Oncology

Key Facts

Cancer staging and grading provide standardised frameworks for describing the extent and aggressiveness of cancer. They are essential for treatment planning, prognosis, clinical trial enrolment, and communication between healthcare professionals.

Epidemiology

• Stage at diagnosis is the single most important prognostic factor for most solid tumours
• In the UK, approximately 45% of cancers are diagnosed at Stage I-II (early) and 40% at Stage III-IV (advanced)
• Routes to diagnosis affect stage: screening picks up earlier stages than emergency presentations

Aetiology

• Not applicable (classification system)

Pathophysiology

• Grading reflects the degree of differentiation: well-differentiated tumours more closely resemble normal tissue and tend to be less aggressive
• Together, stage and grade predict biological behaviour, response to treatment, and overall prognosis

Clinical Staging

• Based on physical examination, imaging, and pre-operative investigations
• May be revised after surgery (pathological staging, pTNM)

Pathological Staging

• Based on surgical specimens and histopathological examination
• More accurate than clinical staging
• Includes assessment of margins, lymphovascular invasion, perineural invasion

Red Flags Indicating Advanced Stage

• Multiple organ involvement
• Weight loss >10%
• Performance status ECOG ≥3
• Bone pain (skeletal metastases)
• Neurological symptoms (brain metastases)
• Jaundice (liver metastases or biliary obstruction)

Bedside

• Full clinical examination
• Performance status assessment (ECOG/WHO or Karnofsky)

Bloods

• FBC, U&Es, LFTs, calcium, LDH, albumin
• Tumour-specific markers (PSA, CEA, CA-125, AFP, βhCG)

Imaging

• CT chest/abdomen/pelvis: standard staging for most solid tumours
• MRI: superior for local staging (brain, spine, pelvis, liver)
• PET-CT (18F-FDG): increasingly used for staging, treatment response assessment, recurrence detection
• Bone scan: for suspected skeletal metastases (breast, prostate, lung)
• USS: for superficial lymph nodes, liver, guided biopsy

Special Tests

• Biopsy and histopathology: essential for grading and tumour characterisation
• Immunohistochemistry: tumour classification and origin
• Molecular profiling: predictive biomarkers for targeted therapy
• Sentinel lymph node biopsy: minimally invasive lymph node staging (breast, melanoma)

Non-pharmacological

• MDT discussion mandatory for all new cancer diagnoses
• Treatment decisions based on stage, grade, molecular profile, performance status, and patient preference
• Clinical nurse specialist support and holistic needs assessment

Pharmacological

• Treatment stratified by stage:
  • Early stage (I-II): curative surgery ± adjuvant therapy
  • Locally advanced (III): neoadjuvant or concurrent chemoradiotherapy
  • Metastatic (IV): systemic therapy (palliative intent in most solid tumours)
• Specific regimens are cancer-type dependent

Surgical/Interventional

• Surgery is the primary curative modality for most early-stage solid tumours
• Radiotherapy: curative for some localised cancers (cervix, head & neck, prostate)
• Interventional radiology: ablation, embolisation

Referral Criteria

• All new cancer diagnoses: MDT discussion
• Stage-appropriate treatment at specialist centres
• Clinical trial eligibility assessment

• Stage is the strongest prognostic factor for most cancers
• Stage I: 5-year survival typically 80-95% (site-dependent)
• Stage IV: 5-year survival typically 5-30% (site-dependent)
• Grade independently predicts outcome within each stage
• Performance status strongly predicts treatment tolerance and survival
• Molecular subtypes increasingly influence prognosis (e.g. HER2+ breast cancer has improved outcomes with targeted therapy)

TNM Staging Overview

ECOG Performance Status

Stage Grouping (General)

Key Facts

Chemotherapy remains a cornerstone of cancer treatment, using cytotoxic drugs to target rapidly dividing cells. Understanding mechanisms of action, toxicity profiles, and supportive care measures is essential for safe and effective administration.

