Lung cancer

At a glance

1. Lung cancer is the leading cause of cancer death worldwide. Smoking causes most cases (about 7 in 10 in the UK today); radon, asbestos, air pollution and other carcinogens, and in never-smokers inherited and mutational causes, make up the rest.
2. The first division is small-cell lung cancer (SCLC), a fast-growing neuroendocrine cancer that spreads early, and non-small-cell lung cancer (NSCLC), mainly adenocarcinoma, squamous carcinoma and large-cell carcinoma.
3. A cough for more than three weeks, haemoptysis, weight loss, chest pain, recurrent or slow-resolving pneumonia, and clubbing call for a chest film and then a CT. Many patients present with advanced disease, or with its effects: hoarseness, SVC obstruction, a Pancoast syndrome, bone, brain or liver metastases, or a paraneoplastic syndrome.
4. Diagnosis needs tissue, from bronchoscopy, EBUS or a CT-guided biopsy, with molecular tests (EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS and HER2, and PD-L1) in NSCLC, ideally on a gene panel. Staging uses the TNM system, CT, PET-CT and brain imaging.
5. Early NSCLC is treated by surgery or stereotactic radiotherapy; stage III by chemoradiotherapy then immunotherapy; stage IV by targeted drugs or immunotherapy with or without chemotherapy. SCLC is treated with platinum-etoposide chemotherapy, with radiotherapy in limited stage and immunotherapy in extensive stage.
6. Survival depends on stage, from over 80 per cent at 5 years for the smallest tumours in the staging database to a few per cent for metastatic disease (lower in population data), though targeted drugs and immunotherapy have improved it. Low-dose CT screening of heavy smokers lowers mortality.

01Definition and overview

Lung cancer (bronchial carcinoma) is a malignant tumour that arises from the epithelium of the airways or lung. It is divided by the cells seen under the microscope, because the cell type decides the behaviour and the treatment:

NSCLC is the combined term for the first three. Carcinoid tumours are rare, slow-growing neuroendocrine tumours, and mesothelioma is a separate cancer of the pleura, caused by asbestos. Metastases from other cancers in the lung are common, as multiple round shadows.

02Etiology and pathophysiology

Causes

• Cigarette smoking (including passive smoking) causes most lung cancer: older estimates put it at about 80 per cent in men and 90 per cent in women, current UK estimates are lower, about 72 per cent, and the share in never-smokers is rising. The risk depends on the number of cigarettes, the years smoked and the age of starting, and falls after stopping but remains above that of never-smokers. Smoking and asbestos exposure act together, and raise the risk far more than the sum of the two. Smoke contains polycyclic aromatic hydrocarbons and nitrosamines.
• Environmental: radon (a radioactive gas from the ground), asbestos, air pollution, ionizing radiation, and occupational exposure to arsenic, chromium, nickel, silica and diesel fumes.
• Host: pre-existing lung disease (COPD, pulmonary fibrosis), HIV, a family history, and inherited variants.
• Never-smokers account for a significant minority, and their cancers are mostly adenocarcinomas, with particular driver mutations, in which radon, air pollution and passive smoke have a part.

Pathogenesis

Carcinogens damage DNA across the airway lining (field cancerisation), so that mutations accumulate step by step: from dysplasia to carcinoma in situ to invasive cancer. The common changes are the loss of TP53 and RB1 (SCLC almost always has both), and in NSCLC activating mutations in driver oncogenes:

• EGFR (an epidermal growth factor receptor tyrosine kinase): in adenocarcinoma, particularly in never-smokers, women and people of Asian descent;
• ALK and ROS1 fusions: younger, never- or light-smokers;
• KRAS (commonly smokers), BRAF V600E, MET exon 14 skipping, RET fusions, NTRK fusions and HER2 mutations.

These alterations are "druggable", which is why molecular testing is essential. Tumours also turn on the PD-1/PD-L1 pathway to hide from T cells, which is the target of immune checkpoint inhibitors.

