Lung cancer metastasizes commonly to: ^[2]

Constitutional symptoms: malaise, weight loss, cachexia, loss of appetite ^[2]

• Mechanism: Tumour-derived cytokines (TNF-α, IL-6, IL-1) → systemic inflammatory response → cancer cachexia (muscle wasting, anorexia, fatigue).
• Weight loss is a poor prognostic indicator.
• Fever may occur due to tumour necrosis, post-obstructive pneumonia, or paraneoplastic mechanisms.

Pancoast Syndrome (Superior Sulcus Tumour)

Pancoast's syndrome = Horner's syndrome + brachial plexopathy + shoulder pain + small hand muscle wasting ^[2][3]

• Pancoast tumour: apical lung tumour (usually NSCLC) invading:
  • Stellate ganglion / cervical sympathetic chain → Horner's syndrome (ipsilateral miosis [small pupil], partial ptosis [drooping lid], anhidrosis [absent sweating], apparent enophthalmos [sunken eye])
  • Brachial plexus (C8–T1) → pain along medial arm/forearm (ulnar distribution), weakness and wasting of intrinsic hand muscles
  • First/second ribs, vertebral bodies → shoulder pain, rib destruction

Superior Vena Cava Obstruction (SVCO)

SVCO: puffy face, dilated chest veins, Pemberton's sign ^[2][3][13]

• Most common cause: lung cancer (especially SCLC and right-sided tumours, because the SVC is on the right).
• Pemberton's sign: raising both arms above head for > 1 minute → facial plethora, cyanosis, distended neck veins (due to thoracic inlet compression worsening SVC obstruction).
• This is an oncological emergency — requires urgent treatment. ^[13]

Phrenic Nerve Palsy

• Elevated hemidiaphragm on CXR → paradoxical upward movement on sniffing (sniff test / fluoroscopy). ^[2]

CXR raises suspicion of malignancy but is non-diagnostic. ^[21]

• Role: First-line screening investigation when lung cancer is suspected. Cheap, quick, widely available, low radiation.
• Why it is non-diagnostic: A CXR cannot tell you what a lesion is — only that there is an abnormal shadow. A 1 cm nodule can be missed, especially if retrocardiac or behind the diaphragm.

Key CXR findings in CA lung:

Contrast CT thorax + upper abdomen is the modality of choice for diagnosis and staging. ^[21]

• Why contrast: Intravenous contrast enhances vascular structures, allowing differentiation of tumour from vessels and assessment of mediastinal invasion. Without contrast, you lose critical staging information.
• Coverage must include liver and adrenals ^[21] — because these are common metastatic sites.

Key CT findings and their interpretation:

PET-CT has high sensitivity for occult metastasis. ^[21]

Principle: Injection of 18FDG tracer → tissues with increased metabolic rate show increased glucose uptake → tracer retained because FDG cannot be incorporated into glycolysis → tissues with increased metabolic rate will "light up" (SUVmax > 2.5). ^[21]

• "PET" = Positron Emission Tomography. The tracer (FDG = fluoro-deoxy-glucose) is a glucose analogue. Cancer cells are metabolically active ("Warburg effect" — preferential aerobic glycolysis) → they take up more FDG than normal tissue.
• PET alone has low resolution → combination with CT provides anatomical detail. ^[21]

Roles of PET-CT in lung cancer:

Imaging with CT scans or PET-CT scans help in diagnosis, staging and identifying sites for biopsy. ^[26][28]

MRI thorax: ^[21]

• Advantage: good soft tissue differentiation
• Disadvantage: only anatomical detail, expensive
• Indication: if symptoms suggestive of:
  • Staging of Pancoast tumour (frequent soft tissue invasion)
  • Assessment of chest wall/brachial plexus invasion
• MRI brain: Gold standard for detecting brain metastases (superior to CT and PET-CT for this purpose). Indicated when there are neurological symptoms or in advanced disease for staging.

