Non-small-cell lung cancer

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Non-small-cell lung cancer describes a group of epithelial lung malignancies dominated by adenocarcinoma and squamous carcinoma. Tobacco exposure remains the principal cause, but never-smokers can develop oncogene-driven adenocarcinoma and should not be clinically stereotyped. A peripheral early lesion may be incidental, while central disease produces cough, haemoptysis, collapse or recurrent infection. Apical tumours can invade brachial plexus and sympathetic chain; advanced disease commonly spreads to brain, bone, liver, adrenal and pleura.

The first therapeutic classification combines histology and TNM anatomy. Contrast CT maps primary, regional nodes and common metastatic sites. PET-CT improves whole-body staging when radical treatment is contemplated, but inflammatory uptake creates false-positive nodes and small or low-avidity disease creates false negatives. EBUS or EUS samples accessible mediastinal nodes, with surgical staging when a negative result remains discordant with high risk. Any solitary distant lesion that changes intent from curative to palliative deserves confirmation when safely feasible.

Curative local treatment depends on both resectability and physiological fitness. Lobectomy or another anatomical resection with systematic nodal assessment is standard for many operable early tumours; sublobar resection is selected for tumour and reserve. A patient unable or unwilling to undergo surgery may receive stereotactic ablative or other radical radiotherapy. Stage III is heterogeneous: some undergo induction and surgery, while unresectable disease may receive concurrent or sequential chemoradiotherapy followed by funded consolidation according to tumour biology and fitness.

Advanced NSCLC is a set of molecular diseases. Adequate genomic profiling and PD-L1 testing should return before a non-urgent first regimen because EGFR, ALK and other actionable alterations can make targeted treatment preferable and influence later immunotherapy safety. Without an actionable driver, PD-L1, histology, performance and organ function guide immunotherapy alone or combined with chemotherapy. At apparent progression, distinguish diffuse cancer growth from oligoprogression and immune or radiation change before abandoning an otherwise effective systemic strategy.

Key points

NSCLC includes adenocarcinoma, squamous carcinoma and less common subtypes; subtype determines tissue handling, predictive testing and systemic options.
Diagnosis requires adequate tissue with morphology and immunohistochemistry while preserving material for genomic and PD-L1 testing.
First-line anatomical staging uses contrast CT chest and upper abdomen, followed by PET-CT when curative treatment is possible; suspicious nodes often need EBUS or EUS tissue confirmation.
Gold-standard pathological stage comes from systematically sampled or dissected nodes and resection tissue when surgery occurs; PET uptake alone is neither cancer proof nor complete nodal exclusion.
Early resectable disease is considered for anatomical resection with systematic nodal evaluation; stereotactic ablative radiotherapy is a preferred curative alternative for selected medically inoperable early disease.
Stage III disease requires a thoracic MDT because resectable and unresectable subgroups need different sequences of surgery, systemic treatment and radiotherapy.
Before non-emergency advanced treatment, obtain the current NHS genomic panel and PD-L1 result; an actionable driver usually changes the preferred first systemic sequence.
Supportive and palliative care, smoking treatment, nutrition, exercise and symptom control run alongside curative or systemic therapy rather than after anticancer options end.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Tobacco carcinogen exposure

Cumulative smoking is the largest preventable cause, producing widespread bronchial DNA damage, but never-smokers also develop biologically distinct NSCLC.

Environmental and occupational exposure

Radon, asbestos, silica, diesel exhaust, air pollution and some workplace metals add risk with long latency and possible smoking interaction.

Previous thoracic injury

Prior radiotherapy, pulmonary fibrosis and chronic inflammatory lung disease increase risk through persistent tissue injury and genomic stress.

Acquired oncogenic drivers

EGFR, ALK, ROS1, BRAF, MET, RET, KRAS and other alterations can create targetable growth dependence independent of clinical stereotype.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Clonal epithelial transformation
Accumulated driver activation and tumour-suppressor loss allow bronchial or alveolar epithelial cells to proliferate, resist death and evade repair.
2
Local invasion obstructs structures
Tumour invades airway, pleura, chest wall, vessels and nerves, causing cough, collapse, pain, bleeding, effusion and superior sulcus syndromes.
3
Lymphatic stage develops
Spread through hilar and mediastinal nodes changes resectability and radiotherapy volume, making pathological nodal confirmation central to curative planning.
4
Haematogenous metastasis evolves
Circulating clones seed brain, bone, liver, adrenal and contralateral lung, while immune escape and molecular heterogeneity drive treatment resistance.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Central primary

Cough, haemoptysis, unilateral wheeze, lobar collapse or recurrent infection suggests an endobronchial squamous or other central lesion.

Peripheral adenocarcinoma

A spiculated peripheral nodule or mass may be asymptomatic until pleural pain, distant spread or incidental imaging detection.

Superior sulcus pattern

Shoulder and medial-arm pain, hand weakness, Horner syndrome or rib destruction indicates apical chest-wall and neural invasion.

Mediastinal involvement

Hoarseness, phrenic palsy, dysphagia or upper-body venous congestion suggests local nodal or direct invasion affecting curative stage.

