Non-small-cell lung cancer

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

NSCLC management begins with adequate diagnosis and stage. A small localised tumour in a physiologically fit person may be cured with surgery, whereas the same anatomy in someone unable to tolerate resection may be approached with radical radiotherapy. Mediastinal nodal status can switch the treatment strategy, so PET-CT and invasive nodal staging are used when their results matter. Pathological resection specimens may create indications for adjuvant chemotherapy, immunotherapy or targeted therapy under current NICE guidance. Decisions should be made in a specialist MDT and explained as estimates of benefit, toxicity and uncertainty rather than as automatic consequences of age.

Advanced NSCLC is biologically diverse. Histology, genomic alterations and PD-L1 expression divide patients into treatment groups for targeted agents, immunotherapy, cytotoxic combinations or supportive care. Starting empirical systemic therapy before decision-changing biomarkers return can forfeit the most effective sequence unless the clinical situation is genuinely urgent. Disease control must be balanced with toxicity, organ function, frailty and preference. At progression, confirm whether this is widespread, oligoprogressive, treatment-related inflammation or a different process before changing the whole strategy; local treatment to selected sites may sometimes preserve an otherwise effective systemic therapy.

Key points

Non-small-cell lung cancer includes adenocarcinoma, squamous carcinoma and less common subtypes; histology influences sampling, biomarker testing and systemic therapy.
Treatment is organised by TNM stage, anatomical resectability, cardiopulmonary fitness, performance status, molecular drivers, PD-L1 expression and the person's goals.
Early resectable disease is considered for anatomical lung resection with systematic nodal assessment; medically inoperable disease may be treated with stereotactic ablative radiotherapy or another radical schedule.
Stage III disease is heterogeneous and requires thoracic MDT planning across surgery, systemic anticancer therapy and radiotherapy rather than a single default regimen.
Before non-emergency treatment of advanced non-squamous NSCLC, obtain adequate genomic and PD-L1 results because a targetable driver can change first-line therapy fundamentally.
NICE technology appraisals and the NHS Genomic Test Directory evolve; verify current eligibility, prior-treatment and commissioning criteria at the actual prescribing decision.
Immune-related toxicity can affect lung, bowel, liver, endocrine organs, kidney, skin, heart or nervous system and can present after the last checkpoint-inhibitor dose.
Supportive and palliative care, smoking support, symptom control, nutrition and advance care planning should run alongside active anticancer treatment, not be reserved for its end.

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

Tobacco smoke

Cumulative exposure to tobacco carcinogens causes most cases, with risk persisting after cessation while gradually declining.

Environmental and occupational carcinogens

Radon, asbestos, silica, diesel exhaust and air pollution add risk independently and may interact with smoking.

Molecularly driven disease

Some tumours, particularly adenocarcinomas in never-smokers, arise through targetable oncogenic alterations without a heavy tobacco history.

Host susceptibility

Age, family history, previous thoracic radiotherapy and fibrotic lung disease increase risk through accumulated or inherited vulnerability.

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

1
Clonal epithelial transformation
Accumulated genomic and epigenetic damage gives a bronchial or alveolar epithelial cell sustained growth and survival advantages.
2
Local tumour growth
The clone invades airway, parenchyma and adjacent structures, causing obstruction, collapse, bleeding or pain according to location.
3
Angiogenesis and immune escape
Tumour cells recruit blood supply and suppress antitumour immunity, enabling expansion beyond normal tissue constraints, which links the underlying lesion to the observed respiratory dysfunction.
4
Lymphatic and blood spread
Malignant cells reach regional nodes and distant organs, establishing stage-dependent metastatic disease and systemic symptoms, contributing to the resulting loss of respiratory reserve.

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

Early localised NSCLC

A peripheral primary without nodal or distant disease may be asymptomatic or incidentally detected; resectability and cardiopulmonary reserve, not symptom burden, drive curative planning.

Locally advanced disease

Mediastinal nodal involvement, chest-wall or mediastinal invasion and superior sulcus anatomy require precise staging because potentially curative multimodality options may remain.