• Largely replaced by PET-CT in centres where PET is available.
• Still used if PET-CT unavailable. High sensitivity for osteoblastic metastases but cannot distinguish degenerative from metastatic disease well.

Sputum cytology ^[26][28]

• Method: Collect sputum (ideally early morning × 3 consecutive days) → cytological examination for malignant cells.
• Best for: Central tumours that exfoliate cells into the airway (SCC, SCLC).
• Limitations: Low sensitivity (~60-70% for central, ~20% for peripheral lesions). A negative result does NOT exclude malignancy. Being increasingly replaced by bronchoscopy.
• Still useful as a non-invasive first step, especially in patients too frail for bronchoscopy.

Flexible bronchoscopy with bronchial lavage and biopsy ^[26][28]

• Principle: A flexible fibre-optic scope is passed through the nose/mouth → trachea → bronchi, allowing direct visualisation of the airway mucosa down to subsegmental level.
• Best for: Central endobronchial lesions (visible tumour in the airway).

Techniques during bronchoscopy:

Limitations: Cannot reach peripheral lesions beyond subsegmental bronchi well. For peripheral nodules, CT-guided biopsy or surgical excision is preferred.

EBUS-TBNA ± EUS-FNA for mediastinal staging ^[21]

• Principle: A bronchoscope with an ultrasound probe at the tip → real-time ultrasound guidance → needle passed through bronchial wall into mediastinal/hilar lymph nodes.
• Why this matters: Mediastinal nodal status (N2/N3) is the single most important factor determining surgical resectability. N2 disease requires MDT assessment of station number, bulk, invasiveness, technical resectability and fitness. Selected patients may have surgery as part of multimodality treatment; N2 is not an automatic permanent contraindication. EBUS-TBNA provides tissue confirmation rather than relying on CT size alone.
• EUS-FNA (endoscopic ultrasound — fine needle aspiration via the oesophagus) is complementary, reaching stations inaccessible to EBUS (e.g., stations 8, 9, left adrenal).

Approach to mediastinal staging based on risk: ^[21]

Other means of obtaining lung tissue — percutaneous lung biopsy, usually done under CT guidance ^[26][28]

• Best for: Peripheral lung lesions not accessible by bronchoscopy.
• Method: Under CT guidance, a needle is advanced through the chest wall into the lesion. Can be fine-needle aspiration (FNA) for cytology or core biopsy (Trucut) for histology.
• Fine needle biopsy is quite accurate (80-95% accuracy) and safe ( < 2% complication rate). ^[25]
• Complications: Pneumothorax (~20-25%, but only ~5% requiring chest drain), haemoptysis, air embolism (rare).
• Contraindications: Uncorrected coagulopathy (platelets < 50,000 or INR > 1.5), inaccessible lesion (surrounded by bone/vessels), uncooperative patient ^[25].

Biopsy or cytology of metastatic lesions: e.g., pleural fluid, lymph nodes ^[26][28]

• If a patient has an accessible metastatic site (e.g., supraclavicular lymph node, pleural effusion, liver metastasis), biopsy of this site can simultaneously diagnose the cancer AND confirm the metastatic stage — this is the most efficient approach.
• Pleural fluid cytology: Send at least 20 mL × 3 samples for cytology. Sensitivity ~60% for malignant pleural effusion.
• Lymph node FNAC or core biopsy: Supraclavicular/cervical nodes — ultrasound-guided FNAC or excision biopsy.
• Liver biopsy: US-guided for suspected liver metastases.

When all less-invasive methods fail to provide a diagnosis:

• Wedge resection for frozen section — allows intra-operative decision: if frozen section confirms malignancy, proceed to lobectomy. ^[20]
• Video-Assisted Thoracoscopic Surgery (VATS): Minimally invasive; allows direct visualisation of pleural surface, lung parenchyma, and lymph nodes. Can biopsy pleural nodules, peripheral lung lesions, and perform pleurodesis simultaneously.
• Medical thoracoscopy / pleuroscopy: For pleural disease — allows biopsy of parietal pleura under direct vision. Superior to blind pleural biopsy for malignant pleural effusion diagnosis ^[27].

