Lung cancer

Lung cancer is the leading cause of cancer death in the US, accounting for almost a quarter of all cancer-related fatalities; 80–90% of cases can be attributed to smoking. Lung cancer is generally divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is a single histological category and is characterized by its central location, rapid tumor growth, early metastasis, and association with numerous paraneoplastic syndromes. NSCLC accounts for ∼ 85% of all lung cancers and has multiple histological subtypes including adenocarcinoma and central squamous cell carcinoma. Patients with lung cancer are usually asymptomatic during the early stages of the disease. Lung cancer may be diagnosed after the incidental discovery of a pulmonary nodule on imaging. Late-stage disease can manifest with pulmonary symptoms, extrapulmonary symptoms, paraneoplastic syndromes (e.g., syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia), and/or signs of metastatic disease. Patients with lung cancer frequently present with metastasis to the brain, liver, adrenal glands, and/or bones. Evaluation generally begins with CT imaging of the chest and the diagnosis is confirmed with a bronchoscopic or CT-guided biopsy. Patients with no evidence of distant metastases may be eligible for curative surgical resection (with or without adjunct chemotherapy) or radiation therapy. Unfortunately, most patients present with metastatic disease and are, therefore, not eligible for curative resection. These patients often receive palliative chemoradiotherapy. Prognosis is generally poor, with a 5-year survival rate below 20%.

• Incidence ^[1][2]
  • Second most common cancer
  • Leading cause of cancer death worldwide
• Age: peak incidence at 65–75 years ^[1]
• Sex ^[1]
  • ♂ > ♀
    • Except for adenocarcinoma, which is more common in women ^[3]
    • Declining incidence in men
    • Mortality rates for men and women are converging ^[4]

Epidemiological data refers to the US, unless otherwise specified.

• Tobacco smoking ; ^[5][6][7]
  • Associated with the development of 80–90% of lung cancers
  • The risk of cancer is determined by the number of pack years (quantity of cigarette packs a person smoked per day multiplied by the number of years of cigarette consumption)
  • Weaker association with lung adenocarcinoma
• Occupational and environmental exposure to carcinogens ^[6]
  • Passive smoking
  • Radon (2^nd leading cause of lung cancer) and uranium (radioactively decays into radon) ^[8]
  • Asbestos ^[9]
  • Occupational carcinogens (e.g., arsenic, chromium, nickel, beryllium, silica)
  • Environmental air pollution
• Family history (genetic predisposition)
• Other risk factors: pulmonary scarring, previous radiation, pulmonary fibrosis, chronic infections (e.g., tuberculosis, HIV) ^[10]

Smokers exposed to asbestos have a significantly higher risk of developing lung cancer compared to smokers that are not.

Classification of lung cancers ^[6][11]

Squamous cell and Small cell lung cancer are both Sentrally located.

For squamous cell lung cancer, imagine a Squawking Parrot doing Karate in the Center of a Cave under a Bridge while Smoking: Squamous cell, PTHrP → hypercalcemia, Keratin pearls, Central location, Cavitation, intercellular Bridges, Smoking.

For small cell lung cancer, think of small blue KulChA flatbread In a Synapse: Kulchitsky cells, Chromogranin A, neuron-specific Enolase, Synaptophysin.

Variants of lung cancer

Pancoast tumor ^[20][21]

• An apical lung carcinoma
• Located in the superior sulcus of the lung (superior sulcus tumor)
• Predominantly NSCLC
• May lead to the development of Pancoast syndrome: a constellation of symptoms secondary to the mass effect of the tumor on surrounding structures
  • Cervical sympathetic ganglion (stellate ganglion): Horner syndrome (ipsilateral miosis, ptosis, and anhidrosis)
  • Brachial plexus
    • Localized pain in the axilla and shoulder (plexus neuralgia)
    • Upper limb motor and sensory deficits (e.g., hand muscle weakness and atrophy)
  • Recurrent laryngeal nerve: hoarseness
  • Brachiocephalic vein
    • Unilateral edema of the arm
    • Facial swelling
  • Phrenic nerve: paralysis of the hemidiaphragm (visible as elevated hemidiaphragm on chest x-ray)

Lymphangitic carcinomatosis

• Spread of cancer cells along lymphatic vessels
• On imaging, a streaky-reticular pattern may be observed.

Symptoms of lung cancer may be related to the local effects of the tumor in the lung or spread of disease beyond the chest. Lung cancer often only becomes symptomatic in late stages, generally affecting prognosis negatively.

