Lung carcinoma is the leading cause of cancer-related death worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain, weight loss, and, less commonly, hemoptysis; however, many patients present with metastatic disease without any clinical symptoms. The diagnosis is typically made by chest x-ray or CT and confirmed by biopsy. Depending on the stage of the disease, treatment includes surgery, chemotherapy, radiation therapy, or a combination. For the past several decades, the prognosis for a lung cancer patient was poor, with only 15% of patients surviving > 5 yr from the time of diagnosis. For patients with stage IV (metastatic) disease, the 5-yr overall survival rate was < 1%. However, outcomes have improved because of the identification of certain mutations that can be targeted for therapy.
In 2012, an estimated 226,160 new cases of lung cancer were diagnosed in the US, and 160,340 people died from the disease. The incidence of lung cancer has been declining in men over the past 2 decades and has leveled off and begun a slight decline in women.
Cigarette smoking is the most important cause of lung cancer, accounting for about 85% of cases. The risk of cancer differs by age, smoking intensity, and smoking duration; the risk of cancer declines after smoking cessation, but it never returns to baseline. About 15 to 20% of people who develop lung cancer have never smoked or have smoked minimally.
The risk of lung cancer increases with combined exposure to toxins and cigarette smoking. Other possible risk factors include air pollution, exposure to cigar smoke and second-hand cigarette smoke, and exposure to carcinogens (eg, asbestos, radiation, radon, arsenic, chromates, nickel, chloromethyl ethers, polycyclic aromatic hydrocarbons, mustard gas, coke-oven emissions, primitive cooking, heating huts). It is also suspected that COPD, α1-antitryptsin deficiency, and pulmonary fibrosis may increase susceptibility to lung cancer. People whose lungs are scarred by other lung diseases (eg, TB) are potentially at increased risk of lung cancer. Also, active smokers who take β-carotene supplements have an increased risk of developing lung cancer.
Respiratory epithelial cells require prolonged exposure to cancer-promoting agents and accumulation of multiple genetic mutations before becoming neoplastic (an effect called field carcinogenesis). In some patients with lung cancer, secondary or additional mutations in genes that stimulate cell growth (K-ras, MYC), cause abnormalities in growth factor receptor signaling (EGFR, HER2/neu), and inhibit apoptosis contribute to proliferation of abnormal cells. In addition, mutations that inhibit tumor-suppressor genes (p53, APC) can lead to cancer. Other mutations that may be responsible include the EML-4-ALK translocation and mutations in ROS-1, BRAF, and PI3KCA. Genes such as these that are primarily responsible for lung cancer are called driver mutations. Although driver mutations can cause or contribute to lung cancer among smokers, these mutations are particularly likely to be a cause of lung cancer among nonsmokers. In a 2011 analysis, the Lung Cancer Mutation Consortium (LCMC) found driver mutations in 54% of 516 lung cancers among smokers and nonsmokers (23% K-ras mutations, 18% EGFR mutations, 9% EML-4-ALK, and 2% BRAF mutations). Novel therapies aimed at driver mutations are being developed.
Lung cancer is classified into 2 major categories:
SCLC is highly aggressive and almost always occurs in smokers. It is rapidly growing, and roughly 80% of patients have metastatic disease at the time of diagnosis.
The clinical behavior of NSCLC is more variable and depends on histologic type, but about 40% of patients will have metastatic disease outside of the chest at the time of diagnosis. Driver mutations have been identified primarily in adenocarcinoma, although attempts are being made to identify similar mutations in squamous cell carcinoma.
Other features of the 2 categories (eg, location, risks, treatment, complications) also vary (see Table 3: Features of Lung Cancer).
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Symptoms and Signs
About 25% of lung cancers are asymptomatic and are detected incidentally with chest imaging. Symptoms and signs can result from local tumor progression, regional spread, or distant metastases. Paraneoplastic syndromes and constitutional symptoms may occur at any stage of the disease. Although symptoms are not specific to the classification or histology of the cancer, certain complications may be more likely with different types (see Table 3: Features of Lung Cancer).
The local tumor can cause cough and, less commonly, dyspnea due to airway obstruction, postobstructive atelectasis, and parenchymal loss due to lymphangitic spread. Fever may occur with postobstructive pneumonia. Up to half of patients report vague or localized chest pain. Hemoptysis is less common, and blood loss is minimal, except in rare instances when the tumor erodes into a major artery, causing massive hemorrhage and often death by asphyxiation or exsanguination.