Once tissue is obtained, the pathology workup includes:

Step 1: Histological subtype (H&E staining)

• Is it NSCLC or SCLC?
• If NSCLC: adenocarcinoma, SCC, large cell, or other?

Step 2: Immunohistochemistry (IHC)

Step 3: Molecular Testing (Essential for Advanced NSCLC, Especially Non-Squamous)

Why molecular testing is critical: A patient with an EGFR-mutant adenocarcinoma treated with an EGFR-TKI has a median PFS of ~18-24 months with osimertinib, compared with ~5-6 months with conventional platinum-based chemotherapy. This represents a transformative difference in outcome. Not testing = not offering the patient the best available treatment.

Role of blood markers e.g. CEA ^[26][28]

• CEA (carcinoembryonic antigen) may be elevated in lung adenocarcinoma but is not diagnostic — poor sensitivity and specificity.
• Useful for monitoring treatment response and detecting recurrence after treatment, NOT for screening or diagnosis.

TNM 9 is the current edition introduced in 2025, and is already shown in the faculty CMB40 perioperative lecture (p. 4). Older faculty decks and pivotal treatment trials often use TNM 7 or 8: keep the edition attached to their eligibility criteria.

The key changes are single-station N2a versus multistation N2b, and M1c1 (multiple distant metastases in one organ system) versus M1c2 (multiple organ systems). Count nodal stations, not individual nodes. T size thresholds are retained, with refinements of anatomical invasion descriptors. IASLC staging project, IASLC stage-group development, PMID 38447919.

T (Primary Tumour):

N (Regional Lymph Nodes):

M (Distant Metastasis):

TNM 9 stage groups (M0):

Any T/N with M1a or M1b = IVA; M1c1 or M1c2 = IVB. TisN0M0 is stage 0; T1miN0M0 is IA1. In particular, T1N2a is now IIB, so “N2 always means stage III” is outdated. The regional nodal burden still requires specialist multimodality assessment; a new stage label does not automatically make a patient eligible for a regimen studied under an older edition.

Record TNM for SCLC too, especially when considering rare early surgery, and use limited/extensive stage to organise chemoradiation planning:

Assess both FEV1 and DLCO, calculate their predicted postoperative percentage values, and integrate exercise capacity, cardiovascular risk, frailty and the planned operation. Repeat lung function after neoadjuvant treatment when planning surgery.

The old preoperative absolute FEV1 heuristics (1.5 L for lobectomy, 2 L for pneumonectomy) must not be relabelled as ppo thresholds. Segment counting is appropriate for functioning segments in lobectomy; pneumonectomy usually needs split-function assessment. ERS/ESTS guideline, 2025.

• ECG: Baseline — arrhythmia, ischaemia.
• Echocardiography: If clinical suspicion of cardiac disease, valvular disease, or pulmonary hypertension.
• Cardiology referral: If significant coronary artery disease or heart failure.

• Generally, ECOG 0-1 patients are candidates for surgery or aggressive chemotherapy; ECOG ≥ 3 are usually for best supportive care only.

Surgical options: ^[21]

Surgical approach: ^[21]

• Open thoracotomy: Traditional approach; better for complex cases
• VATS (Video-Assisted Thoracoscopic Surgery): Minimally invasive; more common now. Advantages: less pain, faster recovery, shorter hospital stay, similar oncological outcomes
• Robotic-assisted: Emerging; similar principles to VATS

+ Mediastinal LN dissection (usually routine in resectable NSCLC) ^[21]

• Why: Even if pre-operative staging suggests N0, occult N1/N2 disease can be found in up to 10-15% of patients. Systematic mediastinal lymph node dissection provides accurate pathological staging and may improve survival.