Metastatic presentationRed flag

Seizure, bone pain, fracture, jaundice, hypercalcaemia, adrenal lesion or weight loss may reveal distant disease.

Oncogene-dependent tumour

Driver alterations occur across ages and smoking histories and are identified by testing rather than phenotype.

Red flags requiring action

Large-volume haemoptysis, stridor, monophonic wheeze, severe hypoxaemia or inability to clear secretions suggests central airway or bleeding threat.
Facial and arm swelling with chest-wall collaterals suggests superior vena cava obstruction and needs severity-based urgent imaging and decompression review.
New focal neurological deficit, seizure, spinal pain with weakness or sphincter change indicates possible metastatic neural compression.
A solitary distant lesion that alone removes curative intent should be confirmed with high diagnostic confidence or tissue where feasible.
New breathlessness during immunotherapy or thoracic radiotherapy requires assessment for pneumonitis, infection, embolism, effusion and progression.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Tissue diagnosis with subtypeFirst step
Why
Confirm malignancy and distinguish adenocarcinoma, squamous and other NSCLC while preserving predictive material.
Interpretation and limitations
Choose the safest biopsy that also provides stage, use a limited immunopanel and request re-biopsy or plasma testing when inadequate tissue would block decision-changing analysis.
02
First-line contrast CT chest and upper abdomenFirst line
Why
Define primary anatomy, nodes, pleura, liver and adrenal disease and identify biopsy targets.
Interpretation and limitations
CT suggests but does not pathologically prove nodal or distant stage; review airway, vessels and resectability at the thoracic MDT.
03
PET-CT for radical-intent staging
Why
Map metabolically active nodal and distant disease before surgery or radical radiotherapy.
Interpretation and limitations
Biopsy PET-positive mediastinal nodes or a solitary decisive distant lesion where feasible because infection and inflammation can be avid.
04
EBUS or EUS nodal sampling
Why
Obtain pathological mediastinal and hilar stage with minimally invasive access.
Interpretation and limitations
Systematically sample relevant stations rather than only the largest node; consider surgical staging after a negative study when pre-test risk remains high.
05
Pulmonary and exercise assessment
Why
Estimate risk and residual function after resection or high-dose thoracic treatment.
Interpretation and limitations
Use spirometry, gas transfer, predicted postoperative values and exercise testing when indicated; optimise reversible lung and cardiac disease before denying radical care.
06
NHS genomic panel and PD-L1
Why
Identify actionable drivers and checkpoint-treatment eligibility in the current national pathway.
Interpretation and limitations
Interpret with histology, stage and tumour fraction and verify current NICE commissioning; an uninformative sample may require repeat tissue rather than meaning no driver.
07
Brain MRI in indicated stage or symptoms
Why
Detect intracranial metastasis before radical or advanced treatment when guideline criteria or symptoms support it.
Interpretation and limitations
MRI is more sensitive than CT; treat acute neurological pressure or seizure before completing elective thoracic staging.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection and inflammatory mass

Pneumonia, tuberculosis, fungal disease, sarcoidosis and organising inflammation can be FDG-avid and mimic primary or nodal cancer.

Small-cell lung cancer

Neuroendocrine morphology, rapid dissemination and distinct immunohistochemistry define SCLC, whose staging and systemic treatment pathway differs.

Pulmonary metastasis

A lung lesion in someone with another cancer may be metastatic disease or a second primary; morphology and molecular comparison can preserve curative options.

Benign pulmonary nodule

Granuloma, hamartoma and scar can remain stable or show characteristic imaging, but growth and high-risk morphology require governed nodule investigation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01DiagnoseObtain tissue that also stagesFirst stepImaging suggests a primary lung cancer.

1Review CT with respiratory and radiology teams and choose bronchoscopy, EBUS, CT-guided core or metastatic-site biopsy that offers adequate tissue with lowest harm.
2Confirm NSCLC subtype and preserve material for the national genomic panel and PD-L1 rather than exhausting it on broad non-decision-changing stains.
3Complete PET-CT and brain or other imaging appropriate to intended treatment and verify any solitary finding that alone removes curative intent.

02Early diseaseChoose curative local therapyDisease appears localised and the patient has no confirmed distant spread.

1Complete mediastinal nodal staging and formal cardiopulmonary assessment and optimise smoking, nutrition and reversible comorbidity.
2Offer anatomical surgical resection with systematic nodal assessment when tumour and patient are operable, tailoring extent to oncological margin and reserve.
3Offer stereotactic ablative or another radical radiotherapy schedule when surgery is unsuitable or declined, and review final stage for adjuvant treatment eligibility.

03Stage IIIBuild one multimodality sequenceMediastinal nodal or locally invasive disease remains potentially radical and no metastasis is confirmed.

1Confirm nodal stations and technical resectability and review jointly with thoracic surgery, clinical and medical oncology, pathology and radiology.
2Use a surgery-containing approach only for selected resectable subgroups and give concurrent chemoradiotherapy to suitable unresectable disease, with sequential therapy when concurrence is unsafe.
3After radical treatment, review pathology or response, molecular findings and current consolidation indications and plan toxicity and recurrence surveillance.

