survival compared with chemotherapy and provides an effective new treatment strategy for patients with resected ALK-positive NSCLC. Treatment with Osimertinib may be considered in patients with NSCLC positive for EGFR (exon 19 deletion, L858R) mutations ineligible for platinum-based chemotherapy or with previous adjuvant chemotherapy.  

Atezolizumab may be considered in patients with NSCLC negative for EGFR exon 19 deletion, L858R mutations or ALK gene fusion with previous adjuvant chemotherapy without any contraindications to immune checkpoint inhibitors.  

Pembrolizumab may be considered in patients with NSCLC negative for EGFR exon 19 deletion, L858R mutations or ALK gene fusion, with previous adjuvant chemotherapy without any contraindications to immune checkpoint inhibitors. It may also be used for patients who received previous neoadjuvant Pembrolizumab plus chemotherapy. Monotherapy with Pembrolizumab has also been approved for patients with stage IB (T2a), II or IIIA NSCLC following resection and platinum-based chemotherapy.  

Durvalumab may be considered in patients who received previous neoadjuvant Durvalumab plus chemotherapy and no known EGFR mutations or ALK gene fusion. Nivolumab may be considered in patients with NSCLC who received previous neoadjuvant Nivolumab and no known EGFR mutations or ALK gene fusion. Subcutaneous injections of Nivolumab and Hyaluronidase-nvhy may be used to substitute IV Nivolumab.
 
NSCLC: Chemoradiotherapy

Chemotherapeutic Regimens Used with Radiation Therapy  

Carboplatin/Cisplatin plus Pemetrexed, Paclitaxel plus Carboplatin, and Cisplatin plus Etoposide combination therapy with concurrent thoracic RT are the preferred regimens for patients with non-squamous cell NSCLC.  

Paclitaxel plus Carboplatin, and Cisplatin plus Etoposide combination therapy with concurrent thoracic RT are the preferred regimens for patients with squamous cell NSCLC.  

Efficacy rates are better in patients given concurrent chemoradiation therapy compared to those given chemotherapy after radiation therapy.  

Consolidation Therapy  

Durvalumab is recommended by the NCCN as consolidation therapy for patients with PS 0-1 with unresectable stage II/III NSCLC who were deemed responsive to ≥2 cycles of chemoradiation therapy, except for those with tumors that are positive for EGFR exon 19 deletion or exon 21 L858R mutations. Osimertinib may also be recommended in patients with PS 0-1, unresectable stage II/III NSCLC with EGFR exon 19 deletion or L858R who are responsive to definitive concurrent chemoradiation.

NSCLC: Systemic Therapy  

Systemic therapy is recommended in patients with advanced, metastatic, or high-risk early resectable disease (ie high-risk stage IB patients [with poorly defined tumors, vascular invasion, wedge resection, minimal margins, >4 cm tumor, visceral pleural involvement, and regional lymph nodes that cannot be assessed] with negative nodal margin, stage IB patients with positive nodal margin), or patients with stage IIA, IIIA, IIIB, or IV regardless of nodal margin status. Increasing size is an important variable when evaluating the need for adjuvant systemic therapy. Systemic therapy may also be considered after completion of chemoradiation for residual disease.   

The selection of systemic therapy is based on the histology of NSCLC. Histologic subtype and molecular testing should be determined before therapy to select the best treatment.  

Targeted therapy is potentially very effective in patients with specific gene mutations or rearrangements and in patients with metastatic disease. Platinum-based chemotherapy lengthens survival, improves symptom control, and offers better quality of life. Contraindications to PD-1/PD-L1 inhibitor treatment include active or previously documented autoimmune disease, progression of PD-1/PD-L1 inhibitor treatment, and current use of immunosuppressive agents.   

First-line Therapy

Assessment of response is done after 2 cycles, then every 2-4 cycles or when clinically indicated; CT with or without contrast of known high-risk sites of disease (eg chest, abdomen, pelvis) is performed. 

Patients with EGFR EXON 19 Deletion or L858R Mutations  

The preferred first-line therapy option for epidermal growth factor receptor (EGFR) mutation-positive patients with advanced, recurrent, or metastatic nonsquamous NSCLC include Osimertinib, Osimertinib with Pemetrexed plus (Cisplatin or Carboplatin), and Amivantamab-vmjw plus Lazertinib. If Amivantamab-vmjw with Lazertinib will be given, prophylactic anticoagulation is recommended at the time of initiation to prevent venous thromboembolic events. Other regimens may be considered, including Afatinib, Dacomitinib, Erlotinib, Erlotinib with Ramucirumab or Bevacizumab, Gefitinib and Lazertinib. A combination of Erlotinib with Bevacizumab or its biosimilar may be considered in patients with nonsquamous NSCLC without a recent history of hemoptysis. Prophylaxis with oral Doxycycline or Minocycline, Clindamycin lotion for scalp, Chlorhexidine for the nails, and a ceramide-based non-comedogenic moisturizer is recommended to reduce dermatologic adverse effects of Amivantamab-vmjw.  

If the mutation was discovered during the first-line systemic chemotherapy, may opt to continue with the current therapy or discontinue current therapy and start therapy for EGFR mutation-positive patients or add Osimertinib to Pemetrexed plus (Cisplatin or Carboplatin).
 
Patients with EGFR S768I, L861Q, and/or G719X Mutations  

Afatinib and Osimertinib are the preferred first-line therapy options for EGFR S768I, L861Q, and/or G719X mutation-positive NSCLC patients. Alternative agents include Dacomitinib, Erlotinib, and Gefitinib.  

If the mutation was discovered during the first-line systemic chemotherapy, may opt to continue with the current therapy or discontinue current therapy with Afatanib or Osimertinib. Treatment with Dacomitinib, Erlotinib or Gefitinib may also be considered. 
 
EGFR Exon 20 Insertion Mutation-Positive Patients  

Amivantamab-vmjw with Carboplatin and Pemetrexed for nonsquamous cell carcinoma and initial treatments used for adenocarcinoma and squamous cell carcinoma may be used as first-line therapy.  

KRAS G12C Mutation-Positive Patients  

Initial systemic therapy used for PD-L1 ≥1% and PD-L1 <1% may be used as a first-line therapy. 

ALK Gene Fusion-Positive Patients  

Alectinib, Brigatinib, Ensartinib, and Lorlatinib are the preferred agents among the first-line therapy options for patients with metastatic NSCLC positive for ALK gene fusion. Ceritinib and Crizotinib are first-line therapy options for locally advanced or metastatic ALK gene fusion-positive NSCLC.  