± Adjuvant chemotherapy in stage II-III and high-risk stage IB ^[21]

• Rationale: Even after "complete" resection, microscopic residual disease may remain. Adjuvant chemotherapy reduces the risk of recurrence and improves overall survival by ~5% at 5 years for stage II-III.
• Regimen: Platinum-based doublet chemotherapy — typically cisplatin + vinorelbine (4 cycles).
• Trial-edition caution: older “stage IB ≥ 4 cm” trials used earlier TNM editions. Under current size categories, > 4–5 cm N0 is T2b/stage IIA. For stage IB, discuss adverse pathological features and biomarker-specific evidence rather than copying an old stage label.

± Adjuvant RT if positive surgical margin, or intra-op detection of mediastinal LN mets (p-stage III) ^[21]

• Positive margin (R1/R2 resection): Adjuvant RT reduces local recurrence.
• Completely resected pN2 disease: PORT is not routine solely because N2 nodes were found. Lung ART did not show a significant disease-free survival benefit and found greater cardiopulmonary toxicity. Consider individual margin/local-recurrence risks; R1/R2 disease is a different setting. Lung ART, PMID 34919827

Adjuvant targeted therapy (newer paradigm):

• Osimertinib adjuvant therapy (ADAURA trial): For resected stage IB-IIIA NSCLC with EGFR exon 19 deletion or L858R mutation, 3 years of adjuvant osimertinib dramatically improves disease-free survival. This is now standard of care.
• Atezolizumab adjuvant (IMpower010): For resected stage II-IIIA NSCLC with PD-L1 ≥ 1%, adjuvant atezolizumab improves DFS.

Clearly indicate how we approach a patient with lung cancer and consider for surgery: ^[31] Confirm the diagnosis and staging; Indication of surgery; Resectability; Operability ^[31]

This is the surgeon's checklist:

Describe physiological evaluation of patient planning for lung resection: ^[31]

Spirometry + DLCO ± function tests ^[31]

Calculate postoperative predicted value using "segmental counting" ^[31]

• Segmental counting method: The lung has 19 segments (10 right, 9 left). If you are removing a lobe with, say, 3 segments, and the patient's current FEV1 is 2.0 L, then:
  • ppo FEV1 = 2.0 × (19 − 3) / 19 = 2.0 × 16/19 = 1.68 L
• Alternatively, use quantitative perfusion scan to calculate the percentage of perfusion to the lung/lobe being resected.

Assess risk rather than applying an absolute pass/fail cutoff: use ppo FEV1 and ppo DLCO percentages, exercise capacity/CPET, cardiac risk, frailty and the extent of resection. Around ≥60% predicted is lower pulmonary risk, 40–59% increased risk and <40% high risk. A low result prompts specialist assessment and discussion of alternatives; it does not by itself prohibit surgery. The historical 1.5 L/2 L figures are preoperative FEV1 rules, not postoperative requirements. Repeat PFTs after neoadjuvant therapy. See the Ix tab and ERS/ESTS 2025.

Understand principles of postoperative care after lung resection and concept of early recovery after surgery: ^[31]

Multimodal analgesia ^[31]

• Why important: Pain after thoracotomy/VATS is significant and impairs coughing → atelectasis → pneumonia. Effective analgesia allows early mobilisation and deep breathing exercises.
• Modalities: Thoracic epidural (gold standard for thoracotomy), paravertebral block, intercostal nerve block, patient-controlled analgesia (PCA), NSAIDs (cautious — avoid if pleurodesis planned), paracetamol, gabapentinoids for neuropathic pain.

Early removal of chest drain ^[31]

• Post-lobectomy chest drains are kept until: (1) No air leak, (2) Drainage < 200–400 mL/day, (3) Lung fully expanded on CXR. Modern protocols aim for removal by day 1–3 to reduce hospital stay.

