Lung cancer
Description
The primary division: small cell vs non-small cell
| NSCLC (~85%) | SCLC (~15%) | |
|---|---|---|
| Behaviour | Local then regional then distant | Disseminated at presentation in ~2/3 |
| Surgery | Cornerstone in early stage | Almost never |
| Driver mutations | Common in adenocarcinoma | Essentially none actionable |
| Chemo/RT sensitivity | Moderate | Exquisite, but relapses |
| Paraneoplastic | Hypercalcaemia (SCC), HPOA | SIADH, ectopic ACTH, LEMS, encephalomyelitis |
NSCLC subtypes
- Adenocarcinoma (~40%, and rising) - the commonest subtype in Australia
- Peripheral; the subtype in never-smokers, women, Asian ancestry
- Most likely to carry a targetable driver (EGFR, ALK, ROS1, RET, MET, BRAF, KRAS G12C, NTRK, HER2)
- TTF-1 and napsin A positive
- Squamous cell (~25-30%) - central, cavitates, strongly smoking-related
- PTHrP -> hypercalcaemia; p40/p63/CK5-6 positive
- Large cell / neuroendocrine (~5-10%)
- Carcinoid - low grade neuroendocrine; young, non-smokers; carcinoid syndrome is rare from a lung primary without liver metastases
SCLC
- Central, bulky mediastinal nodal disease, rapid doubling time, near-universally in heavy smokers
- Neuroendocrine markers: chromogranin, synaptophysin, CD56, high Ki-67 (>50-90%)
- Limited stage (confinable to one tolerable radiotherapy port) vs extensive stage
Named presentations
- Pancoast (superior sulcus) tumour - apical; shoulder/arm pain (C8-T1), Horner syndrome, small muscle wasting of the hand, rib destruction
- SVC obstruction - facial and arm swelling, distended non-pulsatile neck veins, Pemberton sign
- Lambert-Eaton myasthenic syndrome - SCLC; proximal weakness that improves with repetition, absent reflexes that return after exercise, autonomic features
Epidemiology
- Leading cause of cancer death worldwide and in Australia, despite not being the most commonly diagnosed cancer
- ~15,000 Australian diagnoses/yr; ~8,700 deaths/yr
- 5-year survival ~26% overall - the poorest of the major cancers, because ~half present with metastatic disease
- M>F, but the gap is closing; incidence falling in men, plateauing/rising in women
- Aboriginal and Torres Strait Islander peoples ~2x incidence and mortality
- ~15-20% of Australian cases occur in never-smokers - a distinct disease: adenocarcinoma, younger, female, driver-mutation enriched
- Adenocarcinoma has overtaken squamous cell as smoking patterns and cigarette design changed
Aetiopathogenesis
Risk factors
- Tobacco smoking - ~80-90% of attributable risk; dose- and duration-related
- Risk falls after cessation but never returns to never-smoker baseline
- Second-hand smoke, radon (2nd commonest cause in never-smokers)
- Asbestos - multiplicative with smoking (~50-90x combined vs ~5x asbestos alone)
- Silica, diesel exhaust, arsenic, chromium, nickel, cadmium, beryllium, engineered stone dust
- Air pollution (PM2.5), indoor biomass fuel
- Pre-existing lung disease: COPD (independent of smoking), pulmonary fibrosis (~5-10x), prior TB
- Prior thoracic radiotherapy, HIV, family history
Driver mutations - the whole basis of modern NSCLC treatment
| Driver | Frequency (adeno) | Notes |
|---|---|---|
| KRAS | ~25-30% - commonest | G12C now targetable (sotorasib, adagrasib); mutually exclusive with EGFR |
| EGFR | ~10-15% Caucasian, ~40-50% East Asian | Exon 19 del, L858R = sensitising; T790M = resistance |
| ALK | ~4-5% | Young, never-smokers |
| ROS1, RET, NTRK, MET exon 14, BRAF V600E, HER2 | 1-3% each | All have approved targeted agents |
- *Test every non-squamous NSCLC (and never-smoker squamous) for the full panel plus PD-L1 before starting systemic therapy*
- SCLC and squamous cell rarely harbour actionable drivers
Molecular pathology
- Smoking -> polycyclic aromatic hydrocarbons, nitrosamines -> high tumour mutational burden
- High TMB predicts immunotherapy response - why smokers respond better to checkpoint inhibitors than never-smokers with driver mutations
- TP53 and RB1 loss - near-universal in SCLC
- Adenocarcinoma sequence: atypical adenomatous hyperplasia -> adenocarcinoma in situ -> minimally invasive -> invasive
Diagnosis
Presentation
- Local: cough (change in a smoker's cough), haemoptysis, dyspnoea, chest pain, recurrent or non-resolving pneumonia, monophonic wheeze/stridor
- Regional: hoarseness (recurrent laryngeal nerve), SVC obstruction, dysphagia, Horner syndrome, phrenic palsy, pleural or pericardial effusion, arrhythmia