If the mutation was discovered during first-line systemic chemotherapy, may opt to continue with the current therapy or discontinue current therapy and start therapy with Alectinib, Brigatinib, Ensartinib, Lorlatinib, Certinib, or Crizotinib.

Studies showed that patients given Crizotinib have very high response rates and significantly improved symptoms like pain, dyspnea, or cough, as well as improved survival rates. It may be used for NSCLC patients with PS 0-4. It may cause a few side effects (eg increase in aminotransferase) or rare life-threatening pneumonitis. It also targets ROS1 gene fusion and MET amplification.  

Based on the phase III CROWN study, Lorlatinib showed, after 5 years of follow-up, 60% progression-free survival (PFS) rate, which is the longest PFS reported with any single-agent molecular targeted therapy in advanced NSCLC as compared with prior data on Alectinib (ALEX study).  
 
ROS1 Gene Fusion-Positive Patients  

Crizotinib, Entrectinib, Reprotectinib, and Taletrectinib are preferred first-line therapy options for ROS1 gene fusion-positive NSCLC. Studies showed that ROS1 gene fusion-positive NSCLC patients given Crizotinib produce high response rates (70-80%). Entrectinib, Repotrectinib, and Taletrectinib are preferred options for patients with brain metastases.  

If the mutation was discovered during the first-line systemic chemotherapy, may opt to continue with the present treatment or may discontinue present treatment then switch to Crizotinib, Entrectinib, Repotrectinib or Taletrectinib.

BRAF V600E Mutation-Positive Patients  

The combination treatment with Dabrafenib plus Trametinib and Encorafenib plus Binimetinib is preferred in these patients. Monotherapy with Vemurafenib, Dabrafenib, or initial treatments used for adenocarcinoma and squamous cell carcinoma may also be used as first-line therapy.  

If the mutation was discovered during the first-line systemic chemotherapy, may opt to complete or discontinue present treatment then switch to Dabrafenib plus Trametinib or Encorafenib plus Binimetinib therapy. 

NRG1 Gene Fusion-Positive Patients  

Treatments for adenocarcinoma and squamous cell carcinoma are the preferred first-line therapy options for NRG1 gene fusion-positive NSCLC.

NTRK1/2/3 Gene Fusion-Positive Patients

Entrectinib, Larotrectinib, Repotrectinib or first-line treatments for adenocarcinoma and squamous cell carcinoma are the preferred first-line therapy options for NTRK1/2/3 gene fusion-positive NSCLC.  

If gene fusion was discovered during the first-line chemotherapy, may opt to continue with the present treatment or may discontinue present treatment then switch to another regimen of Larotrectinib, Entrectinib or Repotrectinib.

MET Exon14 Skipping Mutation-Positive Patients 

Capmatinib or Tepotinib are the preferred first-line therapy options for patients with MET exon 14 skipping mutation-positive NSCLC. Crizotinib and initial treatments used for adenocarcinoma and squamous cell carcinoma may also be used as first-line therapy options.  

If the mutation was discovered during the first-line chemotherapy, may opt to continue with the present treatment or may discontinue present treatment then switch to by Capmatinib, Tepotinib or Crizotinib. In China, Savolitinib is approved for use in patients with locally advanced or metastatic NSLC with MET exon 14 skipping mutations who have progressed after or are intolerant to standard platinum-based chemotherapy, given in combination with Osimertinib, 

RET Gene Fusion-Positive Patients

Selpercatinib and Pralsetinib are preferred first-line therapy options for patients with RET gene fusion-positive NSCLC. If the mutation was discovered during the first-line chemotherapy, may opt to continue with the present treatment or may discontinue present treatment then switch to Selpercatinib (preferred) or Pralsetinib (preferred). 

FGFR Alterations-Positive Patients  

Erdafitinib is a novel targeted agent for patients positive for FGFR mutations.

ERBB2 (HER2) Mutation-Positive Patients  

Systemic agents for adenocarcinoma and squamous cell carcinoma, and Zongertinib are the preferred first-line therapy options for patients with ERBB2 mutation-positive NSCLC. Zongertinib was recently approved as a first-line therapy option. 

PD-L1 Expression-Positive Patients (≥50%)  

Pembrolizumab, Atezolizumab or Cemiplimab-rwlc monotherapy, (Carboplatin or Cisplatin) plus Pemetrexed plus Pembrolizumab, or Cemiplimab-rwlc plus Pemetrexed plus (Carboplatin or Cisplatin) are the preferred therapy options for PD-L1 expression-positive (≥50%) adenocarcinoma, large cell NSCLC NOS patients negative for actionable molecular markers without contraindications to PD-L1/ PD-1 inhibitors. Other recommended first-line regimens include Carboplatin plus Paclitaxel plus Bevacizumab plus Atezolizumab, Carboplatin plus albumin-bound Paclitaxel plus Atezolizumab, Nivolumab plus Ipilimumab plus Pemetrexed plus (Carboplatin or Cisplatin), Cemiplimab-rwlc plus Paclitaxel plus (Carboplatin or Cisplatin), and Tremelimumab-actl plus Durvalumab plus Carboplatin or Cisplatin plus Pemetrexed or albumin-bound Paclitaxel. Nivolumab plus Ipilimumab may be considered in patients with high tumor mutational burden. 

Pembrolizumab, Atezolizumab, Cemiplimab-rwlc monotherapy, or Carboplatin plus (Paclitaxel or albumin-bound Paclitaxel) plus Pembrolizumab, or Cemiplimab-rwlc monotherapy plus Paclitaxel plus (Carboplatin or Cisplatin) combination therapy are the preferred therapy options for PD-L1 expression-positive (≥50%) squamous cell carcinoma patients negative for actionable molecular markers without contraindications to PD-L1/PD-1 inhibitors. Other recommended first-line regimens include Nivolumab plus Ipilimumab plus Paclitaxel plus Carboplatin, Tremelimumab-actl plus Durvalumab plus Carboplatin or Cisplatin plus Gemcitabine or albumin-bound Paclitaxel, and Nivolumab plus Ipilimumab (patients with high tumor mutational burden).  

May proceed to maintenance treatment if with stable disease or adequate treatment response, depending on the initial treatment. Immunohistochemistry (IHC) testing for PD-L1 expression may be done prior to the initiation of therapy.  