Common and key postoperative complications: ^[31]

This is the gap the surgical pathway does not cover: peripheral T1 N0 (Stage IA) disease in a patient who cannot, or will not, have an operation. NCCN NSCL-2 is the standard algorithm. ^[35]

Who counts as inoperable. NCCN groups three situations together: medically inoperable, high surgical risk as determined by a thoracic surgeon, and patients who decline surgery after thoracic surgical consultation. Operability is a surgical judgement — do not label someone inoperable from PFTs alone without that consult. ^[31][35]

Pretreatment evaluation (same work-up whether or not surgery is planned): ^[35]

Node-status branch:

• Positive mediastinal nodes → this is no longer Stage IA. Manage as Stage IIB/III (chemoradiation ± systemic therapy), not with SABR alone. ^[35]
• Negative mediastinal nodes → decide operability.

Initial treatment if inoperable / high-risk / declines surgery: definitive radiation therapy, preferably SABR (stereotactic ablative body radiotherapy). Then surveillance. ^[33][35]

• SABR/SBRT delivers a high, tightly conformal dose in few fractions (e.g. 54 Gy in 3 fractions). Local control is ~90% for T1–2 N0 tumours — the non-surgical curative option for Stage I. ^[33]
• Conventional fractionated RT is inferior to SABR when SABR is available.
• Image-guided thermal ablation (IGTA) — cryotherapy, microwave, or radiofrequency — is an option for selected patients (typically very peripheral, small lesions when SABR is unsuitable). ^[35]
• Operable patients should still hear about SABR as an alternative via shared decision-making; resection remains first-line. ^[35]

Concurrent chemoirradiation as treatment of choice ^[21]

• Why concurrent rather than sequential: Concurrent administration provides better local control because chemotherapy acts as a radiosensitiser — it makes tumour cells more susceptible to radiation-induced DNA damage. The survival benefit outweighs the increased toxicity.
• Chemotherapy regimen: usually cisplatin + etoposide or weekly carboplatin + paclitaxel ^[21]
• Radiotherapy: usually full-dose IMRT (60 Gy in 30 daily fractions) ^[21]
  • "IMRT" = Intensity-Modulated Radiation Therapy — allows precise dose delivery to the tumour while sparing surrounding normal tissue (heart, oesophagus, spinal cord).

Consolidation after CRT without progression: osimertinib for eligible EGFR exon 19 deletion/L858R disease; durvalumab for other appropriate patients

• PACIFIC trial: Durvalumab (anti-PD-L1) for up to 12 months after completion of concurrent chemoRT in unresectable stage III NSCLC → significantly improved PFS and OS. This is now standard of care.
• Durvalumab = "dur-val-u-mab" — dur = durable, mab = monoclonal antibody.

• CheckMate 816 trial: Neoadjuvant nivolumab + platinum-doublet chemotherapy → surgery in resectable stage IB-IIIA → significant improvement in pathological complete response and event-free survival.
• This is an evolving paradigm — MDT discussion determines whether neoadjuvant → surgery or concurrent chemoRT is optimal for each patient.

Initial genetic testing to identify driver mutations as biomarkers ^[21]

• Indications: ALL adenocarcinoma and ALL never or minimal remote smokers ^[21]
• Current standard of care is to perform EGFR, ALK, and ROS1 analyses, but 10% patients have other potentially actionable mutations (e.g., other EGFR, CMET, BRAF V600, NTRK, HER2) ^[21]
• In East Asian adenocarcinoma, classic EGFR exon 19 deletion / L858R is the largest slice (~40%); the remaining actionable drivers are each uncommon but still matched to a drug — ALK ~4%, MET exon 14 ~3%, ROS1 ~3%, HER2 exon 20 insertion ~2%, BRAF V600E ~2%, KRAS G12C ~3%, RET ~2%, NTRK < 0.3%. About 1 in 5 have no actionable alteration.

Key targeted therapies:

Why "tyrosine kinase inhibitor"? "Tyrosine" = amino acid that gets phosphorylated; "kinase" = enzyme that adds phosphate groups; "inhibitor" = blocks. TKIs block the phosphorylation step that activates downstream proliferation pathways. When the tumour is driven by a single oncogene ("oncogene addiction"), blocking that pathway has dramatic effects.