Regional spread of tumor may cause pleuritic chest pain or dyspnea due to development of a pleural effusion, hoarseness due to tumor encroachment on the recurrent laryngeal nerve, and dyspnea and hypoxia from diaphragmatic paralysis due to involvement of the phrenic nerve.
Superior vena cava (SVC) syndrome results from compression or invasion of the SVC and can cause headache or a sensation of head fullness, facial or upper-extremity swelling, breathlessness when supine, dilated veins in the neck, face, and upper trunk, and facial and truncal flushing (plethora).
Apical tumors, usually NSCLC (Pancoast tumor), can invade the brachial plexus, pleura, or ribs, causing shoulder and upper-extremity pain and weakness or atrophy of the ipsilateral hand. Horner syndrome (ptosis, miosis, anhidrosis) results when the paravertebral sympathetic chain or cervical stellate ganglion is involved. Spread of the tumor to the pericardium may be asymptomatic or lead to constrictive pericarditis or cardiac tamponade. In rare cases, esophageal compression by the tumor leads to dysphagia.
Metastases eventually cause symptoms that vary by location. Metastases to the liver cause pain, nausea, early satiety, and ultimately hepatic insufficiency. Metastases to the brain cause behavioral changes, confusion, aphasia, seizures, paresis or paralysis, nausea and vomiting, and ultimately coma and death. Bone metastases can cause severe pain and pathologic fractures. Although lung cancer commonly metastasizes to the adrenal glands, it rarely causes adrenal insufficiency.
Paraneoplastic syndromes are symptoms that occur at sites distant from a tumor or its metastases (see Paraneoplastic Syndromes). Common paraneoplastic syndromes in patients with lung cancer include hypercalcemia (in patients with squamous cell carcinoma, which results because the tumor produces parathyroid hormone–related protein), syndrome of inappropriate antidiuretic hormone (SIADH) secretion, finger clubbing with or without hypertrophic pulmonary osteoarthropathy, hypercoagulability with migratory superficial thrombophlebitis (Trousseau syndrome), myasthenia-like symptoms (Eaton-Lambert syndrome), Cushing syndrome, and various other neurologic syndromes, including neuropathies, encephalopathies, encephalitides, myelopathies, and cerebellar disease. Mechanisms for neuromuscular syndromes involve tumor expression of autoantigens with production of autoantibodies, but the cause of most other syndromes is unknown.
Chest x-ray is often the initial imaging test. It may show clearly defined abnormalities, such as a single mass or multifocal masses or a solitary pulmonary nodule (see Solitary Pulmonary Nodule), an enlarged hilum, widened mediastinum, tracheobronchial narrowing, atelectasis, nonresolving parenchymal infiltrates, cavitary lesions, or unexplained pleural thickening or effusion. These findings are suggestive but not diagnostic of lung cancer and require follow-up with CT scans or combined PET–CT scans and cytopathologic confirmation.
CT shows many characteristic anatomic patterns and appearances that may strongly suggest the diagnosis. CT also can guide core needle biopsy of accessible lesions and is useful for staging. If a lesion found on a plain x-ray is highly likely to be lung cancer, PET–CT may be done. This study combines anatomic imaging from CT with functional imaging from PET. The PET images can help differentiate inflammatory and malignant processes.
The method used to obtain cells or tissue for confirmation depends on the accessibility of tissue and the location of lesions. Sputum or pleural fluid cytology is the least invasive method. In patients with productive cough, sputum specimens obtained on awakening may contain high concentrations of malignant cells, but yield for this method is < 50% overall. Pleural fluid is another convenient source of cells; a malignant effusion is a poor prognostic sign. In general, false-negative cytology readings can be minimized by obtaining as large a volume of sputum or pleural fluid as possible early in the day and sending the sample to the pathology laboratory immediately to minimize delays in processing because such delays lead to cell breakdown. Molecular (genetic) studies can be done on paraffin-embedded tumor cell pellets from pleural fluid if the fluid is spun down and the cell pellet preserved in a timely fashion. Biopsy, when done, is core biopsy; fine-needle biopsy retrieves too little tissue for accurate genetic studies.