Pulmonary symptoms ^[22]

• Cough, hemoptysis
• Progressive dyspnea
• Wheezing
• Chest pain

Extrapulmonary symptoms ^[22]

• Constitutional symptoms (weight loss, fever, weakness)
• Signs and symptoms of tumor infiltration and/or compression of neighboring structures
  • Superior vena cava syndrome (SVC syndrome); : Compression of the superior vena cava impairs the venous backflow to the right atrium, resulting in venous congestion in the head, neck, and upper extremities.
  • Hoarseness: paralysis of the recurrent laryngeal nerve ^[22]
  • Dyspnea and diaphragmatic elevation: paralysis of the phrenic nerve
  • Dullness on percussion, reduced breath sounds: malignant pleural effusion on the affected side
  • Postobstructive pneumonia (see “Secondary pneumonia”)
  • Dysphagia: esophageal compression

Recurrent respiratory infections (e.g., pneumonia) in the same pulmonary region in patients ≥ 40 years old should always raise suspicion for lung cancer.

Symptoms of metastatic disease

• Over half of all patients diagnosed with lung cancer have metastatic disease at the time of presentation. ^[1]
• The symptoms of metastatic disease are site-specific
  • Brain: headaches, seizures, focal motor deficits, behavioral changes (see “Brain metastases”)
  • Liver; : typically asymptomatic, but may manifest with nausea, jaundice, ascites (see “Metastatic liver disease”)
  • Adrenal gland: typically asymptomatic
  • Bones: bone pain, elevated serum alkaline phosphatase and calcium

“Lung cancer loves to BLAB:” the most common sites of metastasis from lung cancer are the Brain, Liver, Adrenals, and Bones.

Paraneoplastic syndromes of lung cancer ^[23]

Non-small cell lung cancer ^[11]

Squamous cell carcinoma

• Characteristics
  • Solid, epithelial tumor
  • Intercellular bridges (desmosomes)
  • Keratin pearls
• Immunohistochemical markers: expression of p40, p63, CK5, or CK6 ^[30]
• Subtypes
  • Keratinizing
  • Nonkeratinizing
  • Basaloid
  • Carcinoma in situ

Adenocarcinoma ^[14]

• Characteristics
  • Glandular tumor
  • Mucin-producing cells (positive mucin staining)
• Immunohistochemical makers: expression of napsin A and TTF-1
• Historical terminology
  • Bronchioloalveolar carcinoma (BAC): obsolete term for well-differentiated, noninvasive adenocarcinomas that grow along the alveolar septa.
    • Today, adenocarcinomas of the lung are rather described on a spectrum of lepidic growth.
    • Lepidic growth: noninvasive tumor growth at intact alveoli.
    • BAC has been replaced by a variety of adenocarcinoma subtypes (see “Preinvasive subtypes” and “Invasive subtypes” below)
• Preinvasive subtypes
  • Atypical adenomatous hyperplasia (AAH)
    • Atypical pneumocyte growth along alveolar walls without cytological features of carcinoma
    • Size: ≤ 5 mm
  • Pulmonary adenocarcinoma in situ (formerly BAC)
    • Small (≤ 3 cm) nodule with a lepidic growth pattern
    • Lacks any component of invasion
• Invasive subtypes (classified according to the predominant histopathological growth pattern)
  • Minimally-invasive pulmonary adenocarcinoma (MIA)
    • Small (≤ 3 cm) tumor with a predominantly lepidic pattern
    • ≤ 5 mm of invasion
  • Lepidic-predominant adenocarcinoma (formerly nonmucinous BAC)
    • Tumor primarily shows intraalveolar growth
    • At least one focus of invasion > 5 mm
  • Mucinous-predominant adenocarcinoma (formerly mucinous BAC)
    • Goblet cell or columnar cell growth along alveolar septae
    • Multiple areas of invasion
• Additional subtypes
  • Acinar
  • Papillary
  • Solid
  • Colloid
  • Fetal
  • Enteric

Large cell carcinoma

• Poorly differentiated, large polygonal tumor cells (abundant cytoplasm)
• Prominent nucleoli
• Lacks identifiable glandular, squamous, or neuroendocrine elements on microscopy or immunohistochemistry.
  • Definitive diagnosis cannot be made by biopsy, rather it can only be finalized from completely excised surgical specimens.