Metastatic disease

Bone pain, neurological change, adrenal or liver lesions, pleural malignancy and distant nodes establish different disease burdens; a solitary suspected metastasis often merits confirmation before abandoning curative intent.

Oncogene-driven phenotype

Driver alterations occur across clinical groups and cannot be assigned safely from age or smoking history; molecular testing, not stereotype, should determine targeted-treatment eligibility.

Immune-related adverse event

New diarrhoea, breathlessness, jaundice, severe fatigue, headache, hypotension, rash or weakness during or after checkpoint inhibition should trigger organ-specific toxicity assessment and urgent oncology contact.

Red flags requiring action

New focal deficit, seizure, cord-compression features, severe hypercalcaemia, major haemoptysis or superior vena cava obstruction needs emergency treatment alongside oncological reassessment.
Acute hypoxaemia or diffuse lung change during immunotherapy may represent pneumonitis; withhold further doses and obtain urgent oncology and respiratory assessment rather than assuming infection alone.
Fever or shock during cytotoxic therapy may represent neutropenic sepsis and requires the local emergency antibiotic pathway without waiting for routine clinic contact.
Immune-related myocarditis, severe colitis, adrenal crisis or neurological toxicity can deteriorate rapidly and requires urgent specialist management even when the most recent dose was weeks earlier.
Do not start a non-emergency advanced-disease regimen without checking outstanding molecular and PD-L1 results, because the wrong sequence can reduce benefit or increase harm.

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
Pathology reviewFirst step
Why
Confirm NSCLC subtype and adequacy for predictive testing.
Interpretation and limitations
Integrate morphology and immunohistochemistry while conserving tissue; non-squamous, squamous and not-otherwise-specified results lead to different testing and treatment considerations.
02
TNM staging with CT and PET-CT
Why
Define local, nodal and distant extent before curative treatment selection.
Interpretation and limitations
Verify suspicious sites that would change intent where feasible; inflammatory FDG uptake and small occult metastases limit an uncritical binary reading.
03
Invasive mediastinal staging
Why
Confirm nodal disease when PET-CT findings or tumour anatomy affect radical strategy.
Interpretation and limitations
EBUS or EUS is generally used first for accessible nodes, with surgical staging considered when a negative result remains discordant with substantial risk.
04
Pulmonary function and exercise assessment
Why
Estimate risk from lung resection or radical thoracic therapy.
Interpretation and limitations
Use spirometry and gas transfer with predicted postoperative or exercise testing when indicated; optimise reversible disease and discuss alternatives rather than imposing one cut-off alone.
05
NHS genomic panel
Why
Detect actionable alterations using the current national test directory.
Interpretation and limitations
Tissue quality, tumour fraction and turnaround matter; plasma testing can complement selected pathways, but an uninformative result may require tissue reassessment rather than meaning no driver.
06
PD-L1 immunohistochemistry
Why
Inform eligibility and regimen selection for checkpoint-inhibitor treatment.
Interpretation and limitations
Interpret with stage, driver status, histology and current NICE appraisal; PD-L1 is predictive but imperfect and does not make immunotherapy universally appropriate.
07
Response imaging
Why
Assess disease trajectory after local or systemic treatment.
Interpretation and limitations
Compare target and non-target lesions with treatment timing; immune inflammation or post-radiotherapy change can mimic progression and may require MDT review or tissue.

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

Small-cell lung cancer

Small-cell morphology, neuroendocrine markers and rapid widespread course distinguish a cancer with different staging and systemic treatment strategy.

Pulmonary metastasis

Known extrapulmonary cancer, multiple nodules and comparative histology may indicate secondary disease rather than a new lung primary.

Granulomatous infection

Tuberculosis and fungal disease can form masses, cavities or nodes; exposure, microbiology and tissue prevent erroneous cancer treatment.

Inflammatory nodule

Organising pneumonia, sarcoidosis and rheumatoid nodules may mimic malignancy on imaging, including metabolic uptake, and corroborating objective findings prevent an incorrect diagnostic label.