PD-L1 Expression-Positive Patients (≥1%-49%)   

Carboplatin or Cisplatin plus Pemetrexed plus Pembrolizumab and Cemiplimab-rwlc plus Pemetrexed plus (Carboplatin or Cisplatin) are the preferred first-line therapy for PD-L1 expression-positive (≥1-49%) adenocarcinoma, large cell NSCLC NOS patients negative for actionable molecular markers without contraindications to PD-L1/PD-1 inhibitors. Carboplatin plus Paclitaxel plus Bevacizumab plus Atezolizumab, Carboplatin plus albumin-bound Paclitaxel plus Atezolizumab, Nivolumab plus Ipilimumab plus Pemetrexed plus Carboplatin or Cisplatin, Nivolumab plus Ipilimumab, Cemiplimab-rwlc plus Paclitaxel plus Carboplatin or Cisplatin, Tremelimumab-actl plus Durvalumab plus Carboplatin or Cisplatin plus Pemetrexed or albumin-bound Paclitaxel, and Pembrolizumab are other recommended first-line regimens. 

Carboplatin plus Paclitaxel or albumin-bound Paclitaxel plus Pembrolizumab and Cemiplimab-rwlc plus Paclitaxel plus Carboplatin or Cisplatin are the preferred therapy for PD-L1 expression-positive (≥1-49%) squamous cell carcinoma patients negative for actionable molecular markers without contraindications to PD-L1/PD-1 inhibitors. Nivolumab plus Ipilimumab plus Paclitaxel plus Carboplatin, Nivolumab/Ipilimumab, Tremelimumab-actl plus Durvalumab plus Carboplatin or Cisplatin plus Gemcitabine or albumin-bound Paclitaxel, and Pembrolizumab are other recommended first-line regimens that can be used.  

For patients with PS 3, Atezolizumab monotherapy may be considered regardless of PD-L1 status. May proceed with maintenance if with stable disease or adequate treatment response, depending on the initial treatment.  

Systemic therapy used for adenocarcinoma and squamous cell carcinoma may be used for disease progression despite continuation maintenance therapy. Immunohistochemistry (IHC) testing for PD-L1 expression may be done prior to the initiation of therapy.  

Recommended Regimens for Adenocarcinoma, Large Cell, NSCLC NOS (Advanced or Metastatic NSCLC or NSCLC NOS) with PS 0-2 without Druggable Targets  

Pembrolizumab plus Pemetrexed plus Carboplatin or Cisplatin and Cemiplimab-rwlc plus Pemetrexed plus Carboplatin or Cisplatin combination are the preferred regimen if without contraindications to PD-1 or PD-L1 inhibitorts and no EGFR exon 19 deletion or L858R, ALK, RET or ROS1 gene fusion. Atezolizumab plus Carboplatin plus Paclitaxel plus Bevacizumab, Atezolizumab plus Carboplatin plus albumin-bound Paclitaxel, Nivolumab plus Ipilimumab plus Pemetrexed plus Carboplatin or Cisplatin, or Nivolumab plus Ipilimumab, Cemiplimab-rwlc plus Paclitaxel plus Carboplatin or Cisplatin, and Tremelimumab-actl plus Durvalumab plus Carboplatin or Cisplatin plus Pemetrexed or albumin-bound Paclitaxel combination regimens can also be considered.  

Bevacizumab-based regimens (Bevacizumab plus Pemetrexed plus Carboplatin or Cisplatin, Bevacizumab plus Carboplatin plus Paclitaxel) are recommended for patients with adenocarcinoma, large cell, NSCLC NOS with contraindications to PD-1 or PD-L1 inhibitors or EGFR exon 19 deletion or L959R, ALK, RET, or ROS1 gene fusion. The criteria for receiving Bevacizumab plus chemotherapy are non-squamous NSCLC and the absence of hemoptysis. Bevacizumab should be given until disease progression but should be used cautiously in patients with a risk of thrombocytopenia and bleeding.    

Carboplatin-based combinations (Carboplatin plus either albumin-bound Paclitaxel, Docetaxel, Etoposide, Gemcitabine, Paclitaxel, or Pemetrexed) are recommended for patients intolerant to PD-1 or PD-L1 inhibitors and those with comorbidities. Albumin-bound Paclitaxel combined with Carboplatin for patients with advanced NSCLC with a PS of 0-1 is preferred by the NCCN panel over standard Paclitaxel due to its lesser neurotoxicity and better response rate.  

Cisplatin-based combinations (Cisplatin plus either Paclitaxel, Docetaxel, Gemcitabine, Etoposide, or Pemetrexed) are recommended for patients with non-squamous and squamous cell NSCLC with a PS of 0 to 1 with contraindications to PD-1 or PD-L1 inhibitors or EGFR exon 19 deletion or L858R, ALK, or ROS1 gene fusion.  

Gemcitabine-based combinations (Gemcitabine plus Docetaxel or Vinorelbine) are recommended for patients with contraindications to platinum-based doublets.  

Monotherapy with albumin-bound Paclitaxel, Docetaxel, Gemcitabine, Paclitaxel, and Pemetrexed may also be used. Platinum-based regimens have been shown superior in patients with advanced and non-treatable disease, with 6-12 weeks improvement in median survival and 10-15% improvement in 1-year survival rates.  
 
Recommended Regimens for Squamous Cell Carcinoma (Advanced or Metastatic NSCLC or NSCLC NOS) with a PS of 0-2 without Druggable Targets 

Pembrolizumab plus Carboplatin plus Paclitaxel or albumin-bound Paclitaxel and Cemiplimab-rwlc plus Paclitaxel plus (Carboplatin or Cisplatin) combinations are the preferred options if without contraindications PD-1 or PD-L1 inhibitors and no EGFR exon 19 deletion, L858R, ALK, RET or ROS1 gene fusion. 

Nivolumab plus Ipilimumab, Nivolumab plus Ipilimumab plus Paclitaxel plus Carboplatin, and Tremelimumab-actl plus Durvalumab plus Carboplatin or Cisplatin plus Gemcitabine or albumin-bound Paclitaxel combination regimens may also be considered. 

