OncologyTier 1Disease (DEADMAN)

Cancer - lung

Description

Two therapeutic categories

	NSCLC (~85%)	SCLC (~15%)
Location	Peripheral (adeno) / central (SCC)	Central, bulky mediastinal
Smoking	Variable	Almost universal
Growth	Slower	Very rapid, early dissemination
Surgery	Curative in early stage	Essentially never
Staging	TNM I-IV	Limited vs extensive stage
Paraneoplastic	PTHrP (SCC), HPOA	SIADH, Cushing's, LEMS, encephalitis

NSCLC subtypes

Adenocarcinoma ~50% - peripheral, glandular/mucin
- TTF-1 +, napsin-A +, CK7 +
- Commonest subtype in never-smokers; richest source of targetable drivers
Squamous ~20-30% - central, cavitates, endobronchial
- p40/p63 +, CK5/6 +, CK7 -
- Strongly smoking-linked; often high PD-L1; PTHrP hypercalcaemia
- Cavitation and haemoptysis - avoid bevacizumab (fatal haemorrhage)
Large cell, adenosquamous, sarcomatoid - uncommon

SCLC

Neuroendocrine: small cells, scant cytoplasm, nuclear moulding, high mitotic rate
Chromogranin, synaptophysin, CD56, INSM1 +
RB1 and TP53 inactivated in ~90%
Chemo- and radio-sensitive, but relapses fast

Other thoracic malignancy to distinguish

Carcinoid - low-grade neuroendocrine, non-smoker, endobronchial, octreotide-avid
Mesothelioma - separate entity (see mesothelioma)

Epidemiology

Leading cause of cancer death in Australia (~8,700 deaths/yr) despite being 5th commonest cancer
~15,000 new cases/yr; median age ~72
Smoking causes ~80-90%; incidence falling in men, plateauing/rising in women
Never-smoker lung cancer rising as a proportion - predominantly adenocarcinoma, driver-positive, younger, F>M
Aboriginal and Torres Strait Islander peoples: ~2x incidence, worse stage at diagnosis

Aetiopathogenesis

Risk factors

Smoking - dominant
- Current smoker RR ~9 overall; RR 14-24 if >20/day
- Ex-smoker RR ~4 - risk falls but never returns to baseline
Radon - 2nd commonest cause; granite geology, basements
Asbestos - synergistic (multiplicative) with smoking
Occupational - arsenic, chromium, nickel, silica, diesel exhaust, PAHs
Prior chest RT (Hodgkin, breast)
Pulmonary fibrosis (IPF), COPD (independent of smoking), HIV
Family/personal history of lung cancer

Familial

Retinoblastoma (RB1) - RB1 inactivated in ~90% of SCLC
Li-Fraumeni (TP53)
Inherited EGFR T790M (very rare)

Driver mutations - test every non-squamous NSCLC

Drivers are near-mutually exclusive. Reflex broad NGS panel + PD-L1 on all non-squamous and never-smoker squamous.

Driver	Frequency	Phenotype	Drug
KRAS	20-40%	Smokers, Western	G12C: sotorasib, adagrasib
EGFR	~15% (Asian ~30%, Western ~10%)	Never/light smoker, young, F, adeno	Osimertinib
ALK (EML4-ALK)	~5%	Young, never-smoker, any ethnicity	Alectinib, lorlatinib
ROS1	1-2%	Young never-smoker	Entrectinib, repotrectinib
BRAF V600E	~2%	-	Dabrafenib + trametinib
MET ex14 skip	3-4%	Older	Capmatinib, tepotinib
RET fusion	1-2%	-	Selpercatinib
HER2	~2%	-	Trastuzumab deruxtecan
NTRK	<1%	-	Larotrectinib

EGFR exon 20 insertion does NOT respond to standard TKIs -> amivantamab

Diagnosis

Tissue is mandatory

Biopsy, not cytology alone - need histology + adequate tissue for molecular panel and PD-L1
Route by site: EBUS-TBNA (mediastinal nodes, one-stop diagnosis + staging), bronchoscopy (central), CT-guided core (peripheral), VATS, or biopsy the most accessible metastasis
Plasma ctDNA if tissue insufficient or urgent (negative result does not exclude a driver)

Staging

PET-CT - more sensitive than CT for mediastinal nodes and occult mets
- A PET-positive node must be sampled - upstages and changes intent
CT/MRI brain for all considered for curative therapy, and all SCLC (MRI preferred)
SCLC: limited stage = confined within one tolerable radiation field

Incidental pulmonary nodule

>=6 mm triggers structured follow-up (Fleischner)
Higher risk: upper lobe, spiculated, solid growth, part-solid with growing solid component, smoker, older, prior cancer
Part-solid nodules: the solid component is what matters
<6 mm in a low-risk patient - no routine follow-up

Screening - Australia

National Lung Cancer Screening Program (from July 2025): biennial low-dose CT
- Age 50-70, asymptomatic
- >=30 pack-year history
- Current smoker, or quit within the last 10 years
Based on NLST (dec lung cancer mortality ~20%) and NELSON (~24% in men)