Benign pulmonary tumour

Stable morphology, fat or characteristic calcification may support a benign lesion, but growth and risk require validated pathway assessment.

Additional chapter-specific clues

Treatment complication versus progression

Radiation pneumonitis, infection, pulmonary embolism, immune pneumonitis and tumour progression can all cause new dyspnoea or CT change; timing and pattern guide but do not replace investigation.

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

01EARLYPlan curative local treatmentFirst stepNSCLC appears confined to the lung and regional nodes with no confirmed distant disease.

1Complete PET-CT, appropriate mediastinal staging and physiological assessment, verifying any solitary finding that would remove curative intent when feasible.
2For operable resectable disease, discuss anatomical resection and systematic nodal assessment with thoracic surgery, incorporating minimally invasive approaches when appropriate.
3For a patient unsuitable for or declining surgery, consider stereotactic ablative radiotherapy or another radical radiotherapy option through the lung MDT.
4DefinitiveAfter definitive treatment, review final pathology and current NICE indications for adjuvant systemic or targeted treatment, then place the patient in a structured follow-up plan.

02STAGE IIICoordinate multimodality therapyDisease is locally advanced without confirmed distant metastasis and radical treatment may remain feasible.

1Confirm nodal and distant stage carefully and assess pulmonary function, performance, comorbidity and radiotherapy volume before defining resectability.
2Discuss jointly among thoracic surgery, clinical oncology, medical oncology, respiratory medicine, radiology and pathology because stage III subgroups require different sequences.
3For unresectable suitable disease, consider concurrent chemoradiotherapy where tolerable or a sequential approach when risk makes concurrence unsuitable, following current NICE guidance.
4DefinitiveAfter definitive chemoradiotherapy, review response, driver status and current funded consolidation options rather than assuming one post-treatment strategy for every tumour.

03ADVANCEDPersonalise first systemic treatmentStage IV or recurrent NSCLC needs disease-controlling systemic therapy and no immediate oncological emergency mandates treatment first.

1Confirm histology, performance status, organ function, symptom burden, genomic results and PD-L1, checking the current NHS directory and NICE technology appraisals.
2Use an approved targeted therapy first when an actionable driver and indication are present; otherwise select immunotherapy-based or cytotoxic treatment by PD-L1, histology and fitness.
3Build toxicity education, emergency contacts, baseline organ assessment and early response review into the prescription, while treating pain, dyspnoea and psychosocial needs.
4At progression, distinguish systemic progression, oligoprogression, toxicity and pseudo-progression before choosing local treatment, another systemic line or supportive care.

04TOXICITYRespond to immune-mediated illnessA patient receiving or previously exposed to checkpoint inhibition develops a new inflammatory, endocrine or cardiorespiratory syndrome.

1Hold further immunotherapy for clinically significant suspected toxicity and contact the treating acute oncology service while assessing ABCDE and severity.
2Exclude dangerous alternatives such as infection, pulmonary embolism, tumour progression or medication toxicity using organ-directed blood tests, imaging and cultures.
3Start severity-appropriate specialist management, which may include corticosteroids and additional immunosuppression under protocol, without delaying resuscitation or antimicrobials when indicated.
4Plan taper, prophylaxis, endocrine replacement if needed and the decision about rechallenge with oncology because recurrence risk and cancer benefit vary by organ and grade.

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

Targets sensitising EGFR-mutated NSCLC in defined advanced, adjuvant or post-chemoradiotherapy settings.

Osimertinib

Oral once-daily specialist regimen according to current SmPC and funded NICE indication.

Confirm the qualifying alteration and indication; monitor electrocardiographic, cardiac, ocular and pulmonary toxicity, and investigate new breathlessness urgently for drug-related pneumonitis.

Checkpoint inhibitor used alone or in combinations for selected NSCLC defined by stage, biomarkers and NICE eligibility.

Pembrolizumab

Intravenous fixed-dose schedule administered by oncology according to the licensed regimen.

Immune toxicity can affect any organ and occur after cessation; check driver status, autoimmune context, transplant history, infection and concurrent immunosuppression before treatment.