Carboplatin-based combinations (Carboplatin plus either albumin-bound Paclitaxel, Docetaxel, Gemcitabine, or Paclitaxel) are recommended for patients who are intolerant to PD-1 or PD-L1 inhibitors and those with comorbidities or no EGFR exon 19 deletion, L858R, ALK, RET or ROS1 gene fusion. Albumin-bound Paclitaxel combined with Carboplatin for patients with advanced NSCLC with a PS of 0 to 1 is preferred by the NCCN panel over standard Paclitaxel due to its lesser neurotoxicity and better response rate. 

Cisplatin-based combinations (Cisplatin plus either Paclitaxel, Docetaxel, Gemcitabine, or Etoposide) are recommended for patients with a PS of 0-2. Gemcitabine-based combinations (Gemcitabine plus Docetaxel or Vinorelbine) are recommended for patients with contraindications to platinum-based doublets.  

Monotherapy with albumin-bound Paclitaxel, Docetaxel, Gemcitabine, Paclitaxel, and Pemetrexed may also be used. Platinum-based regimens have been shown superior in patients with advanced and non-treatable disease, with 6-12 weeks improvement in median survival and 10-15% improvement in the 1-year survival rate.   

Subsequent Therapy  

Assessment of response is done every 6-12 weeks; CT with or without contrast of known high-risk sites of disease (eg chest, abdomen, pelvis) is performed. Plasma or tissue-based testing via broad molecular testing should be considered at progression to check for T790M mutation and other genomic resistance mechanisms. It must be noted that tissue-based testing with rebiopsy material is strongly recommended if plasma-based testing is negative.

Patients with EGFR EXON 19 Deletion or L858R Mutations with Progressive Disease  

Patients with disease progression despite Osimertinib or Lazertinib with or without Amivantamab that is asymptomatic or symptomatic, may continue treatment unless multiple lesions are present. Definitive local therapy (eg stereotactic radiosurgery) may also be considered only if the lesion is in the brain or with an isolated systemic lesion. If with multiple lesions, may consider Amivantamab-vmjw plus Carboplatin plus Pemetrexed for nonsquamous NSCLC or Lazretinib plus Amivantamab-vmjw if these were not previously given, or systemic therapy options for adenocarcinoma or squamous cell carcinoma. If Amivantamab-vmjw with Lazertinib will be given, prophylactic anticoagulation is recommended at the time of initiation to prevent venous thromboembolic events.
 
Asymptomatic patients positive for T790M mutation may be initiated with Osimertinib treatment; may continue present therapy with Erlotinib (with or without Ramucirumab or Bevacizumab), Afatinib, Dacomitinib or Gefitinib therapy if T790M mutation-negative. Osimertinib may be considered in patients with progressive CNS disease or leptomeningeal disease, regardless of T790M status. Definitive local therapy (eg stereotactic body RT [SBRT], surgery) may also be considered for progressive disease.  

For symptomatic patients with progressive brain disease without T790M mutation, if continuing with current first- or second- generation tyrosine kinase inhibitors (TKIs), patient may need to be given local therapy (ie RT, surgery).  

Symptomatic patients with systemic metastasis positive for T790M mutation but lesions are isolated may opt to continue present therapy with Erlotinib (with or without Ramucirumab or Bevacizumab) Afatinib, Gefitnib, Dacotinib therapy if T790M mutation-negative. For oligoprogressive disease, continue the same TKI with local ablative therapy (eg SBRT, surgery).  

Symptomatic patients with systemic metastasis positive for T790M mutation but with multiple lesions or with progressive disease despite chemotherapy, one may consider initiating Osimertinib treatment (if Osimertinib-naive). If the patient is T790M mutation negative, may consider treatment for adenocarcinoma or squamous cell carcinoma. Amivantamab-vmjw with Carboplatin and Pemetrexed may be considered for nonsquamous cell carcinoma.  

Afatinib plus Cetuximab is an option for patients who progress despite treatment with TKI and chemotherapy. 

EGFR S768I, L861Q, and/or G719X Mutation-Positive Patients with Disease Progression  

Treatment options for patients with disease progression after first-line therapy is the same as that for patients with EGFR exon 19 deletion or L959R mutations based on first-line therapy used.

EGFR Exon 20 Insertion Mutation-Positive Patients with Disease Progression  
For patients with disease progression after preferred first-line therapy, Sunvozertinib and systemic therapy for adenocarcinoma and/or squamous cell carcinoma may be considered. If agents for adenocarcinoma and/or squamous cell carcinoma were given as first-line therapy, Sunvozertinib or Amivantamab-vmjw may be considered. 

KRAS G12C Mutation-Positive Patients with Disease Progression  

Sotorasib and Adagrasib are the recommended treatment options for patients with disease progression after first-line therapy. May be used after at least one line of therapy or second-line and beyond if there is no previous KRAS G12C-targeted therapy. 

If still with disease progression despite completion of Sotorasib or Adagrasib therapy, treatment using agents for adenocar­cinoma and/or squamous cell carcinoma may be considered in patients with a PS of 0-2.  

ALK Gene Fusion-Positive Patients with Disease Progression 

For asymptomatic patients and those with brain involvement previously given Alectinib, Brigatinib, Ceritinib, Ensartinib, Crizotinib or Lorlatinib, one may consider local therapy or continue Alectinib, Brigatinib, Ceritinib, Ensartinib or Lorlatinib therapy. Lorlatinib is an option for resistant mutations (eg ALK G1202R, L1196M). One may continue with Crizotinib only if without brain involvement. In patients with brain involvement with further progression, Lortatinib (if not previously given) or systemic therapy for adenocarcinoma and squamous cell carcinoma may be given.  

For symptomatic patients with systemic involvement but with limited progression previously given Alectinib, Brigatinib, Ceritinib, Ensartinib, Crizotinib or Lorlatinib, consider local therapy or continue either Alectinib, Brigatinib, Ceritinib, Ensartinib or Lorlatinib therapy. Lorlatinib as an option for resistant mutations (eg ALK G1202R, L1196M). While systemic therapy for adenocarcinoma and squamous cell carcinoma is also to be considered.  

For symptomatic patients with systemic involvement and with multiple lesions previously given Alectinib, Brigatinib, Ceritinib, Ensartinib, Crizotinib or Lorlatinib, continue Alectinib, Brigatinib, Ceritinib, Ensartinib or Lorlatinib therapy or consider systemic therapy for adenocarcinoma or squamous cell carcinoma. For symptomatic patients with systemic involvement but with limited metastases previously given Alectinib, Brigatinib, Ceritinib, Ensartinib or Lorlatinib, consider treatment with Lorlatinib if still with disease progression (eg ALK G1202R, L1196M) or if Lorlatinib-naïve; if with multiple lesions consider Lorlatinib if not given previously or consider treatment for adenocarcinoma or squamous cell carcinoma.