04AdvancedPersonalise the first systemic lineMetastatic or recurrent NSCLC requires disease-controlling systemic therapy without an immediate complication forcing treatment.

1Confirm performance, organ function, histology, full genomic result and PD-L1 and address pain, dyspnoea, thrombosis and brain or bone complications concurrently.
2Use an approved targeted therapy first for a qualifying driver; otherwise select checkpoint-based or cytotoxic treatment from PD-L1, histology, contraindications and patient goals.
3At progression, establish diffuse versus oligoprogression and toxicity or pseudoprogression, then select local ablation, another systemic line, trial or symptom-focused care.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Inhibits sensitising EGFR-driven tumour signalling and penetrates the central nervous system in defined treatment settings.

Osimertinib for qualifying EGFR-mutated NSCLC

Give osimertinib 80 mg orally once daily under the current licensed and NICE-funded early, locally advanced or metastatic indication, continuing until the protocol stop point or unacceptable toxicity.

Confirm the qualifying alteration and indication. Monitor ECG and QT, electrolytes, ventricular function when indicated, eye symptoms and blood count and investigate new breathlessness urgently for interstitial lung disease.

Restores antitumour T-cell activity as monotherapy or with chemotherapy in selected driver-negative NSCLC.

Pembrolizumab

Give pembrolizumab 200 mg intravenously every 3 weeks or 400 mg every 6 weeks within the licensed NSCLC regimen and current NICE biomarker and combination criteria.

Immune toxicity can affect any organ and occur after stopping; review autoimmune disease, transplant, infection and immunosuppression and hold treatment for clinically significant suspected toxicity.

Provides neoadjuvant, adjuvant, chemoradiotherapy or advanced disease control when anatomy and tumour biology support cytotoxic treatment.

Platinum doublet chemotherapy

Use the histology- and stage-specific NHS protocol, such as a platinum with pemetrexed for suitable non-squamous disease, dosed by body surface area and renal function over the planned cycle number.

Check DPD status when fluoropyrimidines are involved and regimen-specific marrow, renal, hearing, neurological, emesis and thrombosis risks; cisplatin and carboplatin are not interchangeable without reason.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Airway obstruction and infection

Central tumour narrows bronchus, causing lobar collapse, retained secretion, recurrent post-obstructive pneumonia and eventual respiratory failure.

Pleural malignant disease

Pleural dissemination causes recurrent effusion, trapped lung, chest pain and a metastatic stage requiring symptom and systemic treatment planning.

Neurological and skeletal metastasis

Brain lesions cause seizure or pressure, while bone disease causes pain, fracture, hypercalcaemia and metastatic spinal cord compression.

Treatment-related organ toxicity

Surgery, platinum therapy, targeted agents, checkpoint inhibitors and thoracic radiation can injure lung, marrow, kidney, nerves, heart and endocrine organs.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Before radical treatment, document anatomical stage, pathological nodal evidence, pulmonary reserve, performance, frailty and smoking and rehabilitation needs.
Before systemic therapy, ensure all decision-changing genomic and PD-L1 results are final or record why emergency treatment cannot wait.
During targeted therapy, follow agent-specific ECG, cardiac, blood and imaging surveillance and investigate respiratory or ocular symptoms promptly.
During checkpoint treatment, ask about bowel, lung, liver, endocrine, cardiac, renal, skin and neurological toxicity at every contact and after the last dose.
Compare response imaging with treatment timing and baseline and review an isolated new lesion or inflammatory pattern before changing the whole regimen.
After curative therapy, follow the tumour-specific surveillance plan, support smoking cessation and investigate new symptoms between scheduled scans.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Biopsy can stage twice

Sampling the highest relevant node or an accessible distant lesion may establish both histology and stage while conserving procedures.

PET is probability not pathology

Inflammation can be avid and microscopic nodal cancer can be missed, so tissue remains decisive when stage changes curative treatment.

Operability has two meanings

A tumour may be anatomically resectable while the person cannot tolerate surgery, or physiologically fit while anatomy requires another radical modality.

Genotype cannot be guessed

Never-smoking and young age enrich some drivers but do not replace the national test result in any eligible patient.

One progression site can be local

Selected oligoprogression may be ablated while an otherwise effective targeted therapy continues, avoiding a premature whole-system switch.

11Common pitfallsFrequent interpretation and management errors.

01
Using a small cytology sample without conserving tissue for genomic and PD-L1 testing.
02
Treating PET-positive mediastinal nodes as proven without tissue when the result changes curative management.
03
Abandoning curative intent because of one unconfirmed distant lesion.
04
Calling a tumour inoperable without separating anatomical resectability from cardiopulmonary fitness.
05
Starting non-urgent advanced therapy before the genomic result that determines the preferred first sequence.
06
Assuming new lung change on immunotherapy is progression without assessing pneumonitis, infection and embolism.
07
Using an outdated remembered NICE drug indication instead of checking the current biomarker and stage criteria.