Percutaneous biopsy is the next least invasive procedure. It is more useful for metastatic sites (eg, supraclavicular or other peripheral lymph nodes, pleura, liver, adrenals) than for lung lesions. Risks include a 20 to 25% chance of pneumothorax (primarily in patients with significant emphysema) and the risk of obtaining a false-negative result.
Bronchoscopy is the procedure most often used for diagnosing lung cancer. In theory, the procedure of choice for obtaining tissue is the one that is least invasive. In practice, bronchoscopy is often done in addition to or instead of less invasive procedures because diagnostic yields are greater and because bronchoscopy is important for staging. A combination of washings, brushings, and biopsies of visible endobronchial lesions and of paratracheal, subcarinal, mediastinal, and hilar lymph nodes often yields a tissue diagnosis.
Mediastinoscopy is the standard test for evaluating mediastinal lymph nodes but is a higher risk procedure that is usually used before thoracic surgery to confirm or exclude the presence of tumor in enlarged mediastinal lymph nodes. Endobronchial ultrasound-guided biopsy (EBUS) can be done in a fashion similar to bronchoscopy.
Open lung biopsy, done via open thoracotomy or using video assistance (see Thoracoscopy and Video-Assisted Thoracoscopic Surgery), is indicated when less invasive methods do not provide a diagnosis in patients whose clinical characteristics and radiographic features strongly suggest that the tumor is resectable.
To date, no screening studies are universally accepted. Prior clinical trials have evaluated screening chest x-rays in high-risk patients (smokers) to try to detect lung cancers at earlier stages, but mortality rates largely did not decline. Screening CT is being evaluated because it is more sensitive. However, CT may produce more false-positive results, which increase the number of unnecessary invasive diagnostic procedures needed to verify the CT findings. Such procedures are costly and risk additional complications.
Recent studies have suggested a 20% decrease in lung cancer deaths among former or active smokers (mainly ages 55 to 74 and with a heavy smoking history) when annual screening is done using low-dose helical CT (LDCT) as compared to chest x-ray. However, screening LDCT may not be appropriate for patients not at high risk.
In the future, lung cancer screening may involve some combination of molecular analysis for genetic markers (eg, K-ras, p53, EGFR), sputum cytometry, and detection of cancer-related volatile organic compounds (eg, alkane, benzene) in exhaled breath.
SCLC has 2 stages:
Limited-stage SCLC disease is cancer confined to one hemithorax (including ipsilateral lymph nodes) that can be encompassed within one tolerable radiation therapy port, unless there is a pleural or pericardial effusion.
Extensive-stage disease is cancer outside a single hemithorax or the presence of malignant cells detected in pleural or pericardial effusions. Less than one third of patients with SCLC will present with limited-stage disease; the remainder of patients often have extensive distant metastases.
NSCLC has 4 stages, I through IV (using the TNM system). TNM staging is based on tumor size, tumor and lymph node location, and the presence or absence of distant metastases (see Table 4: New International Staging System for Lung Cancer).
Tests for initial evaluation and staging:
All lung cancer patients need whole-body imaging. Different combinations of tests can be done. Some tests are done routinely, and others are done depending on whether the results would impact treatment decisions:
If PET–CT is not available, thin-section high-resolution CT (HRCT) from the neck to the upper abdomen (to detect cervical and supraclavicular and hepatic and adrenal metastases) is one of the first staging tests for both SCLC and NSCLC. However, CT often cannot distinguish postinflammatory changes from malignant intrathoracic lymph node enlargement or benign lesions from malignant hepatic or adrenal lesions (distinctions that determine stage). Thus, other tests are usually done when abnormalities are present in these areas.
PET scanning is a reasonably accurate, noninvasive test used to identify malignant mediastinal lymph nodes and other distant metastases (metabolic staging). Integrated PET–CT scanning, in which PET and CT images are combined into a single image by scanners in a single gantry, is more accurate for NSCLC staging than CT or PET alone or than visual correlation of the 2 tests. The use of PET and integrated PET–CT is limited by cost, availability, and specificity (ie, the test is quite sensitive and has an excellent negative predictive value, but its positive predictive value is not as high). When PET scan results are indeterminate, bronchoscopy, mediastinoscopy, or video-assisted thoracoscopic surgery (VATS) can be used to biopsy questionable mediastinal lymph nodes. Without PET scanning, hepatic or adrenal lesions must be evaluated by needle biopsy.