ROS1 Gene Fusion-Positive Patients with Disease Progression  

Asymptomatic and symptomatic patients with limited metastases previously given Entrectinib, Crizotinib, Repotrectinib, or Ceritinib may consider local therapy or may continue Entrectinib, Crizotinib, Repotrectinib, Ceritinib, or may initiate Reprotrectinib (if not previously given), or Lorlatinib therapy. 

Symptomatic patients with brain involvement may consider local therapy for limited lesions or may initiate Repotrectinib or Taletrectinib if not previously given, or Loratinib therapy if with history of previously given Entrectinib, Crizotinib, Repotrectinib or Taletrectinib, or Entrectinib if Crizotinib was previously given. Enrollment into a clinical trial should be considered.   

For symptomatic patients with systemic involvement but with multiple lesions, one may initiate Repotrectinib or Taletrectinib if not previously given, or Lorlatinib therapy if Entrectinib, Crizotinib, Repotrectinib or Taletrectinib was previously given, or consider treatment for adenocarcinoma or squamous cell carcinoma. If with disease progression despite subsequent treatment, consider first-line treatments for adenocarcinoma and squamous cell carcinoma.
 
BRAF V600E Mutation-Positive Patients with Disease Progression  

Consider first-line treatments for adenocarcinoma and squamous cell carcinoma if disease progression occurs despite initial treatment with Dabrafenib plus Trametinib, Bimetinib plus Encorafenib, or Dabrafenib or Vemurafenib monotherapy for treatment-naive patients. Dabrafenib plus Trametinib and Encorafenib plus Binimetinib combination therapies may also be considered if the disease progresses despite using first-line treatments for adenocarcinoma and/or squamous cell carcinoma. 

NRG1 Gene Fusion-Positive Patients with Disease Progression  

Zenocutuzumab-zbco is used if there is disease progression or after systemic therapy in NRG1 gene fusion-positive patients. Subsequent-line systemic treatments for adenocarcinoma and/or squamous cell carcinoma are options for disease progression after therapy with Zeunocutuzumab-zbco. 

NTRK1/2/3 Gene Fusion-Positive Patients with Disease Progression  

Consider Repotrectinib if without history of treatment or first-line treatments for adenocarcinoma and squamous cell carcinoma if disease progression occurs despite treatment with Larotrectinib, Repotrectinib or Entrectinib therapy. Entrectinib, Larotrectinib or Repotrectinib therapy may also be considered if disease progresses despite using first-line treatments for adenocarcinoma and/or squamous cell carcinoma.
 
MET Exon14 Skipping Mutation-Positive Patients with Disease Progression

Consider first-line treatments for adenocarcinoma and squamous cell carcinoma if disease progression occurs despite treatment with Capmatinib, Tepotinib, or Crizotinib.  

Capmatinib or Tepotinib therapy may also be considered if the disease progresses despite using first-line treatments for adenocarcinoma and/or squamous cell carcinoma. Crizotinib therapy may also be considered.  

If the mutation was discovered during first-line systemic chemotherapy and the disease progressed despite the completion of first-line treatments, therapy using first-line agents for adenocarcinoma and/or squamous cell carcinoma may be considered.  

RET Gene Fusion-Positive Patients with Disease Progression  

Consider first-line treatments for adenocarcinoma and squamous cell carcinoma if disease progression occurs despite treatment with Selpercatinib, Pralsetinib, or Cabozantinib. Selpercatinib or Pralsetinib therapy may also be considered if the disease progresses despite using the first-line treatments for adenocarcinoma and/or squamous cell carcinoma. Cabozantinib therapy may also be considered.  

If the mutation was discovered during first-line chemotherapy and the disease progressed despite completion of the first-line treatments, therapy using first-line agents for adenocarcinoma and/or squamous cell carcinoma may be considered.  

ERBB2 (HER2) Mutation-Positive Patients with Disease Progression  

Fam-trastuzumab (Fam-trastuzumab deruxtecan-nxki, Trastuzumab deruxtecan, T-Dxd), Zongertib and Sevabertinib are the preferred therapy for patients with ERBB2 mutation-positive NSCLC with disease progression after first-line therapy. Ado-trastuzumab may also be considered. If Zongertinib was used as first-line agent, systemic agents for adenocarcinoma and squamous cell carcinoma, Fam-trastuzumab and Ado-trastuzumab emtansine may be used for subsequent therapy.
 
PD-L1 Expression-Positive Patients (≥50% and ≥1%-49%) with Disease Progression  

For patients previously given anti-PD1 or anti-PD-L1 agents as first-line therapy, treatment with standard platinum doublet chemotherapy should be considered if single-agent immunotherapy was given, or standard second-line options for advanced or metastatic disease if combined chemo-immunotherapy as first-line therapy was used. Pembrolizumab may only be given in PD-L1 expression-positive patients.

Patients with Adenocarcinoma, Large Cell, NSCLC NOS with Progressive Disease without Druggable Targets  

Nivolumab, Pembrolizumab, and Atezolizumab are among the preferred therapy for patients with a PS of 0-2 with disease progression despite first-line systemic therapy if no prior exposure to anti-PD1/L1. Datopotamab deruxtecan-dlnk is the preferred therapy for EGFR exon 19 deletion or L858R mutation-positive patients with PS 0-2 with disease progression despite first-line systemic therapy. Famtrastuzumab deruxtecan-nxki may be given as subsequent therapy to patients with HER2 IHC 3+ with progression of advanced or metastatic disease. Telisotuzumab vedotin-tllv may be given as subsequent therapy to c-MET/MET ≥50% ICH3+ and EGFR wild-type disease with progression of advanced or metastatic disease. Docetaxel, Gemcitabine, Pemetrexed, albumin-bound Paclitaxel, or Ramucirumab plus Docetaxel are indicated as second-line or beyond therapy for patients with PS 0-2. 

Patients with Squamous Cell Carcinoma with Progressive Disease without Druggable Targets

Nivolumab, Pembrolizumab, or Atezolizumab is indicated as the preferred subsequent therapy for patients with a PS of 0-2 without contraindications to PD-1 or PD-L1 inhibitors.  

