Lung Cancer

Classification and General CharacteristicsTop

1. Non–small cell lung carcinomas (NSCLCs; 80%-85%):

1) Adenocarcinoma (~40%-50%): The most common type of lung cancer, occurs most often in the small airways (peripheral parts of the lungs). Association with tobacco smoke is not as strong as that observed in squamous cell carcinoma. Patients with adenocarcinoma should have their tumors tested for the presence of a driver mutation (eg, mutated epidermal growth factor), anaplastic lymphoma kinase (ALK), and increasingly other mutations, given the dramatic therapeutic implications.

2) Squamous cell carcinoma (SCC) (~30%) is strongly associated with exposure to tobacco smoke and occurs more often in men, usually in large bronchi (hilar areas). It is often associated with narrowing of the bronchial lumen with atelectasis and inflammatory changes in the lung parenchyma.

3) Large cell carcinoma (LCC) is difficult to define, as the tumor represents a malignant epithelial neoplasm lacking glandular, squamous, or neuroendocrine differentiation. Natural history is traditionally similar to that of adenocarcinoma in terms of propensity for spread.

2. Small cell lung carcinoma (SCLC) (~15%) is characterized by aggressive growth and early spread to lymph nodes and distant organs, and is very strongly related to smoking. The primary focus is usually localized in the perihilar area, usually with involvement of hilar and mediastinal lymph nodes. In most patients metastases are present on diagnosis (typically in the liver, bones, marrow, central nervous system [CNS], adrenal glands); paraneoplastic symptoms are possible. Chemotherapy is the primary treatment option.

3. Rare lung neoplasms (<5%): Carcinoid, adenosquamous carcinoma, sarcoma, salivary gland tumors (mucoepidermoid carcinoma, adenocystic carcinoma), and very rare mesenchymal, embryonic, or lymphatic tumors.

Clinical FeaturesTop

Early lung cancer is usually asymptomatic.

1. Systemic symptoms: Progressive weight loss, weakness, or low grade fever occur late.

2. Symptoms related to local growth: Cough is the most common symptom (in smokers there is often a change in the nature of cough), shortness of breath, chest pain, hemoptysis, recurrent pneumonia (especially in the same localization); superior vena cava syndrome (with massive mediastinal involvement), pleural pain (with pleural involvement), shoulder pain and Horner syndrome (tumor at the apex of the lung), arrhythmias (with pericardial and heart infiltration), hoarseness (as a result of recurrent laryngeal nerve paralysis), dysphagia (as a result of secondary esophageal compression or massive upper mediastinal involvement) in advanced disease.

3. Symptoms related to metastases: Enlargement of supraclavicular, cervical, or axillary lymph nodes; bone pain (or soreness), pathologic fractures or compression symptoms; in CNS metastases: headache, focal neurologic symptoms and other neurologic manifestations (eg, seizures, balance disorders), behavioral changes and personality disorders; in liver metastases: hepatomegaly, epigastric pain, nausea, jaundice.

4. Paraneoplastic syndromes:

1) Endocrine: Cushing syndrome (SCLC), syndrome of inappropriate antidiuretic hormone secretion (SIADH; SCLC), carcinoid syndrome, hypercalcemia (SCC), and other.

2) Neuromuscular: Peripheral neuropathies (SCLC), encephalopathies, degeneration of the cerebellar cortex, Lambert-Eaton myasthenic syndrome (SCLC), polymyositis.

3) Cutaneous: Dark keratosis, dermatomyositis, systemic lupus erythematosus (SLE), systemic scleroderma.

4) Bone: Hypertrophic osteoarthritis, finger clubbing.

5) Vascular: Migratory superficial thrombophlebitis, nonbacterial thrombotic endocarditis.

6) Hematologic: Anemia, disseminated intravascular coagulation (DIC).

Diagnosis and StagingTop

Diagnostic Tests

1. Imaging studies:

1) Chest radiography (posteroanterior and lateral projection; lower sensitivity than computed tomography [CT] imaging): Tumor in the lung parenchyma, atelectasis, enlargement of the hilar or mediastinal lymph nodes, fluid in the pleural cavity, unilateral diaphragmatic paralysis and elevation, lesions indicating direct infiltration or metastasis in the bones. Normal chest X-ray does not exclude lung cancer.

2) Chest CT scan is the basic examination to assess the nature, local extension, and metastatic involvement.

3) Positron emission tomography (PET), usually with the use of 18F-FDG (FDG-PET), and concomitant CT permit the detection of small metastases in mediastinal lymph nodes and determination of the tumor extent within the atelectasis, and allow for detection of neoplastic lesions outside the chest. PET improves optimal disease characterization and staging to facilitate management. Endobronchial ultrasonography (EBUS) with transbronchial needle aspiration is commonly used to diagnose and stage patients with lung cancer.

4) Magnetic resonance imaging (MRI) of the brain is used to evaluate for brain metastases: routinely in SCLC and to assess asymptomatic patients with NSCLC. MRI can also be useful in assessing some tumor locations, for instance, in the vicinity of or within the spine, or at the lung apex.