MRI of the chest is slightly more accurate than high-chest HRCT for staging apical tumors and cancers close to the diaphragm and provides an evaluation of the vasculature surrounding the tumors.
Blood tests are usually done. Ca and alkaline phosphatase levels, if elevated, suggest possible bone metastases. Other blood tests, such as CBC, serum albumin levels, AST, ALT, total bilirubin, electrolytes, and creatinine levels, have no role in staging but provide important prognostic information about the patient's ability to tolerate treatment and may demonstrate the presence of paraneoplastic syndromes.
After diagnosis, all patients with lung cancer should undergo brain imaging; MRI is preferred to CT. Brain imaging is especially necessary in patients with headache or neurologic abnormalities.
Patients with bone pain or elevated serum Ca or alkaline phosphatase levels should undergo PET–CT or radionuclide bone scanning if PET–CT is not available.
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The overall prognosis for SCLC is poor. The median survival time for limited-stage SCLC is 20 mo, with a 5-yr survival rate of 20%. Patients with extensive-stage SCLC do especially poorly, with a 5-yr survival rate of < 1%.
The 5-yr survival rate of patients with NSCLC varies by stage, from 60 to 70% for patients with stage I disease to < 1% for patients with stage IV disease. On average, untreated patients with metastatic NSCLC survive 6 mo, whereas the median survival for treated patients is about 9 mo. Recently, patient survival has improved in both early and later stage NSCLC. Evidence shows improved survival in early-stage disease (stages IB to IIIB) when platinum-based chemotherapy regimens are used after surgical resection. In addition, targeted therapies have improved survival in patients with stage IV disease, in particular patients with an EGFR mutation or EML-4-ALK translocation.
Treatment varies by cell type and by stage of disease. Many patient factors not related to the tumor affect treatment choice. Poor cardiopulmonary reserve, undernutrition, frailty or poor physical performance status, comorbidities, including cytopenias, and psychiatric or cognitive illness all may lead to a decision for palliative over curative treatment or for no treatment at all, even though a cure with aggressive therapy might technically be possible.
Radiation therapy carries the risk of radiation pneumonitis when large areas of the lung are exposed to high doses of radiation over time. Radiation pneumonitis can occur up to 3 mo after treatment is completed. Cough, dyspnea, low-grade fever, or pleuritic chest pain may signal the condition, as may crackles or a pleural friction rub detected on chest auscultation. Chest x-ray may have nonspecific findings; CT may show a nonspecific infiltrate without an obvious mass. The diagnosis is often one of exclusion. Radiation pneumonitis can be treated with a corticosteroid taper over several weeks and bronchodilators for symptom relief.
Radiofrequency ablation, in which high-frequency electrical current is used to destroy tumor cells, is a newer technique that can sometimes be used in patients who have small, early-stage tumors or small tumors that have recurred in a previously irradiated chest. This procedure may preserve more lung function than open surgery does and, because it is less invasive, may be appropriate for patients who are not candidates for open surgery.
SCLC of any stage is typically initially responsive to treatment, but responses are usually short-lived. Chemotherapy, with or without radiation therapy, is given depending on the stage of disease. In many patients, chemotherapy prolongs survival and improves quality of life enough to warrant its use. Surgery generally plays no role in treatment of SCLC, although it may be curative in the rare patient who has a small focal tumor without spread (such as a solitary pulmonary nodule) who underwent surgical resection before the tumor was identified as SCLC.
Chemotherapy regimens of etoposide and a platinum compound (either cisplatin or carboplatin) are commonly used, as are other drugs, such as irinotecan, topotecan, vinca alkaloids (vinblastine, vincristine, vinorelbine), alkylating agents (cyclophosphamide, ifosfamide), doxorubicin, taxanes (docetaxel, paclitaxel), and gemcitabine. When disease is confined to a hemithorax, radiation therapy further improves clinical outcomes; such response to radiation therapy was the basis for the definition of limited-stage disease. The use of cranial radiation to prevent brain metastases is also advocated in certain cases; micrometastases are common in SCLC, and chemotherapy has less ability to cross the blood-brain barrier.