Docetaxel, Gemcitabine, albumin-bound Paclitaxel, Ramucirumab plus Docetaxel or Fam-trastuzumab deruxtecan-nxki (HER2 IHC 3+) are indicated as second-line therapy for patients with a PS of 0-2.   

Continuation Maintenance Therapy  

Maintenance therapy is given after 4-6 cycles of chemotherapy for patients with a PS of 0-2 with tumor response or disease that did not progress. This utilizes at least 1 of the agents given as first-line treatment.  

PD-L1 Expression-Positive Patients (≥50% and ≥1%-49%) Continuation Maintenance Therapy

The recommended continuation maintenance agents for PD-L1 expression positive (≥50% and ≥1%-49%) adenocarcinoma include Pembrolizumab with or without Pemetrexed, Atezolizumab with or without Bevacizumab, Nivolumab/Ipilimumab, Cemiplimab-rwlc with or without Pemetrexed (monotherapy is only used for patients with PD-L1 ≥50%), and Durvalumab with or without Pemetrexed.  

The recommended continuation maintenance agents for PD-L1 expression positive (≥50% and ≥1%-49%) squamous cell carcinoma include Pembrolizumab, Nivolumab/Ipilimumab, Cemiplimab-rwlc, and Durvalumab. Atezolizumab may be considered in patients with PD-L1 ≥50% if patient was started on Atezolimumab/Carboplatin/albumin-bound Paclitaxel therapy.   

Continuation Maintenance Therapy Regimens for Adenocarcinoma, Large Cell, NSCLC NOS (Advanced or Metastatic NSCLC or NSCLC NOS) with PS 0-2 without Druggable Targets  

The following may be considered in patients with adenocarcinoma, large cell, NSCLC NOS negative for rear­rangements or mutations: Monotherapy with Gemcitabine, Pemetrexed, Bevacizumab, Atezolizumab, Cemiplimab or Durvalumab; or the combination therapy with (Bevacizumab, Pembrolizumab, Cemiplimab or Durvalumab) plus Pemetrexed or Atezolizumab plus Bevacizumab or Nivolumab plus Ipilimumab.  

Continuation Maintenance Therapy Regimens for Squamous Cell Carcinoma (Advanced or Metastatoc NSCLC or NSCLC NOS) with PS 0-2 without Druggable Targets  

Monotherapy with Pembrolizumab, Gemcitabine, Cemiplimab or Durvalumab, or combination therapy with Nivolumab plus Ipilimumab may be considered.  

Switch Maintenance Therapy  

Switch maintenance therapy utilizes other agents not part of the first-line regimen. This includes Pemetrexed or Docetaxel.  

Pemetrexed used after first-line chemotherapy showed an advantage in progression-free and overall survival. Pemetrexed may be started after 4-6 cycles of first-line platinum-doublet chemotherapy in patients with histology other than squamous cell carcinoma. Docetaxel may be started after 4-6 cycles of a first-line platinum-doublet regimen in patients with squamous cell carcinoma.  

Postoperative Therapy  

Platinum-based chemotherapy is recommended for patients with a PS of 0-1 who underwent complete resection for NSCLC stage II-IIIA.  

SCLC Systemic Therapy  

Initial Therapy  

Single-agent or combination chemotherapy may be used in managing patients with SCLC such as Cisplatin or Carboplatin plus Etoposide, Irinotecan plus Cisplatin/Carboplatin, Carboplatin plus Etoposide plus Atezolizumab, Cisplatin or Carboplatin plus Etoposide plus Durvalumab.  

Cisplatin plus Etoposide and Carboplatin plus Etoposide are the preferred regimen for patients with limited disease SCLC. The dose of Cisplatin may be reduced if not tolerated. For patients with extensive disease SCLC, the preferred regimens include Carboplatin plus Etoposide plus Atezolizumab, Carboplatin plus Etoposide plus Durvalumab and Cisplatin plus Etoposide plus Durvalumab. Alternative regimens include Carboplatin/Cisplatin plus Etoposide and Carboplatin/Cisplatin plus Irinotecan.  

Carboplatin may be substituted with Cisplatin to decrease vomiting, neuropathy, and nephropathy. It should only be given to patients with limited disease if Cisplatin is poorly tolerated or contraindicated. 

Agents used for maintenance therapy in extensive disease SCLC patients include Atezolizumab, Durvalumab and Lurbinectedin plus Atezolizumab, to be based on what was used during treatment initiation. The addition of Lurbinectedin to maintenance Atezolizumab showed longer PFS and overall survival rate in the IMforte trial. Maintenance therapy should continue until progression or intolerable toxicity. Consolidation therapy with Durvalumab is preferred for patients with limited disease SCLC in the absence of disease progression after systemic therapy with concurrent RT and may be given until disease progression or intolerable toxicity, or for a maximum of 24 months. This recommendation is based on the ADRIATIC trial that showed statistically significant and clinically meaningful overall survival and PFS improvement in patients receiving Durvalumab compared to placebo.

Subsequent Therapy  

Subsequent therapy provides important palliation in patients with SCLC but the effect depends on the time from the initial therapy to relapse. Dose reduction or growth factor support should be considered with PS2. Enrollment into a clinical trial should be considered. If the interval is <3 months, the effect of regimen is ≤10%, which indicates a refractory SCLC. If the interval is >3 months, the expected effect is approximately 25%.  

Irinotecan, Lurbinectedin, Tarlatamab, and Topotecan are the preferred agents for subsequent therapy. Tarlatamab is an option for extensive disease SCLC patients with disease progression on or after platinum-based chemotherapy. Irinotecan should be considered for patients with CNS disease.  Cyclophosphamide plus Doxorubicin plus Vincristine (CAV), Docetaxel, Etoposide (oral), Gemcitabine, Nivolumab, Tarlatamab, Temozolomide, Topotecan, Paclitaxel, and Pembrolizumab are treatment also options. Immune checkpoint inhibitors (eg Nivolumab, Pembrolizumab) should not be used if there is disease progression during maintenance therapy with Atezolizumab or Durvalumab. Retreatment with previous platinum-based doublet regimen is recommended if there has been prolonged disease-free time.
 
Palliative Care for Lung Cancer  

Identify all patients who may benefit from palliative care and specialist referral should be done immediately.  





Pain  

Mild to moderate pain may be treated with Acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). Titrating short-acting opioids may be considered if pain control with NSAIDs or Acetaminophen is inadequate. Increasing the dose or switching to combination therapies containing opioids may also be considered.  