Neuroendocrine tumors ^[31]

Small cell lung cancer

• Characteristics
  • High number of mitotic figures ^[32]
  • Kulchitsky cells
    • Small, dark blue neuroendocrine cells
    • Hyperchromatic nuclei (salt and pepper appearance)
    • Scarce cytoplasm
• Immunohistochemical markers
  • Chromogranin A
  • Neuron-specific enolase
  • Synaptophysin
  • CD56 ^[33]

Large cell neuroendocrine carcinoma

• Cell characteristics
  • Large cells with abundant eosinophilic cytoplasm organized in trabecular or palisading patterns
  • Coarse and granular nuclear chromatin
  • Prominent necrosis
  • High number of mitotic figures ^[32]
• Immunohistochemical markers
  • Chromogranin A
  • Synaptophysin

Bronchial carcinoid

• Typical (low-grade) carcinoid subtype
  • Polygonal cells arranged in organoid, trabecular, or insular patterns
  • Fine chromatin with small nucleoli
  • Few mitotic figures ^[32]
• Atypical (intermediate-grade) carcinoid subtype
  • Similar to typical carcinoid subtype
  • Diagnosis requires the additional presence of either necrosis or a higher number of mitotic figures ^[32]
• Immunohistochemical markers
  • Chromogranin A
  • Synaptophysin
  • CD56

Approach ^{[34][35][36][37]}

• Screening: annual low-dose CT scan in high-risk patients (see “Screening for lung cancer” for specific indications)
• Initial diagnostic steps: depend on clinical presentation (see “Clinical features of lung cancer” and “Red flags for cough”)
  • Pulmonary or extrapulmonary symptoms: Obtain laboratory studies and chest imaging to assess for underlying disease.
  • Pulmonary nodule found incidentally or upon screening: Obtain a thin-slice CT chest and manage according to findings (see “Solitary pulmonary nodules”).
• Diagnostic confirmation: histopathology
  • Obtain samples through biopsies or cytology.
  • Establishes a diagnosis of SCLC or NSCLC (see “Pathology”)
• Imaging for lung cancer staging: may include cross-sectional imaging of the head, chest, and abdomen
• Molecular testing: to identify mutations or markers that may guide treatment
  • SCLC: not routinely indicated ^[34]
  • NSCLC: Obtain PD-L1 and mutation testing in patients with metastatic disease. ^[38]

Early diagnosis of lung cancer is challenging, as symptoms are usually mild and/or nonspecific until the disease is advanced. ^[37]

Initial studies

Common laboratory studies ^[34][35][39]

• CBC: may detect anemia, neutropenia, and/or thrombocytopenia
• CMP
  • Hypercalcemia: may indicate bone metastasis or paraneoplastic syndrome
  • Elevated alkaline phosphatase: may indicate bone and/or liver metastasis
  • Abnormal liver function test: may indicate liver metastasis
• LDH: possibly elevated ^[40]

Imaging ^[37][39][41]

See also “Imaging for lung cancer staging.”

• Modalities
  • Chest x-ray: indicated as first-line imaging study ^[41]
  • CT chest: indicated in all patients with an abnormal chest x-ray or suspicion of lung cancer ^[37]
• Findings
  • Visualization of nodules and/or masses with features suggestive of malignancy, including: ^[42][43]
    • Irregular margins (i.e., scalloped or spiculated)
    • Large size (> 2 cm)
    • Upper lobe location
    • The absence of calcifications
    • See “Management of a solitary pulmonary nodule” for details on features suggestive of malignancy.
  • Indirect signs of malignancy
    • Atelectasis
    • Postobstructive pneumonia
    • Pleural effusion (particularly unilateral)
    • Mediastinal widening
  • Examples of findings in specific subtypes
    • Hazy infiltrates (characteristic of adenocarcinoma in situ) ^[44]
    • Cavitating lesion with air-fluid levels (characteristic of squamous cell carcinoma)

A normal x-ray does not rule out lung cancer, as 10–20% of patients with lung cancer will not have findings visible on x-ray. ^[37][45][46]

Consider an early chest CT for all patients with suspected lung cancer. ^[47]

Confirmation of diagnosis

Histopathological analysis of tissue biopsies is required to confirm the diagnosis of lung cancer; cytology may be confirmatory in select cases.