03Clinical features

Symptoms and signs arise from local growth, metastases and distant (paraneoplastic) effects.

Local effects

• Cough (the commonest symptom, and a change in a smoker's cough counts): a cough of three weeks or more merits a chest X-ray.
• Haemoptysis, breathlessness (airway obstruction, collapse, effusion, coexistent COPD), and chest pain: pleuritic if the pleura or chest wall is invaded, or a dull central ache from nodal disease.
• A monophonic wheeze, and recurrent or slow-resolving pneumonia beyond an obstructing tumour.
• Hoarseness: compression of the left recurrent laryngeal nerve in the mediastinum.
• Phrenic nerve palsy (a raised hemidiaphragm), dysphagia (oesophagus), pericardial effusion and arrhythmia (pericardium).
• Superior vena cava obstruction: facial and arm swelling, dilated neck and chest veins, headache; treat urgently.
• Pancoast syndrome: a tumour at the lung apex invading the brachial plexus (pain and wasting of the hand, C8 and T1) and the sympathetic chain (Horner syndrome: ptosis, miosis, anhidrosis).

Metastases

Spread is to mediastinal and cervical nodes, liver (anorexia, right upper quadrant pain), bone (pain, fractures, spinal cord compression, an emergency), brain (headache, seizures, focal deficits), adrenals (usually silent) and the pleura (malignant effusion).

Non-metastatic extrapulmonary (paraneoplastic) syndromes

The endocrine syndromes occur in about 10 per cent of cases and are mostly from SCLC; the neurological ones are mostly SCLC too, hypercalcaemia is usually squamous, and clubbing and hypertrophic osteoarthropathy are commoner in NSCLC:

• endocrine: SIADH (hyponatraemia), ectopic ACTH (Cushing syndrome), and hypercalcaemia from parathyroid hormone-related protein (usually squamous);
• neurological: the Lambert–Eaton myasthenic syndrome, subacute cerebellar degeneration, sensory neuropathy and limbic encephalitis;
• skeletal: clubbing (about 30 per cent) and hypertrophic pulmonary osteoarthropathy (painful wrists and ankles, periostitis); and
• haematological: thrombocytosis, anaemia and migratory thrombophlebitis (Trousseau syndrome).

Weight loss, anorexia and fatigue are common. The chest film may show a mass, a hilar mass or widening of the mediastinum, collapse of a lobe, a slow-resolving consolidation, a pleural effusion, or reticular shadowing from lymphangitis carcinomatosa; it can also be normal.

04Diagnosis and management

Diagnosis and staging

Investigations have three aims: a tissue diagnosis, staging, and an assessment of fitness for treatment.

1. Chest X-ray, then contrast CT of the chest and upper abdomen (liver and adrenals) for the extent of disease. A normal film does not exclude cancer, particularly in a smoker over 40 with haemoptysis. In the UK, an urgent chest X-ray is advised for anyone aged 40 or over with two or more unexplained symptoms (cough, fatigue, breathlessness, chest pain, weight or appetite loss), or one if they have ever smoked, and referral on the suspected cancer pathway if the film suggests lung cancer or there is unexplained haemoptysis at 40 or over. A contrast CT comes before any biopsy.
2. Tissue: the least invasive route to the most advanced site is preferred. Options: bronchoscopy (central tumours), endobronchial ultrasound (EBUS) with needle aspiration of nodes, CT-guided biopsy of peripheral lesions, ultrasound-guided biopsy of a node, liver lesion or pleura, pleural aspiration, or thoracoscopy. Cytology of effusions and sputum can be diagnostic.
3. Molecular and immune tests on non-squamous NSCLC (and on squamous tumours in non-smokers): EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS and HER2, together with PD-L1 expression on the tumour. A gene panel is now preferred to single-gene tests. A plasma liquid biopsy for circulating tumour DNA can be used when tissue is limited.
4. PET-CT to look for distant disease when radical treatment is planned, and brain MRI (or CT) for stage II and above in many pathways. Bone scan or MRI spine if there is a suspicion.
5. Blood tests: count, calcium, sodium, liver tests.
6. Fitness: ECOG performance status (0 to 5) and, before radical treatment, lung function with gas transfer, and cardiopulmonary exercise testing or cardiac assessment when needed.