Severe pain may be treated with opioids, although Meperidine is not used if pain medication will be given continuously as it may cause dysphoria, agitation, or seizure. Medications for constipation may be given prophylactically if opioid is used. Tricyclic antidepressants, anticonvulsants, and neuropathic agents may be given to enhance the effect of pain medications.  

For bone pain secondary to cancer metastasis, RT is recommended for pain relief. Bisphosphonates (eg Pamidronate, Zoledronic acid) are advised together with RT. They effectively relieve bone pain, treat hypercalcemia of malignancy, and delay the onset of bone disease progression. Denosumab, a RANKL inhibitor, demonstrated pain relief in patients with pain secondary to bone metastases.  

Cachexia or Anorexia  

Appetite stimulants may help improve the quality of life of patients with months to days of life expectancy. Consider consultation with a nutritionist for appropriate calorie supplementation.  

Dyspnea, Cough, and Compression Symptoms  

Opioid and non-opioid antitussives (eg Morphine, Fentanyl, Oxycodone) may be given to the patient to reduce coughing. EBRT is also an option.  

Symptom relief by the administration of opioids may be considered for dyspneic patients. The addition of benzodiazepines may be considered if dyspnea is associated with anxiety.  

Excessive secretions can be managed using Scopolamine, Atropine, Hyoscyamine, or Glycopyrrolate. RT and stents may be considered in patients if there is breathlessness and hemoptysis due to the endobronchial tumor. Relief of pleural effusion should be done primarily by thoracentesis. Recurrent pleural effusions should be managed with chest tube drainage, pleurodesis, or indwelling pleural catheter.  

The use of supplemental oxygen and non-invasive mechanical ventilation may be considered.  

Superior Vena Cava (SVC) Obstruction 

Chemotherapy is recommended for patients with symptomatic superior vena cava obstruction secondary to SCLC.  

Stent insertion and/or RT are recommended for patients with symptomatic superior vena cava obstruction secondary to NSCLC and SCLC who do not respond to chemotherapy.  

Osseous Structural Impairment  

Orthopedic stabilization should be done prior to RT for patients at high risk for fracture due to osseous structural impairment.  

Brain Metastases  

Corticosteroids may be given to relieve headaches, seizures, and sensorimotor deficits and in the presence of symptoms suggestive of spinal cord compression in SCLC patients. Resection of isolated brain metastasis may be considered in NSCLC patients after complete tumor resection and with no metastasis found on other sites. Whole brain RT should follow removal of isolated single brain metastasis.  

Stereotactic RT, given alone, after surgical resection, or with whole brain RT may be considered in patients with single brain metastasis. 

Depression  

Depression should always be assessed and managed in patients with lung cancer.  

NSCLC  

The resectability of the tumor, surgical staging, and pulmonary resection should be fully assessed. Surgery may offer the best chance of survival and possible cure in NSCLC patients with stage I-II disease. It may be considered in patients with N2 disease responsive to induction chemotherapy or in selected cases with single-station non-bulky N2 disease. It is considered as the first option for operable patients with negative nodes; stereotactic ablative radiotherapy (SABR) may be offered as an alternative. 

Surgery is recommended for patients with the following: 

• ≥8 mm solid nodule on low-dose CT scan screening that has a high probability of cancer as shown on PET/CT scan
• ≥8 mm solid nodule that increased in size in chest CT with contrast and/or PET/CT scan with a high probability of cancer
• ≥15 mm solid nodule with the same measurements in PET/CT scan with a high probability of cancer
• ≥6 mm part-solid nodule with ≥6 to <8 mm solid component in follow-up low-dose CT scan with high probability for cancer in PET/CT scan
• New or growing part-solid nodule with ≥4 mm solid component in low-dose CT scan with high probability for cancer in chest CT scan with contrast and/or PET/CT scan
• Growing non-solid nodule ≥20 mm in size during follow-up or annual low-dose CT scan

Surgery is the treatment of choice for stage I and II NSCLC. In the absence of medical contraindications to surgery, complete resection (ie lobectomy) with clear surgical margins should be achieved as much as possible. In patients with comorbidities who are not able to tolerate lobectomy, sublobar resection (segmentectomy or wedge resection) is recommended. Parenchymal resection margins of ≥2 cm or more than the nodule's size is preferred. Contraindications to lobectomy or indications for sublobar resection include impaired pulmonary function or a peripheral nodule of ≤2 cm with at least 1 of the following: Pure adenocarcinoma in situ, nodule with ≥50% ground-glass appearance on CT scan, or long doubling time of ≥400 days on imaging. Nodal dissection is preferred over simple intraoperative sampling for mediastinal lymph nodes. Sleeve lobectomy is recommended for total resection of centrally or locally advanced NSCLC.

   

Surgery in stage IIIA N2 lung cancer is controversial. Surgery is considered in resectable stage IIIA N0-1 tumor, followed by adjuvant systemic chemotherapy. Adjuvant therapy depends on molecular profile (ie EGFR mutation-/ALK rearrangement-positive tumors for targeted therapy, PD-L1 expression-positive tumors for anti-PD-L1 treatment). Perioperative chemo-immunotherapy should be considered. A formal ipsilateral lymph node dissection is indicated for patients undergoing planned resection. For patients undergoing VATS with N2 disease, the procedure may be halted to start induction therapy or may opt to continue with the surgery. Preoperative sampling with EBUS or mediastinoscopy should be part of N2 assessment to achieve 3 N2 nodal stations.

En-bloc resection of the involved structure with negative margins is required for patients with T3 and T4 local invasion tumors. Video-assisted thoracic surgery is a less invasive and reasonable approach for patients with no anatomic or surgical contraindications. For highly selected patients with recurrent NSCLC, stereotactic radiation surgery and surgical resection of isolated cerebral metastasis are recommended.

SCLC  

Surgery for SCLC is considered only for patients with clinical stage I-IIA and in limited disease patients with sufficient pulmonary function and no evidence of metastases to mediastinal or supraclavicular lymph nodes.  

Lobectomy or pneumonectomy should be done followed by a detailed dissection of the mediastinal lymph node. Platinum-based adjuvant chemotherapy is recommended after complete resection.