Provides perioperative, chemoradiotherapy or advanced-disease treatment when histology, stage and fitness support benefit.

Platinum-based chemotherapy

Intravenous combination cycles calculated and adjusted by oncology protocol and organ function.

Myelosuppression, infection, renal or neurological toxicity, hearing effects, nausea and thrombosis require regimen-specific assessment; frailty and kidney function influence agent selection.

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

Airway obstruction

Endobronchial growth causes lobar collapse, post-obstructive pneumonia, wheeze and progressive respiratory failure, adding morbidity beyond the initial pulmonary disorder.

Pleural and pericardial disease

Malignant effusion compresses lung or heart and usually signifies advanced spread, requiring urgent symptom control when physiologically important.

Metastatic organ injury

Brain, bone, liver and adrenal metastases cause neurological deficits, fracture, pain, metabolic disturbance and organ dysfunction.

Venous thromboembolism

Cancer-associated coagulation and treatment increase deep-vein thrombosis and pulmonary embolism risk, and increasing the burden of otherwise local respiratory disease.

Treatment-related pulmonary harm

Surgery, radiotherapy, systemic therapy and immunotherapy can cause pneumonitis, infection, reduced reserve or other toxicity requiring specialist distinction from progression.

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

Before systemic treatment, record symptoms, performance status, weight, organ function, comorbidity, concomitant medicines and all outstanding genomic or PD-L1 results.
During targeted therapy, use agent-specific blood, electrocardiographic, cardiac and imaging surveillance and investigate new pulmonary symptoms rather than automatically labelling progression.
During immunotherapy, ask directly about bowel, respiratory, skin, endocrine, neurological, cardiac, renal and hepatic symptoms at every contact and beyond the last dose.
During cytotoxic treatment, monitor full blood count, renal and hepatic function, infection, neuropathy, hearing or emesis according to the chosen agents and local protocol.
Assess response at clinically meaningful intervals using symptoms and comparable imaging; an apparent isolated progression should be reviewed for local treatment or diagnostic uncertainty.
After curative therapy, coordinate surveillance, smoking support, rehabilitation and management of treatment sequelae, with clear routes for new haemoptysis, pain or neurological symptoms.

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

Stage is not the whole patient

Two people with identical TNM disease may need different plans because pulmonary reserve, frailty, values and tumour biology alter both benefit and risk.

Do not infer the genotype

Smoking history and phenotype shift probability but cannot replace testing. Missing an actionable driver can expose a patient to a less effective first sequence.

Solitary metastasis deserves scrutiny

When one distant lesion alone changes treatment from curative to palliative, pathological or high-confidence multidisciplinary confirmation may prevent major mis-staging.

Toxicity can mimic cancer

Checkpoint pneumonitis, radiation change and infection can resemble progression on symptoms and CT. Timing, distribution, cultures and MDT review guide safe separation.

Guidance is dynamic

New targeted and immune indications enter NICE guidance frequently. Teach the decision structure and verify the live appraisal rather than memorising a frozen drug list.

Palliative care is concurrent

Early specialist symptom support can improve breathlessness, pain, communication and planning while anticancer treatment continues; it does not signal therapeutic abandonment.

11Common pitfallsFrequent interpretation and management errors.

01
Choosing treatment from stage alone without confirming histology, molecular drivers, PD-L1, physiological fitness and the patient's priorities.
02
Starting non-urgent advanced-disease chemotherapy while predictive genomic results are pending and may indicate a better first-line targeted option.
03
Treating PET-positive mediastinal nodes as proven cancer when pathological confirmation could preserve a curative plan.
04
Assuming chronological age automatically excludes surgery or multimodality treatment without formal cardiopulmonary and frailty assessment.
05
Calling new breathlessness progression during immunotherapy without investigating pneumonitis, infection, embolism and cardiac toxicity.
06
Continuing checkpoint treatment through a significant suspected immune adverse event without urgent oncology discussion.
07
Quoting an old NICE drug indication from memory instead of checking current biomarker, stage, prior-treatment and commissioning criteria.