- Metastatic: bone pain, hypercalcaemia, neurological deficit or seizure (brain), jaundice/RUQ pain (liver), adrenal, skin nodules
- Systemic: weight loss, anorexia, fatigue, clubbing
- Paraneoplastic (see Associations)
- Increasingly, an incidental nodule or a screen-detected lesion in an asymptomatic person
Screening - Australia has a national programme since July 2025
National Lung Cancer Screening Program (NLCSP)
- Age 50-70, asymptomatic
- >=30 pack-year history
- Currently smoking, or quit within the past 10 years
- Biennial low-dose CT via Medicare; interval scans at 3, 6 or 12 months by nodule risk category
- Smoking cessation support is embedded in the programme; smoking cessation is not a condition of participation
- Evidence base: NLST (dec lung cancer mortality 20%) and NELSON (dec 24% in men)
Imaging and staging
- CXR - normal in a significant minority; a normal CXR never excludes lung cancer
- CT chest/abdomen with contrast (adrenals) - characterise, stage
- FDG-PET/CT - mandatory before any radical treatment; upstages ~20%
- False positives: infection, sarcoid, inflammation. False negatives: carcinoid, bronchioloalveolar/lepidic adenocarcinoma, lesions <8 mm
- MRI brain - all stage III and above, all SCLC, all considered for curative therapy
- Bone scan only if PET unavailable
Tissue - get the most informative biopsy, staging the highest node
- EBUS-TBNA - the standard for mediastinal staging; samples N2/N3 stations
- Bronchoscopy for central lesions; CT-guided percutaneous biopsy for peripheral (pneumothorax ~15-25%)
- Pleural fluid cytology / thoracoscopy; biopsy an accessible metastasis if one exists (it stages and diagnoses at once)
- Mediastinoscopy if EBUS negative and suspicion remains
- Send enough tissue for immunohistochemistry + full molecular panel + PD-L1 - rebiopsy for inadequate material is a common and avoidable delay
- Liquid biopsy (plasma ctDNA) where tissue is insufficient or urgent
Staging - TNM 9th edition, in use since January 2025
- Key change: N2 is now split by nodal burden
- N2a - single ipsilateral mediastinal/subcarinal station
- N2b - multiple ipsilateral mediastinal stations
- M1c split: M1c1 (multiple lesions, one extrathoracic organ) vs M1c2 (multiple organs)
- T and M1a/M1b descriptors unchanged; stage groupings redistributed accordingly
- SCLC is still described as limited vs extensive stage in practice, though TNM is applied
Fitness for radical treatment
- Spirometry and DLCO; predicted post-operative FEV1 and DLCO >40% generally required
- CPET if borderline - VO2max >20 mL/kg/min = low risk; <10 = prohibitive
- Cardiac assessment, performance status (ECOG), nutrition, frailty
- *Every case through a lung cancer MDT*
Solitary pulmonary nodule
- Risk features: size, spiculation, upper lobe, growth, age, smoking, prior cancer (Brock model)
- Benign features: fat (hamartoma), popcorn or central/laminated calcification, stability >2 years
- Subsolid nodules grow slowly, need longer follow-up; a growing solid component in a part-solid nodule signals invasion
Management
Every case: MDT, smoking cessation, symptom control, and staging complete before treatment.
NSCLC by stage
### A. Stage I-II (early, resectable)
- Lobectomy with systematic mediastinal nodal dissection - preferably VATS/robotic
- Sublobar resection (segmentectomy) is non-inferior for peripheral tumours <=2 cm with adequate margins (JCOG0802, CALGB140503)
- SABR/SBRT if medically inoperable or refusing surgery - excellent local control
- Adjuvant therapy after resection:
- Adjuvant cisplatin-based chemotherapy for stage II-III (and IB >4 cm)
- Adjuvant osimertinib for 3 years if EGFR exon 19del/L858R (ADAURA - DFS and OS benefit)
- Adjuvant alectinib if ALK-positive (ALINA)
- Adjuvant atezolizumab or pembrolizumab if PD-L1 positive and driver-negative
- Perioperative/neoadjuvant immunochemotherapy (nivolumab CheckMate-816; perioperative pembrolizumab KEYNOTE-671, durvalumab AEGEAN) for resectable stage II-IIIA driver-negative disease
- *Do not give neoadjuvant immunotherapy to EGFR/ALK-positive disease* - poor response and inc toxicity with subsequent TKI
### B. Stage III (locally advanced)
- Heterogeneous - the MDT decides resectable vs not
- Unresectable stage III: concurrent chemoradiotherapy, then consolidation durvalumab for 12 months (PACIFIC) - the standard of care
- Resectable: neoadjuvant chemo-immunotherapy then surgery
### C. Stage IV - biomarker-directed
Always test before treating.