• Obtaining samples: Less invasive methods are preferred. ^[39][48]
  • Pulmonary lesions
    • Central: bronchoscopy with transbronchial biopsy
    • Peripheral: needle aspiration guided by endobronchial ultrasound or CT
  • Pleural effusion: thoracocentesis with cytology of the effusion; pleural biopsy if cytology is negative
  • Metastasis to other organs (e.g., mediastinum, lymph nodes): percutaneous or surgical biopsy, bone marrow biopsy if there is suspected bone marrow infiltration ^[34][48]
  • Lesions that cannot be accessed using less invasive techniques : mediastinoscopy, anterior mediastinotomy, or VATS
• Findings
  • Confirms the diagnosis and identifies the SCLC or NSCLC subtype (e.g., adenocarcinoma, squamous cell carcinoma, large cell carcinoma)
  • See “Pathology” for detailed findings in each subtype.

Obtain confirmation of metastatic disease with histopathological studies if feasible. ^[48]

Advanced studies

Since the majority of patients present with metastatic disease, a complete staging evaluation is required. Molecular testing can identify mutations and markers that help inform treatment selection.

Imaging for lung cancer staging ^{[34][35][38][41]}

Obtain cross-sectional imaging of the brain, chest, and abdomen. PET-CT is increasingly used for staging because of its high sensitivity for metastatic disease. See “Lung cancer staging” for interpretation. ^{[34][35][38][41]}

• CT thorax and abdomen ^{[34][35][38][41]}
  • Recommended in all patients
  • Metastatic disease is most common in the liver and adrenal glands.
• Brain imaging ; ^[34][35][41]
  • MRI brain with gadolinium enhancement: preferred
  • CT brain with contrast: alternative
• PET-CT ^[34][35][38]
  • Indicated for the assessment of thoracic and abdominal metastases in NSCLC; may be used in SCLC
  • Preferred method to assess bone metastases in all subtypes
  • May prevent unnecessary invasive procedures by demonstrating metastatic disease that was occult on other imaging ^[41][49][50]

PET-CT is the most sensitive imaging modality for detecting mediastinal metastases, lymph node involvement, and extrathoracic metastases including adrenal, liver, and bone. ^{[34][35][38][41]}

All metabolically active lesions suspicious for malignancy should undergo biopsy or excision for diagnostic confirmation.

Molecular diagnostics ^[38]

Molecular testing may provide guidance for the therapy of SCLC, but it is considered mandatory for patients with advanced or metastatic NSCLC as the presence of certain biomarkers modifies therapy. ^[51]

• Genetic testing: next-generation sequencing (entire genome) or RT-PCR for specific mutations ^[38]
  • Indications: patients with advanced or metastatic NSCLC and nonsmokers with SCLC ^[38][51][52]
  • Goal: to identify oncogenic mutations that may be therapeutically targeted
  • Recommended biomarkers
    • Epidermal growth factor receptor (EGFR) mutations
    • Anaplastic lymphoma kinase (ALK) fusions
    • c-ROS oncogene 1 (ROS1) rearrangements
• Immunohistochemistry: programmed death-ligand 1 (PD-L1) testing
  • Description: PD-L1 is a coregulatory molecule expressed on tumor cells that inhibits T-cell mediated death; cytotoxic T cells express PD-1 (a negative regulator) that binds PD-L1.
  • Indication: patients with advanced or metastatic NSCLC
  • Goal: to identify patients who may respond to immune checkpoint inhibitors ^[51]

Staging of NSCLC ^[53][54]

The staging of NSCLC is based on the AJCC TNM staging system. This classification defines four stages, corresponding to cancer spread.

As soon as distant metastases are detected, the cancer is classified as AJCC stage IV.

Staging of SCLC ^[31]

Staging of SCLC is based on the extent of tumor spread within or beyond one hemithorax and includes two major stages: limited-stage and extensive-stage. The TNM staging system can be used as well.

Overview

• Management is determined by the type of lung cancer and the stage at presentation.
• If available, multidisciplinary tumor board involvement is recommended in the care of all patients with lung cancer. ^[38]
• Early implementation of palliative care measures improves the patient's quality of life and may prolong survival. ^[46]

The majority of lung cancers are diagnosed at an advanced stage and treatment is largely palliative, not curative. ^[35]

Although SCLC generally has a good initial response to chemotherapy, most patients have a recurrence within 6 months. ^[34]