In extensive-stage disease, treatment is based on chemotherapy rather than radiation therapy, although radiation therapy is often used as palliative treatment for metastases to bone or brain. In patients with an excellent response to chemotherapy, prophylactic brain irradiation is sometimes used as in limited-stage SCLC to prevent growth of SCLC in the brain. It is unclear whether replacing etoposide with topoisomerase inhibitors (irinotecan or topotecan) improves survival. These drugs alone or in combination with other drugs are also commonly used in refractory disease and in cancer of either stage that has recurred.
In general, recurrent SCLC carries a poor prognosis, although patients who maintain a good performance status should be offered a clinical trial.
Treatment for NSCLC typically involves assessment of eligibility for surgery followed by choice of surgery, chemotherapy, radiation therapy, or a combination of modalities as appropriate, depending on tumor type and stage.
For stage I and II disease, the standard approach is surgical resection with either lobectomy or pneumonectomy combined with mediastinal lymph node sampling or complete lymph node dissection. Lesser resections, including segmentectomy and wedge resection, are considered for patients with poor pulmonary reserve. Surgery is curative in about 55 to 70% of patients with stage I and in 35 to 55% of patients with stage II disease.
Preoperative pulmonary function is assessed. Surgery is done only if NSCLC patients will have adequate pulmonary reserve once a lobe or lung is resected. Patients with preoperative forced expiratory volume in 1 sec (FEV1) > 2 L generally tolerate pneumonectomy. Patients with FEV1 < 2 L should have a quantitative xenon radionuclide perfusion scan to determine the proportion of function they can expect to lose as a result of resection. Postoperative FEV1 can be predicted by multiplying percent perfusion of the nonresected lung by the preoperative FEV1. A predicted FEV1 > 800 mL or > 40% of the predicted normal FEV1 suggests adequate postoperative lung function, although studies of lung volume reduction surgery in COPD patients suggest that patients with FEV1 < 800 mL can tolerate resection if the cancer is located in poorly functional, bullous (generally apical) lung regions. Patients undergoing resection at hospitals that do more resections have fewer complications and are more likely to survive than those who undergo surgery at hospitals that do fewer lung cancer procedures.
Adjuvant chemotherapy after surgery is now standard practice for patients with stage II or stage III disease and possibly also for patients with stage IB disease and tumors > 4 cm. Clinical trials have shown an increase in 5-yr survival rates with the use of adjuvant chemotherapy. However, the decision to use adjuvant chemotherapy depends on the patient's comorbidities and risk assessment. A commonly used chemotherapy regimen is a cisplatin-based doublet (combination of a cisplatin and another chemotherapy drug, such as vinorelbine, docetaxel, paclitaxel). Neoadjuvant (preoperative) chemotherapy in early-stage NSCLC is also commonly used and consists of 4 cycles of a cisplatin-doublet. In patients who cannot receive cisplatin, carboplatin can be substituted.
Stage III disease is treated with either chemotherapy, radiation therapy, surgery, or a combination of therapies; the sequence and choice of treatment depend on the location of the patient's disease and comorbidities. In general, concurrent chemotherapy and radiation therapy are considered standard treatment for unresectable clinically staged IIIA disease, but the survival remains poor (median survival, 10 to 14 mo). Patients with stage IIIB disease with contralateral mediastinal nodal disease or supraclavicular nodal disease are offered either radiation therapy or chemotherapy or both. Patients with locally advanced tumors invading the heart, great vessels, mediastinum, or spine usually receive radiation therapy. In some patients (ie, those with T4 N0 M0 tumors), surgical resection with either neoadjuvant or adjuvant combined chemotherapy and radiation therapy may be feasible. The 5-yr survival rate for patients with treated stage IIIB disease is 5%.
In stage IV disease, palliation of symptoms is the goal. Chemotherapy, targeted drugs, and radiation therapy may be used to reduce tumor burden, relieve symptoms, and improve quality of life. However, if no mutation treatable with a targeted drug is identified, median survival is only 9 mo, and < 25% of patients survive 1 yr. Surgical palliative procedures may be required and may include thoracentesis and pleurodesis of recurrent effusions, placement of indwelling pleural drainage catheters, bronchoscopic fulguration of tumors involving the trachea and mainstem bronchi, placement of stents to prevent airway occlusion, and, in some cases, spinal stabilization for impending spinal cord compression.