2. Cytologic examination of the sputum (rarely used), pleural fluid, bronchial lavage; material from transbronchial fine-needle aspiration biopsy (FNAB), transesophageal (ultrasound-guided) FNAB, or transthoracic (usually ultrasound-guided or CT-guided) FNAB for peripheral lung tumors.

3. Bronchofiberoscopy (bronchoscopy): Assessment of local advancement of endobronchial lesions, collecting specimens for microscopic examination (biopsy specimens of the bronchial wall/tumor, EBUS-guided transbronchial lung and lymph node biopsy, bronchial lavage, endobronchial brushing).

4. Other methods: FNAB or histologic examination of peripheral lymph nodes with suspicion of metastasis (supraclavicular, in the scalene fissure), mediastinal endoscopy (mediastinoscopy), mediastinotomy, videothoracoscopic surgery.

5. Laboratory tests: Determination of tumor markers in serum is not clinically useful.

Diagnostic Criteria

Histologic (preferred) or cytologic examination of tumor material. The specific investigation used depends on the size and location of the lesion.

Differential Diagnosis

1. Peripheral tumors: Metastatic lesion, benign tumors, tuberculoma, lung abscess, fungal lesions, teratoma, hamartoma.

2. Enlarged mediastinal lymph nodes: Lymphoproliferative disorders, infection (mycobacterial, fungal), sarcoidosis (usually symmetrical involvement of the hila and mediastinal nodes), other inflammatory conditions (eg, berylliosis).

Staging

The main determinant of treatment is the precise staging of the neoplasm. Always perform a chest CT scan with contrast agent (the examination should be extended to the upper abdominal cavity). Other studies: see below.

1. NSCLC: Perform brain MRI and skeletal scintigraphy in patients at high risk of dissemination or with clinical symptoms suggesting metastasis in these organs. To determine chest lymph node involvement, perform PET-CT and/or ultrasound-guided lymph node biopsy through the bronchial wall and/or esophagus or during mediastinoscopy. The anatomic extent of the tumor is defined according to the clinical tumor, node, metastasis (cTNM) classification: Table 1. Disease stages: Table 2. Histologic examination serves as the basis for the assessment of pathologic advancement (pTNM) and histologic grading (G) of the tumor. Genotype subtype analysis in NSCLC and the development of targeted therapy for specific gene mutations (epidermal growth factor receptor [EGFR], ALK, ROS1, and other) have resulted in individually tailored therapies.

2. SCLC: Perform CT of the chest and abdominal cavity with administration of a contrast agent, MRI or CT of the brain. In patients without dissemination, order whole-body PET-CT or, if impossible, bone scintigraphy with additional radiographic evaluation of suspicious foci. Cancer staging by spread:

1) Limited disease (LD): Disease is confined to one side of the chest, and involved regional lymph nodes can be included in a single tolerable radiotherapy port, neoplastic ipsilateral pleural effusion is possible.

2) Extensive disease (ED): Lesions are present outside the LD area. The current recommendation is to use the same TNM classification as in NSCLC.

TreatmentTop

The treatment modality is decided upon on a case-by-case basis by a multidisciplinary team comprising specialists in thoracic surgery, oncologic radiotherapy, clinical oncology, and imaging diagnostics. All smokers should receive antismoking advice and help to overcome the addiction (see Nicotine Addiction).

Treatment of NSCLC

The treatment method depends mostly on the stage of the cancer, but other important factors include individual organ (dys)function and the patient’s general condition.

1. Surgical treatment: Complete resection of the lung parenchyma by open thoracotomy or videothoracoscopy is the method of choice in stages I, II, and selected IIIA cases. The most common resection involves one lobe (lobectomy) or, less often, in the case of the right lung, 2 lobes (bilobectomy), or the entire lung (pneumonectomy) and regional lymph nodes (selective resection of selected nodes from all groups that drain the affected area of ​​the lung can be used as an alternative). Segmentectomy is performed sporadically in patients with a tumor <2 cm in diameter (T1a) and with contraindications for lobectomy. In patients with N2 feature (metastases in mediastinal lymph nodes on the side of the lesion), radical radiotherapy is used in combination with chemotherapy or (in selected patients) resection preceded by chemotherapy.

Assessment prior to surgery usually involves simple stress tests (walking up the stairs, brisk walking), arterial blood gas measurement at rest and after exercise, pulmonary function testing, and further assessment of the cardiovascular system as needed.

Combined treatment:

1) Preoperative radiotherapy, usually together with chemotherapy, is used in patients with a tumor located at the apex of the lung (Pancoast tumor).

2) Postoperative radiotherapy can be considered in patients after incomplete resection, although the value of such treatment has not been verified.

3) Preoperative chemotherapy is used in patients potentially eligible for resection, provided that initial tumor regression is achieved (mostly IIIA N2).