NSCLC  

Radiation therapy is used as an adjunct for patients with resectable lesions, as initial primary local treatment for medically unfit patients and with unresectable disease, as definitive therapy for locally advanced NSCLC, treatment of recurrences and metastases, and as a palliative modality for patients with advanced diseases. Preoperative RT is recommended for patients with resectable superior sulcus tumors and may be considered in patients with stage IIIA with minimal lymph node involvement and are candidates for lobectomy. Postoperative radiation therapy may be considered in patients with mediastinal involvement, multiple positive lymph nodes, extracapsular extension of lymph nodes, bulky lymph nodes, or with positive surgical margins. It can be given to patients with stage IV NSCLC with extensive metastasis as palliative care. 

Radical Radiotherapy or External Beam Radiation Therapy (EBRT)  

Radical radiotherapy or EBRT therapy is recommended for patients with stage I and II who are not fit for or do not consent to surgery. It should be offered, in combination with chemotherapy, to patients with stage IIIA or IIIB NSCLC of good PS, in whom the tumor can be safely encompassed.  

Stereotactic Ablative Radiotherapy (SABR)/Stereotactic Body Radiotherapy (SBRT)  

SBRT is recommended for patients with stage I and IIA who are not fit for or do not consent to surgery. It is considered for medically inoperable (T2a-3, N0) larger tumors. It may also be considered for patients at high risk for complications following lobectomy (eg ≥75 years old, poor lung function). Retrospective data suggest that SABR in addition to chemotherapy provides a survival advantage for patients with large tumors (≥5 cm) who are node-negative. If SABR is not feasible, definitive radiation therapy or concurrent chemoradiation could be considered.

Definitive Chemoradiation  

Definitive chemoradiation is recommended for patients with stage II-III NSCLC with unresectable disease. It is superior to radiation alone or sequential chemotherapy followed by radiation in patients with locally advanced NSCLC but may be considered in frail patients intolerant to concurrent therapy. Preoperative concurrent chemoradiation is recommended for operable superior sulcus lesions and may be considered in operable stage IIIA lesions. It may also be given postoperatively or in trimodality therapy.  

Consolidation Durvalumab after chemoradiotherapy is recommended for patients with stage III disease (if there is no EGFR exon 19 deletion or L858R). The recommended dose is 60-70 Gy in 2 Gy fractions.  

Interstitial Radiotherapy or Laser Therapy  

Interstitial RT or laser therapy is recommended for patients with recurrent NSCLC associated with endobronchial lesions.  

Palliative Radiotherapy  

Definitive or consolidative local RT is recommended for local palliation or symptom prevention in patients with advanced or metastatic NSCLC.  

Shorter courses of RT (single-fraction stereotactic RT of 12-16 Gy) are preferred for patients with poor PS and/or shorter life expectancy.  

Fractionated, higher dose is recommended for patients with thoracic symptoms and good PS but do not meet the requirements for radical RT for palliation of symptoms.  

Higher dose or longer courses are recommended (eg ≥30 Gy in 10 fractions) modestly improves patient survival and symptoms.  

SCLC  

Since SCLC is radiosensitive, RT is a vital part of treatment. It is recommended for post-lobectomy limited disease SCLC patients with clinical stage I-IIA with pathologic N2 involvement. It may also be considered in patients with pathologic N1. It is important for palliation of symptoms in extensive disease SCLC patients with brain, epidural, and bone metastasis.  

Critical components of modern RT include appropriate simulation, accurate target definition, conformal RT planning, and ensuring accurate delivery of the planned treatment. This includes 4D-CT and/or FDG-PET/CT simulation, intensity-modulated RT (IMRT)/ volumetric modulated arc therapy (VMAT), image-guided RT (IGRT), and motion management strategies.  

RT, once started, should proceed without interruption. Advise the patient to stop smoking prior to radiotherapy.  

Stereotactic Ablative Radiotherapy (SABR or SBRT)  

SBRT is recommended for limited disease SCLC patients with stage I-IIA who are not fit for or do not consent to surgery. There are no existing recommended optimal dose and schedule for patients with limited disease SCLC, but accelerated doses of 40-42 Gy in 3 weeks given in once-daily fractionation based on clinical studies may be considered. Higher doses (60-70 Gy) may be considered if using once-daily conventionally fractionated RT.  

Thoracic Irradiation  

Thoracic irradiation may be given to limited disease SCLC patients simultaneously with first or second chemotherapy cycle. It may also be given after completing chemotherapy if good response within the thorax is achieved.  

After completion of chemotherapy, RT may be offered to extensive disease SCLC patients provided a complete response on the distant sites and at least partial response within the thorax are achieved. The recommended dose range is 30 Gy in 10 fractions/day to 60 Gy in 30 fractions/day.  

Prophylactic Cranial Irradiation (PCI)  

Prophylactic cranial irradiation aims to eradicate microscopic brain metastasis and to increase the patient’s overall survival. It increases the overall survival while decreasing the incidence of brain metastasis in patients with limited disease SCLC who responded to initial treatment. It decreases the incidence of brain metastasis in patients with extensive disease SCLC who responded to systemic therapy.  

It is considered in patients with limited disease or extensive disease SCLC (pathologic stage IIB-III) of PS 0-2 in whom a complete or partial response to primary treatment is achieved. It should be incorporated within 3-5 weeks of the last cycle of chemotherapy.  

It is recommended after adjuvant systemic therapy in patients who had complete resection; however, it is not recommended for patients with poor PS or impaired neurocognitive functioning.  

The recommended dose is 25 Gy in 10 fractions/day and the dose is reduced for patients with extensive disease SCLC. Memantine may be administered during and post-RT to decrease neurocognitive impairment.  

Hippocampal-avoidance prophylactic cranial irradiation using intensity-modulated RT may be considered.  

Whole Brain Radiation Therapy (WBRT)   

WBRT is recommended for patients with brain metastasis. Repeat WBRT may be considered in some patients who developed brain metastases post-prophylactic cranial irradiation. The recommended dose is 30 Gy in 10 fractions per day.  

Hippocampal-sparing WBRT using IMRT plus Memantine is preferred for patients with better prognosis due to lesser cognitive function failure compared to conventional WBRT therapy plus Memantine.  

Palliative Radiotherapy  

For extracranial metastases, common radiation dose-fractionation regimens (eg 30 Gy in 10 fractions, 20 Gy in 5 fractions, 8 Gy in 1 fraction) may be considered. Conformal techniques and/or higher dose intensity approaches may also be considered in select patients.