Liquid biopsy: ^[21] Sample required: ^[21]

• On biopsy sample: traditional method, but risk of resistance heterogeneity
• On plasma/urine (liquid biopsy): detection of cell-free DNA in plasma and urine → minimally invasive (allows serial testing) and representative of dominant tumour molecular profile

Screening for programmed death ligand 1 (PD-L1) expression by immunohistochemistry ^[29]

Mechanism:

• Tumour cells upregulate PD-L1 on their surface → PD-L1 binds to PD-1 receptor on T-cells → sends an "off" signal to the T-cell → T-cell undergoes apoptosis or becomes anergic → tumour escapes immune surveillance.
• Monoclonal antibody against PD-1 and PD-L1 ^[29]
• Prevention of apoptosis of T-cells and enhance immune system ^[29]
• By blocking the PD-1/PD-L1 interaction, the T-cell remains active and can attack the tumour.

Key checkpoint inhibitors:

PD-L1 expression guides treatment selection (for patients WITHOUT driver mutations):

Side effects of immunotherapy: ^[29]

• Dermatological: Rash / Mucositis / Dry mouth
• Gastrointestinal: Diarrhoea / Immune-mediated colitis / Hepatotoxicity
• Endocrinological: Autoimmune thyroid disease / Adrenal insufficiency / Hypophysitis / Type 1 DM

For patients without actionable mutations and with low PD-L1, or in combination with immunotherapy:

• Platinum-based doublet: Standard backbone.
  • Cisplatin + pemetrexed (non-squamous) or gemcitabine (squamous)
  • Carboplatin + paclitaxel or nab-paclitaxel (often preferred due to better tolerability)
• Usually 4–6 cycles → then maintenance therapy (pemetrexed or immunotherapy).

For cT1-2N0M0 limited stage disease: ^[21]

• Primary surgery: lobectomy + mediastinal LN sampling/dissection
• Adjuvant chemotherapy: 4 cycles of cisplatin-based chemotherapy
• ± Adjuvant chemo/RT if LN involvement identified intra-operatively

This is the only scenario where surgery plays a role in SCLC — and it is uncommon because SCLC is rarely caught this early.

For unresectable limited stage (LS-SCLC) disease: ^[21]

• Concurrent platinum–etoposide + thoracic RT, followed by durvalumab in eligible patients without progression (ADRIATIC)
• Prophylactic cranial irradiation (PCI): offer after response to definitive chemo/RT if brain MRI shows no metastases and the patient is suitable ^[21][36]

Rationale for PCI: ^[21]

• Occult brain mets occur frequently in SCLC without neurological symptoms
• Brain mets often as sole site of relapse
• Effect in stage II–III LS-SCLC: prophylactic cranial irradiation → increased overall survival + decreased incidence of brain metastasis ^[21][36]
• PCI is less compelling after complete resection of pathologic stage I disease. Consider MRI surveillance instead in older/frail patients, those with poor performance status or baseline cognitive impairment, and those who prioritize avoiding neurotoxicity ^[36].

For extensive stage (ES-SCLC) disease: ^[21]

• Induction chemotherapy: mainstay, usually given for 4-6 cycles (± atezolizumab, PD-L1 mAb)
• Further thoracic EBRT if good response to initial chemotherapy
• Scheduled brain MRI surveillance is generally preferred over routine PCI. PCI reduces brain-metastasis risk but has not shown a clear survival benefit when MRI surveillance is available; reserve it for selected responders after shared decision-making ^[36].

The addition of atezolizumab (IMpower133 trial) or durvalumab (CASPIAN trial) to EP chemotherapy is now standard of care for ES-SCLC — this represented the first improvement in OS for ES-SCLC in decades.

After progression on or after platinum chemotherapy: tarlatamab-dlle (Imdelltra) is a DLL3-directed CD3 bispecific T-cell engager. FDA traditional approval (19 November 2025) followed DeLLphi-304, where median OS was 13.6 vs 8.3 months with standard chemotherapy (HR 0.60). Step-up dosing is required; boxed warnings cover cytokine-release syndrome and neurologic toxicity, including ICANS ^[37].