4) Postoperative chemotherapy is used in patients after complete resection of the lung parenchyma in stages II and IIIA, without serious comorbidities, and in good general condition after surgery; postoperative chemotherapy is initiated within 6 to 8 weeks after surgery.

2. Radiotherapy is routinely used in patients who are not eligible for surgery because of the advanced stage of cancer (stage IIIB and most IIIA patients) or contraindications:

1) Radical radiotherapy is performed in selected patients without distant metastases, without pleural effusion, and with adequate respiratory capacity (total radiation dose is 60-66 Gy in daily fractions of 2.0-2.5 Gy, in a 5-day weekly cycle, using 3-dimensional conformal radiation therapy [3D-CRT]), stereotaxic radiotherapy is used in patients with Stage I and IIA tumors who are not eligible for surgery.

2) Radiotherapy combined with simultaneous chemotherapy increases the percentage of long-term survival at the expense of increasing the early toxicity of treatment (consolidation therapy with monoclonal antibody against programmed death ligand 1 [PD-L1] prolongs the time to recurrence in appropriately selected patients); sequential chemotherapy with radiotherapy can be used as an alternative.

3) Palliative radiotherapy is the treatment of choice in patients with symptoms accompanying the primary tumor (pain, dyspnea, dysphagia, symptoms of the superior vena cava syndrome), painful bone metastases, and inoperable symptomatic metastatic lesions in the brain.

3. Endobronchial treatment for locally advanced cancer: Brachytherapy, photodynamic therapy, electrocoagulation, cryotherapy, laser therapy, and endobronchial prostheses (stents).

4. Chemotherapy: In patients with stage IIIA adjuvant chemotherapy has been shown to improve survival. Patients with stage IV disease are treated with systemic therapy or symptom-based palliative therapy (provided they have good performance, no significant weight loss, and no serious comorbidities). First-time chemotherapy includes standard 2-drug regimens containing cisplatin (the drug of choice) or carboplatin in combination with vinorelbine, taxoids (paclitaxel and docetaxel), gemcitabine, or pemetrexed.

5. Molecularly targeted therapy with EGFR tyrosine kinase inhibitors—erlotinib, gefitinib, afatinib, osimertinib—is used in patients with advanced NSCLC (as a first-line treatment and in subsequent relapses of disseminated disease) with mutations in the EGFR gene in the tumor cells. In patients with rearrangements of the ALK and ROS1 genes, an oral ALK inhibitor (eg, alectinib, brigatinib, ceritinib, crizotinib) is used. In patients with non–squamous cell lung cancer, perform additional genetic tests to detect EGFR gene mutations and rearrangement of ALK and ROS1 genes (targeted drugs in selected groups of patients are more effective than conventional chemotherapy).

6. Immunotherapy: Monoclonal antibodies (atezolizumab, nivolumab, pembrolizumab, durvulumab) blocking programmed death receptor 1 (PD-1) or its ligand (PD-L1). These drugs are used in the first and subsequent lines of treatment of advanced lung cancer, as well as in addition to radical radiochemotherapy in patients with local or regional cancer.

Treatment of SCLC

The basic treatment method is chemotherapy (usually 4-6 cycles of a 2-drug regimen containing cisplatin or carboplatin in combination with etoposide). In case of a relapse after the first treatment, consider reusing chemotherapy. Chest complaints and symptomatic CNS or bone metastases in patients after chemotherapy are an indication for palliative irradiation.

1. Treatment of LD (stages I-III): Chemotherapy + irradiation of the primary tumor site in the chest and regional lymph nodes; simultaneous use of both methods is the most effective. Surgical treatment is possible in exceptional cases. In patients with remission of cancer in the chest, additional elective brain irradiation is performed.

2. Treatment of ED (stage IV): In patients with good functional status and clinical condition, chemotherapy is administered according to the rules applying to LD (if available, add atezolizumab to chemotherapy). In patients with cancer remission in the chest, use additional electro-irradiation of the brain and in selected patients, of the chest.

Treatment of a Lung Carcinoid Tumor

Surgical treatment (lobectomy, segmentectomy for small peripheral tumors, conserving procedures are possible if the tumor is located intrabronchially). The treatment of atypical carcinoids (well-differentiated G2 neuroendocrine tumors of the lung) is the same as in the case of lung cancer.

PrognosisTop

Historically, 10% to 15% of patients diagnosed with NSCLC (both operated and not operated) survive 5 years. The 5-year survival rate after complete resection of an NSCLC in stages I, II, and IIIA is 60% to 80%, 40% to 50%, and 15% to 25%, respectively, and in patients with stage III receiving radiotherapy or radiochemotherapy, ~30%. In stage IV the median survival time is 10 to 12 months. With the evolution of immunotherapy and molecularly targeted therapy, long-term outcomes have remarkably improved.

For SCC, the 3-year survival rate in patients with limited disease is ~20%. In patients with disseminated disease, long-term survival is rare.

TablesTop