Medical therapy

• Chemotherapy
  • Indication: most lung cancers
  • Commonly used agents: cisplatin plus a second agent (e.g., etoposide) ^[35]
• Targeted therapy
  • Indication: advanced or metastatic NSCLC with a demonstrated oncogenic mutation ^[35][38][57]
  • Mechanism of action: target up-regulated pathways that cause expression of the malignant phenotype
  • Commonly used agents: tyrosine kinase inhibitors (TKIs) specific to the mutation OR receptor monoclonal antibodies ^[51][58]
    • EGFR mutation: EGFR TKI (e.g., osimertinib) OR receptor monoclonal antibody (e.g., cetuximab)
    • ALK rearrangement: ALK TKI (e.g., alectinib)
    • ROS1 rearrangements: crizotinib
    • BRAF mutation: dabrafenib PLUS trametinib
• Immunotherapy
  • Indications ^[59]
    • Locally advanced or metastatic NSCLC
    • Extensive-stage SCLC
  • Mechanism of action: alters T-cell function and improves intrinsic cell-mediated immunity ^[51]
    • Blocks the PD-L1/PD-1 interaction, improving the antitumor effect of endogenous T cells
    • Commonly referred to as immune checkpoint inhibitors (ICIs) ^[51]
  • Commonly used agents: durvalumab, pembrolizumab, and atezolizumab ^[34][38][60]

Radiation therapy

Radiation therapy is most commonly used in conjunction with chemotherapy in lung cancer, but it also has other indications in lung cancer management.

• Indications ^[34][35][38]
  • Limited-stage SCLC
  • Early or locally advanced (occasionally oligometastatic) NSCLC
  • Palliative care for SVC syndrome, painful bone metastases, tissue invasion, and hemoptysis
  • To prevent or slow the growth of brain metastases ^[34]
• Techniques: Depending on the subtype of lung cancer and the therapeutic goal, different techniques are available.
  • Concurrent radiotherapy and chemotherapy
  • Primary radiotherapy (e.g., stereotactic body radiotherapy)
  • Palliative radiotherapy (e.g., external beam radiation, endobronchial brachytherapy)
  • Prophylactic intracranial irradiation

Surgical management ^[35]

• Indications
  • Stage I–II SCLC and NSCLC without mediastinal lymph node involvement ^[34][35]
  • Select patients with stage III NSCLC
• Contraindications to surgery
  • Disease characteristics: N3 disease, bulky N2, multiple N2
  • Significant comorbidities
    • High cardiac risk (based on revised cardiac risk index)
    • Critically limited pulmonary reserve ^[35]
• Preoperative assessment: Preoperative pulmonary function testing is required prior to lung resection surgery (see “Preoperative cardiac assessment” and “Preoperative pulmonary assessment”). ^[61][62]
  • A preoperative FEV₁ < 1.5 L and DLCO < 60% predicts a poor outcome after lobectomy.
  • A preoperative FEV₁ < 2 L and DLCO < 80% predicts a poor outcome after pneumonectomy.

Complications are common after surgery for lung cancer. Morbidity and mortality are higher for larger surgeries (e.g., pneumonectomy) and increase in patients with preexisting comorbidities. ^[64][65]

Definition

A solitary pulmonary nodule (SPN) is a single, well-defined lesion, ≤ 30 mm in diameter, that is completely located in the pulmonary parenchyma. ^[67]

Initial assessment

• Perform a detailed clinical evaluation.
• Review any previous imaging (if available) to evaluate for changes.
• Obtain a thin-slice CT chest if not already available.
• Identify nodule size, density (solid vs. subsolid), and other characteristics. ^[67]
  • Features suggestive of malignancy include irregular margins, larger size, upper lobe location, and subsolid density.
  • Features suggestive of other etiologies include calcifications (see “Differential diagnosis of pulmonary nodules”).
• Determine the risk of malignancy of a solitary pulmonary nodule.

A solitary pulmonary nodule identified on CXR in a patient with high-risk features (e.g., advanced age, smoking history) should be evaluated to rule out malignancy.

Risk of malignancy in solitary pulmonary nodules

The risk of malignancy can be determined by clinical evaluation and/or predictive modeling and helps guide management and follow-up. ^[67]

• The most extensively validated model is the Mayo Clinic model in which 6 predictors of malignancy are combined in a logarithmic equation to calculate the risk. ^[42]
• Risk categories
  • Low: < 5% (typically, patients with low-risk predictors)
  • Intermediate: 5–65% (typically, patients with a mixture of high-risk and low-risk predictors)
  • High: > 65% (typically, patients with high-risk predictors)

Subsolid nodules are less common than solid nodules and are more likely to be malignant. ^[69]

Assume a solitary pulmonary nodule in a patient with current active cancer is metastatic until proven otherwise. ^[66]

Management

The following recommendations are consistent with the 2013 CHEST guidelines and the 2017 Fleischner Society guidelines on the evaluation and management of SPNs. ^[66][67]

• Patients with any of the following characteristics should be excluded from this approach and require case-by-case management: ^[66]
  • Age < 35 years
  • Immunocompromise
  • Active known primary cancer
  • Symptomatic patients
• Options typically include biopsy, further imaging, or long-term surveillance with serial imaging.