Staging uses the TNM system (the ninth edition, in use since 2025, subdivides the eighth's N2 into N2a and N2b and M1c into M1c1 and M1c2; many textbooks still give the eighth): T by tumour size and invasion, N by lymph node involvement (N1 ipsilateral hilar; N2 ipsilateral mediastinal or subcarinal; N3 contralateral or supraclavicular), and M by distant spread. The stage groups run from IA to IVB. SCLC is also described as limited (confined to one hemithorax and a field that radiotherapy can cover) or extensive.

The approximate 5-year survival by clinical stage in NSCLC (eighth edition) shows why early detection matters. These figures come from an international research database of 94 708 cases, mostly treated before immunotherapy; population-based survival is lower (in England, roughly 65 per cent in stage 1, 40 in stage 2, 15 in stage 3 and 5 in stage 4 for patients diagnosed in 2016 to 2020), and the ninth edition regroups some stages:

Management of NSCLC

Treatment is planned by a multidisciplinary team. In the UK about 75 per cent of patients present with advanced disease, for whom radical treatment is not possible.

• Stages I and II: surgery, usually lobectomy with node sampling (often by video-assisted thoracoscopy), is the standard treatment with curative intent. For patients not fit for surgery, stereotactic ablative radiotherapy (SABR) gives comparable local control. Adjuvant chemotherapy is given after resection of stage II and III disease. After complete resection of stage IB to IIIA disease, osimertinib for 3 years is given for an EGFR mutation (whether or not chemotherapy came first) and alectinib for ALK, and in selected PD-L1 groups an immune checkpoint inhibitor follows the chemotherapy.
• Stage III: for resectable disease, chemotherapy with immunotherapy before (and sometimes after) surgery; for unresectable disease, concurrent chemoradiotherapy followed by durvalumab for a year (in the UK only if PD-L1 is 1 per cent or more and the disease has not progressed on chemoradiotherapy).
• Stage IV: treatment depends on the molecular profile.
  • A driver mutation: a targeted drug, such as osimertinib for EGFR, alectinib or lorlatinib for ALK, entrectinib for ROS1, dabrafenib with trametinib for BRAF V600E, capmatinib or tepotinib for MET, selpercatinib for RET, and KRAS G12C inhibitors (sotorasib, adagrasib) after first-line therapy.
  • No driver and PD-L1 of 50 per cent or more: an immune checkpoint inhibitor (pembrolizumab, atezolizumab or cemiplimab) alone.
  • No driver, lower PD-L1: platinum-based chemotherapy with pembrolizumab (or other combinations).
  • Radiotherapy for symptoms: bone pain, haemoptysis, bronchial obstruction, SVC obstruction, brain metastases (stereotactic radiosurgery or whole-brain).
• Endobronchial laser, cryotherapy, stents and brachytherapy relieve airway obstruction. Pleural effusions and SVC obstruction are managed as described elsewhere (for example, stenting).

Management of SCLC

SCLC is staged as limited or extensive disease and is chemosensitive. Limited disease: platinum with etoposide for four cycles, together with early thoracic radiotherapy, then prophylactic cranial irradiation or MRI surveillance, with durvalumab consolidation now in some pathways. Extensive disease: platinum with etoposide plus an immune checkpoint inhibitor (atezolizumab or durvalumab), with palliative radiotherapy. Relapse is usual. Options are topotecan (the long-standing European standard), platinum rechallenge if the interval has been long, and tarlatamab, authorised in the EU in 2026 but not recommended for routine use in the UK. Lurbinectedin is used for relapse in the USA; in the EU it is licensed as maintenance with atezolizumab after first-line chemo-immunotherapy.