Management

A. NSCLC stage I-II

Anatomical resection (lobectomy) + mediastinal nodal dissection if fit
- Segmentectomy acceptable for peripheral <=2 cm
SABR if medically inoperable (COPD, elderly) - stage I outcomes approach surgery
Adjuvant cisplatin doublet for resected stage II-III (and IB >4 cm)
Adjuvant osimertinib 3 yr if EGFR-mutant, stage IB-IIIA (ADAURA - OS benefit)
Adjuvant alectinib 2 yr if ALK-positive (ALINA)
Perioperative immunotherapy for resectable, driver-negative stage II-III
- Neoadjuvant nivolumab + chemo x3 (CheckMate 816), or perioperative pembrolizumab/durvalumab (KEYNOTE-671, AEGEAN)
- Do not give immunotherapy to EGFR/ALK-positive disease - no benefit, and inc pneumonitis if a TKI follows

B. NSCLC stage III

Resectable, non-bulky N2 -> neoadjuvant chemo-immunotherapy then surgery
Unresectable -> concurrent chemoradiotherapy
- RT is the definitive modality; platinum doublet (cisplatin-etoposide or carboplatin-paclitaxel) acts as radiosensitiser
- -> consolidation durvalumab 12 months (PACIFIC; median OS 47.5 vs 29.1 mo; benefit regardless of PD-L1)
- -> if EGFR-mutant, consolidation osimertinib instead (LAURA)

C. NSCLC stage IV - the algorithm

Step 1: driver mutation? -> targeted TKI first line

EGFR -> osimertinib (+/- chemotherapy, or amivantamab-lazertinib in high-risk)
ALK -> alectinib or lorlatinib (second-gen preferred: crizotinib fails in the CNS)
ROS1, BRAF, MET, RET, NTRK, KRAS G12C -> matched agent
Re-biopsy at progression - resistance mechanisms (MET amplification, small cell transformation) change therapy

Step 2: no driver -> PD-L1 status

PD-L1 >=50% -> pembrolizumab monotherapy
PD-L1 <50% -> platinum doublet + pembrolizumab
- Non-squamous: carboplatin/pemetrexed; squamous: carboplatin/paclitaxel
Second line after chemo alone: nivolumab > docetaxel (CheckMate 017 squamous, 057 non-squamous)
Bevacizumab only in non-squamous, non-haemoptysis

D. SCLC

Limited stage - concurrent platinum-etoposide + thoracic RT (start RT early, cycle 1-2)
- -> consolidation durvalumab (ADRIATIC - OS benefit, new standard)
- Consider PCI (or MRI surveillance) after response
Extensive stage - carboplatin-etoposide + atezolizumab or durvalumab, then maintenance
- Tarlatamab (DLL3 bispecific T-cell engager) at relapse - OS benefit vs chemo
  - Cytokine release syndrome and ICANS - first doses in hospital
- Topotecan or lurbinectedin otherwise
Palliative RT for local symptoms; SCLC responds fast then relapses fast

E. Targeted therapy toxicity

EGFR TKIs
- Acneiform rash weeks 2-4 - predicts response; treat, don't stop (doxycycline, topical steroid)
- Diarrhoea, paronychia, nail and hair change, dry eye
- Osimertinib: rash ~58%, diarrhoea ~58%, QT prolongation ~10%, cardiomyopathy
- *Pneumonitis - insidious dry cough + dyspnoea; stop TKI, high-dose steroids*
ALK TKIs - visual disturbance (light/dark adaptation), transaminitis, bradycardia/QT, oedema, pneumonitis (<2%)
- Lorlatinib: hypercholesterolaemia, CNS/mood effects
Immunotherapy - see irAE note; pneumonitis is the shared trap with both TKIs and RT

F. Supportive

Smoking cessation at every stage - improves treatment tolerance and survival even in metastatic disease
Early palliative care referral in metastatic NSCLC improves QoL and survival
Bone mets -> denosumab/zoledronic acid; brain mets -> SRS preferred over WBRT

Associations

COPD and emphysema (shared cause, independent risk)
Pulmonary fibrosis, esp. IPF
Asbestos exposure - synergistic with smoking; also mesothelioma, asbestosis, pleural plaques
Head/neck, oesophageal, bladder cancer (field cancerisation from smoking)
Hypertrophic pulmonary osteoarthropathy - clubbing + periostitis (NSCLC)
SIADH, ectopic ACTH/Cushing's, LEMS, anti-Hu paraneoplastic encephalomyelitis/cerebellar degeneration (SCLC)
Hypercalcaemia via PTHrP (squamous)
Superior vena cava obstruction, Pancoast tumour (Horner's + T1 wasting), recurrent laryngeal palsy
Venous thromboembolism
Retinoblastoma, Li-Fraumeni

Natural history & complications

~5-yr survival all stages Australia ~24%; stage I ~70-90%, stage IV ~5-10%
Two-thirds present at stage III/IV - no symptoms until locally advanced

SCLC

Median OS limited stage ~30 mo (better with ADRIATIC); extensive stage ~12-13 mo
Near-universal relapse; platinum-sensitive relapse = >6 months and predicts re-challenge response

Driver-positive NSCLC

Osimertinib first-line median PFS ~19 mo, OS ~38 mo
Alectinib median PFS ~35 mo; lorlatinib longer
Transforms metastatic disease into a chronic illness with sequential resistance - not a cure

Complications to anticipate

Post-obstructive pneumonia, haemoptysis (massive with cavitating squamous)
Malignant pleural effusion -> IPC or pleurodesis
SVC obstruction, cord compression, brain metastases
Bone metastases, pathological fracture
Cachexia
Treatment-related: radiation pneumonitis/fibrosis, immune toxicity, TKI pneumonitis

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