For any nodule followed by serial imaging, clear growth or a change in density should prompt evaluation for a biopsy and/or resection. ^[67]

Solid nodule > 8 mm

• High risk: Obtain a surgical biopsy and start treatment based on the results.
• Intermediate or low risk: Obtain a PET-CT scan.
  • Positive PET-CT: Obtain a surgical biopsy.
  • Negative PET-CT and intermediate risk: Obtain a nonsurgical biopsy.
    • Suspicious findings: Obtain a surgical biopsy.
    • Nondiagnostic findings: Start surveillance with serial CT scans.
  • Negative PET-CT and low risk: Observe with serial CT scans. ^[67]

Solid nodule ≤ 8 mm

• Most patients are assessed with serial CT scans. ^[67]
• Surveillance frequency is determined by the patient's malignancy risk and nodule size.
  • Intermediate or high risk
    • < 4 mm: Repeat CT at 12 months; if there is no change in size, no further follow-up is needed.
    • 4–6 mm: Repeat CT at 6–12 months and 18–24 months.
    • 6–8 mm: Repeat CT at 3–6 months, 9–12 months, and 18–24 months.
  • Low risk
    • < 4 mm: Surveillance is optional.
    • 4–6 mm: Repeat CT at 12 months; if there is no change in size, no further follow-up is needed.
    • 6–8 mm: Repeat CT at 6–12 months; if the size remains stable, repeat again at 18–24 months.

Solid lesions that decrease in size but do not completely resolve should be followed until no interval growth has been demonstrated over 2 years. ^[67]

Surveillance is optional for low-risk patients with a solitary pulmonary nodule < 4 mm in diameter. ^[67]

Subsolid pulmonary nodule

Assess with serial CT scans. Surveillance frequency is dictated by the appearance and size of the nodule.

• Pure ground-glass opacification
  • ≤ 5 mm: no further evaluation
  • > 5 mm: annual CT for 3 years
  • > 10 mm: Consider CT at 3 months.
• Partially solid appearance
  • ≤ 8 mm: Observe with serial CT.
  • > 8 mm: Repeat CT at 3 months; obtain PET-CT or biopsy if the nodule persists.

Differential diagnosis of pulmonary nodules ^[70]

Pulmonary nodules are more commonly metastases of other cancers than primary lung cancer.

The differential diagnoses listed here are not exhaustive.

• Overall 5‑year survival rate: approx. 20% ^[1]
• SCLC ^[78]
  • Limited disease 5-year survival: 16% (median survival up to 20 months)
  • Extended disease 5-year survival: 3% (median survival up to 13 months)
• NSCLC
  • Better prognosis
  • Depends primarily on the extent of disease and lymph node status
  • Locally confined stages (no lymph node involvement, no metastasis) have a 5-year survival rate of approx. 60–70%. ^[79]

Smoking cessation ^[80][81]

Smoking cessation can reduce the risk of developing lung cancer by up to 50% after 5–10 years. After 15–20 years, the risk of lung cancer is the same as that of never smokers. ^[82][83][84]

• General measures: counseling on smoking cessation and behavioral support (e.g., cognitive behavioral therapy)
• Pharmacological measures
  • Nicotine replacement therapy (NRT): gum, lozenges, transdermal patches, inhalers, nasal spray
    • Replaces tobacco with other sources of nicotine to reduce craving and withdrawal symptoms until complete nicotine cessation becomes possible.
    • Combined NRT medications (e.g., nicotine patch, a long-acting form of NRT, plus nicotine gum, a short-acting form of NRT) increase the likelihood of success
  • Bupropion: reduces craving and withdrawal symptoms
  • Varenicline (alpha-4-beta-2 nACHR partial agonist): reduces craving and withdrawal symptoms

Lung cancer screening ^[85]

The following recommendations are consistent with those of the US Preventive Services Task Force.

• Annual screening with a low-dose CT scan in patients 50–80 years of age with ≥ 20 pack-year smoking history who have smoked within the past 15 years ^[85]
• Discontinue screening if the patient:
  • Has abstained from smoking for 15 years
  • Develops a comorbidity that substantially limits their life expectancy
  • Expresses unwillingness to have curative lung surgery

In the US, lung cancer screening with low-dose CT chest is estimated to reduce lung cancer mortality by up to 20%. ^[85]

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