- Driver mutation present -> targeted therapy first line
- EGFR -> osimertinib (+/- platinum-pemetrexed in selected; FLAURA2)
- ALK -> alectinib, brigatinib or lorlatinib
- ROS1 -> entrectinib, repotrectinib; RET -> selpercatinib; MET ex14 -> tepotinib/capmatinib
- BRAF V600E -> dabrafenib+trametinib; KRAS G12C -> sotorasib/adagrasib (2nd line)
- Choose CNS-penetrant agents - brain metastases are common in ALK and EGFR disease
- No driver, PD-L1 >=50% -> pembrolizumab monotherapy (or chemo-immunotherapy)
- No driver, PD-L1 <50% -> platinum doublet + pembrolizumab
- Immunotherapy is far less effective in EGFR/ALK-driven disease
- Maintenance pemetrexed in non-squamous
SCLC
- Limited stage: concurrent platinum-etoposide + thoracic radiotherapy
- Prophylactic cranial irradiation if good response (weigh against MRI surveillance and neurocognitive cost)
- Extensive stage: platinum-etoposide + atezolizumab or durvalumab, then maintenance immunotherapy
- Tarlatamab (DLL3 bispecific T-cell engager) for relapsed disease - watch for cytokine release syndrome and neurotoxicity
- Very chemosensitive initially; relapse is near-universal and rapidly chemoresistant
Oncological emergencies
- SVC obstruction - rarely a true emergency; get tissue first unless airway compromised. Steroid, stent, radiotherapy, chemotherapy for SCLC
- Spinal cord compression - dexamethasone immediately, urgent MRI whole spine, radiotherapy or surgery
- Malignant hypercalcaemia - IV fluids then zoledronic acid or denosumab
- Massive haemoptysis - lateral decubitus with the bleeding side down, bronchoscopy, embolisation
- Febrile neutropenia, tumour lysis (SCLC)
- Immune-related adverse events - colitis, pneumonitis, hepatitis, hypophysitis, thyroiditis, myocarditis. Treat with steroids; hold the checkpoint inhibitor; myocarditis carries very high mortality
Supportive and palliative
- *Early specialist palliative care improves quality of life AND survival in metastatic NSCLC (Temel et al.)*
- Malignant pleural effusion -> IPC or talc pleurodesis
- Airway obstruction -> stent, laser, brachytherapy, external beam RT
- Bone metastases -> radiotherapy, bone-modifying agent
- Smoking cessation even after diagnosis - improves treatment tolerance, surgical outcome and survival
Associations
Paraneoplastic syndromes
| Syndrome | Tumour |
|---|---|
| SIADH | SCLC |
| Ectopic ACTH (rapid onset, hypokalaemic alkalosis, hyperpigmentation, minimal Cushingoid habitus) | SCLC |
| Hypercalcaemia (PTHrP) | Squamous cell |
| Lambert-Eaton | SCLC |
| Cerebellar degeneration (anti-Yo/Hu), limbic encephalitis, encephalomyelitis, sensory neuronopathy | SCLC |
| Hypertrophic pulmonary osteoarthropathy (clubbing + painful periostitis of long bones) | NSCLC, esp. adenocarcinoma; also mesothelioma |
| Dermatomyositis, acanthosis nigricans, erythema gyratum repens, tripe palms | NSCLC |
| Migratory thrombophlebitis (Trousseau), NBTE, DIC | Adenocarcinoma |
| Anaemia, thrombocytosis, leukaemoid reaction, eosinophilia | Any |
| Nephrotic syndrome (membranous) | NSCLC |
| Carcinoid syndrome | Carcinoid, with liver metastases |
Comorbid and associated conditions
- COPD (~50-70% of patients), emphysema
- Pulmonary fibrosis - biopsy or resection may precipitate an acute exacerbation
- Cardiovascular disease, PVD
- VTE - markedly increased, especially adenocarcinoma and during chemotherapy
- Second primary malignancies - head and neck, oesophagus, bladder (shared smoking)
- Asbestos exposure -> concurrent pleural plaques, asbestosis, mesothelioma
- Depression, malnutrition, cachexia
Natural history & complications
- ~50% present with distant metastasis; only ~15-20% present with resectable disease
- Commonest metastatic sites: brain, bone, liver, adrenal, contralateral lung
5-year survival (approximate, NSCLC)
| Stage | Survival |
|---|---|
| I | 70-90% |
| II | 50-60% |
| III | 15-35% |
| IV | <10% (but markedly better with a targeted driver - median OS now measured in years) |
- SCLC: limited stage median ~20-25 months, ~25-30% 5-year with chemoradiation + PCI; extensive stage median ~12-15 months with chemo-immunotherapy
- Untreated SCLC: median survival 2-4 months - the fastest-moving common solid tumour
Prognostic factors
- Stage (dominant), performance status, weight loss >5%, sex (F better)
- Histology, driver mutation status (EGFR/ALK-positive disease has transformed survival)
- LDH, neutrophil-lymphocyte ratio, comorbidity
Follow-up after curative treatment
- CT surveillance for recurrence and second primaries (risk ~1-2%/yr)
- Ongoing smoking cessation support, pulmonary rehabilitation
- Late radiotherapy effects: pneumonitis (6 weeks-6 months), fibrosis, oesophagitis, cardiac toxicity
- Long-term TKI complications; immune-related endocrinopathies may be permanent
What to monitor for
- Recurrence, second primary, brain metastasis (low threshold for MRI in ALK/EGFR disease)
- Treatment toxicity - immune-related adverse events can occur months after the last dose
- Malnutrition, VTE, depression, pain
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access