Supportive and palliative care

Palliative care should begin alongside treatment: in a trial of 151 patients with metastatic NSCLC, early specialist palliative care improved quality of life and mood and, as a secondary result, survival, although pooled trials have not shown a survival benefit. Symptoms are managed (breathlessness, cough, pain, haemoptysis, anorexia), with support for the family. Stopping smoking improves outcomes at every stage and should be offered at every contact.

Screening and prevention

Low-dose CT screening of high-risk people (aged 55 to 74 with a heavy smoking history) reduced lung cancer mortality by 20 per cent against chest X-ray in a large American trial, and a Dutch–Belgian trial confirmed a benefit (about 24 per cent in men at 10 years). Programmes are being introduced in several European countries, with the problem of false positives, overdiagnosis and radiation to be managed. The most effective prevention is to avoid and stop smoking (tobacco control, plain packaging, bans in public places, taxes) and to reduce radon, asbestos and air pollution.

05Epidemiology

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. There were about 2.5 million new cases (12.4 per cent of all cancers) and 1.8 million deaths (18.7 per cent of cancer deaths) in 2022. It is the commonest cause of cancer death in both men and women in the UK and in men across Europe, and in European women it is close to breast cancer as the leading cause.

Incidence follows smoking by decades: it has fallen in men in countries where smoking has fallen, and has risen or peaked later in women. In countries where smoking is still rising (parts of Asia, Africa, Eastern Europe), the burden is growing. The share of adenocarcinoma has increased, and with it the proportion of cases in never-smokers. Disease is mostly diagnosed in people over 60, and often late.

06Prognosis

Survival depends on the stage at diagnosis above all (table above), then on cell type, performance status, weight loss, age and comorbidity. Because most patients present late, overall 5-year survival remains low. Older figures were 25 to 30 per cent alive at one year and 6 to 8 per cent at five years; now, in the UK, about 45 per cent are alive at one year and more than 15 per cent at five, and in the USA the 5-year relative survival is about 30 per cent.

• Early NSCLC treated with surgery has a good chance of cure, but local or distant recurrence is common in stage II and III (5-year survival 36 to 60 per cent in the table above).
• Metastatic NSCLC has been transformed in part: with targeted therapy for a driver mutation, median survival is several years in some groups, and with immune checkpoint inhibitors a minority of patients with high PD-L1 survive five years or more. Without these options, median survival is under a year with chemotherapy alone.
• SCLC has a poor prognosis: untreated, survival is a matter of weeks to months. Limited disease is curable in a minority, and in extensive disease the median survival is about a year, even with immunotherapy.

After curative treatment, a specialist appointment within 6 weeks and regular planned follow-up are advised, sometimes with periodic CT scans, since second primary cancers are frequent in smokers. Patients with a sudden clinical change (new bone pain, headache, weakness) should be seen at once.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1Which type of lung cancer is the commonest in people who have never smoked?

Squamous cell carcinomaSmall-cell carcinomaLarge-cell carcinomaAdenocarcinoma

2A smoker has shoulder pain down the inner arm, wasting of the small hand muscles, ptosis and a small pupil. Where is the tumour?

A central tumour near the carinaA tumour in the lung apexA tumour in the left lower lobeA lymphoma in the mediastinum

3A smoker has proximal leg weakness that improves with repeated effort, a dry mouth and mild ptosis. Which tumour is likely to be found?

Small-cell lung cancerLung adenocarcinomaSquamous cell carcinomaPulmonary carcinoid

4A non-smoking woman has stage IV adenocarcinoma with an activating EGFR mutation. What is the preferred first-line treatment?

Platinum-based chemotherapy alonePembrolizumab as a single drugOsimertinib, an EGFR inhibitorRadical thoracic radiotherapy

5Which test used for screening has been shown to cut lung cancer mortality in high-risk smokers?

Annual chest X-raySputum cytology each yearSerum tumour markersLow-dose CT of the chest