In patients with non-squamous cell carcinoma, bevacizumab, a vascular endothelial growth factor inhibitor, can be used in combination with standard chemotherapy (eg, a platinum-based doublet, such as carboplatin plus paclitaxel) to improve outcomes. In stage IV patients with sensitive EGFR mutations (ie, deletion exon 19, exon 21 L858 mutation), EGFR tyrosine kinase inhibitors (TKIs) may be given as first-line therapy; response rates and progression-free survival are better than those obtained using standard chemotherapy. EGFR TKIs include gefitinib and erlotinib. Patients who have EML -4-ALK translocations should receive crizotinib, an ALK and ROS-1 inhibitor. Efforts are underway to make crizotinib available for patients with ROS-1 mutations. Patients with BRAF mutations may benefit from the BRAF inhibitors (eg, vemurafenib). Similarly, patients with PI3K mutations may be expected to respond to PI3K inhibitors, which are being developed. Many other biologic agents are under investigation, including some that specifically target cancer cell signal transduction pathways or the angiogenesis pathways that supply O2 and nutrition to growing tumor cells.
Treatment options for disease that recurs after treatment vary by location and include repeat chemotherapy or targeted drugs for metastases, radiation therapy for local recurrence or pain caused by metastases, and brachytherapy for endobronchial disease when additional external radiation cannot be tolerated. Rarely, surgical resection of a solitary metastasis or for palliative purposes is considered. The treatment of a locally recurrent NSCLC follows the same guidelines as for primary tumor stages I to III. If surgery was used initially, radiation therapy is the main modality. If the recurrence manifests as distant metastases, patients are treated as if they have stage IV disease with a focus on palliation. Treatment for recurrent or metastatic stage IV NSCLC includes chemotherapy or novel targeted drugs. The choice depends on tumor histology, patient functional status, and patient preference. For example, an EGFR TKI, such as gefitinib or erlotinib, can be used as second- or third-line therapy even among patients who do not have sensitive EGFR mutations.
Asymptomatic malignant pleural effusions require no treatment. Initial treatment of a symptomatic effusion is with thoracentesis. Symptomatic effusions that recur despite multiple thoracenteses are drained through a chest tube. Infusion of talc (or occasionally, tetracycline or bleomycin) into the pleural space (a procedure called pleurodesis) scars the pleura, eliminates the pleural space, and is effective in > 90% of cases (see Pleural Effusion).
Treatment of SVC syndrome is the same as treatment of lung cancer, with chemotherapy (SCLC), radiation therapy (NSCLC), or both (NSCLC). Corticosteroids are commonly used but are of unproven benefit.
Treatment of Horner syndrome caused by apical tumors is with surgery with or without preoperative radiation therapy or with radiation therapy with or without adjuvant chemotherapy.
Treatment of paraneoplastic syndromes varies by syndrome (see Paraneoplastic Syndromes).
Because many patients with lung cancer die, the need for end-of-life care should be anticipated (see The Dying Patient). Studies have reported that early palliative care intervention leads to less end-of-life chemotherapy use and may even extend life (ie, by avoiding adverse effects of aggressive treatments). Symptoms of breathlessness can be treated with supplemental O2 and bronchodilators. Preterminal breathlessness can be treated with opioids. Pain, anxiety, nausea, and anorexia are especially common and can be treated with parenteral morphine; oral, transdermal, or parenteral opioids; and antiemetics. The care provided by hospice programs is extremely well-accepted by patients and families, yet this intervention is markedly underused.
No active interventions to prevent lung cancer are proven to be effective except for smoking cessation (see Tobacco Use). Remediation of high radon levels in private residences removes known cancer-promoting radiation, but a reduction in lung cancer incidence is unproven. Increasing dietary intake of fruits and vegetables high in retinoids and β-carotene appears to have no effect on lung cancer incidence. Vitamin supplementation is either unproven (vitamin E) or harmful (β-carotene) in smokers. Preliminary evidence hinting that NSAIDs and vitamin E supplementation may protect former smokers from lung cancer requires confirmation. New molecular approaches targeting cell signaling and cell cycle pathways and tumor-associated antigens are under investigation.
Last full review/revision February 2013 by Anne S. Tsao, MD
Content last modified November 2013