Epidemiology

• Approximately 30% of cancer patients receive chemotherapy as part of their treatment
• Both curative and palliative roles depending on cancer type and stage

Aetiology

• Not applicable (treatment modality)

Pathophysiology

• Cytotoxic drugs exploit the cell cycle by targeting DNA synthesis, repair, and cell division
• Damage to DNA triggers apoptosis in susceptible cells
• Combination regimens use drugs with different mechanisms to maximise cell kill and minimise resistance (Norton-Simon hypothesis, Goldie-Coldman hypothesis)
• Log-kill hypothesis: each cycle of chemotherapy kills a constant fraction of tumour cells

Indications for Chemotherapy

• Neoadjuvant: shrink tumour before surgery (e.g. breast cancer, oesophageal cancer)
• Adjuvant: reduce recurrence risk after curative surgery (e.g. colorectal, breast)
• Curative: primary treatment (e.g. leukaemia, lymphoma, testicular cancer)
• Palliative: improve symptoms and prolong survival (e.g. metastatic disease)

Common Side Effects

• Bone marrow suppression: neutropenia (day 7-14 nadir), anaemia, thrombocytopenia
• GI toxicity: nausea/vomiting, mucositis, diarrhoea
• Alopecia: reversible with most agents
• Fatigue: most common reported symptom
• Infertility: depends on agent and cumulative dose

Red Flags

• Neutropenic sepsis (fever ≥38°C with neutrophils <0.5 × 10⁹/L)
• Tumour lysis syndrome (TLS)
• Anaphylaxis during infusion
• Extravasation of vesicant drugs

Bedside

• Observations (temperature, HR, BP)
• Performance status assessment
• Oral examination (mucositis grading)

Bloods

• Pre-cycle: FBC (ANC >1.5 × 10⁹/L for most regimens), U&Es, LFTs, eGFR
• During treatment: regular FBC monitoring (nadir typically day 7-14)
• Tumour markers as appropriate
• If febrile: blood cultures (peripheral and from central line), lactate, CRP

Imaging

• Response assessment: CT scan typically after 2-3 cycles
• PET-CT for interim response in lymphoma

Special Tests

• Cardiac assessment (echocardiogram/MUGA scan): before anthracyclines
• Audiometry: before cisplatin
• Pulmonary function tests: before bleomycin
• GFR measurement: before platinum-based chemotherapy
• DPD deficiency testing: before fluoropyrimidines (5-FU, capecitabine) - DPYD genotyping

Non-pharmacological

• Pre-treatment counselling: side effects, fertility preservation options (sperm banking, oocyte cryopreservation)
• PICC line or port insertion for repeated IV access
• Scalp cooling to reduce alopecia (where available)
• Dietary advice and nutritional support

Pharmacological

• Antiemetics (emetogenicity-dependent per NICE/MASCC guidelines):
  • High emetogenic (cisplatin): ondansetron 8mg + dexamethasone 12mg + aprepitant 125mg/80mg/80mg (days 1-3)
  • Moderate: ondansetron 8mg + dexamethasone 8mg
  • Low: dexamethasone 4mg or metoclopramide 10mg
• G-CSF (filgrastim 5mcg/kg/day or pegfilgrastim 6mg): primary prophylaxis if febrile neutropenia risk >20%
• Allopurinol or rasburicase: TLS prophylaxis
• Dexrazoxane: cardioprotection with anthracyclines (selected patients)
• Mesna: urothelial protection with cyclophosphamide/ifosfamide
• Folinic acid (leucovorin) rescue: after high-dose methotrexate

Surgical/Interventional

• Central venous access device insertion (PICC, Hickman line, portacath)
• Fertility preservation procedures (pre-chemotherapy)

Referral Criteria

• All chemotherapy prescribed by oncologists within MDT framework
• Neutropenic sepsis: immediate assessment in oncology assessment unit or A&E
• Extravasation: immediate management per local protocol

• Highly variable depending on cancer type, stage, and treatment intent
• Curative regimens (e.g. lymphoma, testicular): 80-95% cure rates
• Adjuvant chemotherapy for breast cancer: reduces recurrence by approximately 30%
• Palliative chemotherapy: extends median survival by weeks to months in most metastatic solid tumours
• Treatment-related mortality: approximately 1-3% for most standard regimens
• Late effects: secondary malignancy (leukaemia after alkylating agents), cardiotoxicity, infertility

Common Chemotherapy Drug Classes

CTCAE Grading (Common Terminology Criteria for Adverse Events)

Key Facts

Immunotherapy has transformed cancer treatment by harnessing the patient's own immune system. Immune checkpoint inhibitors are now standard of care for many tumour types. Understanding mechanisms, indications, and management of immune-related adverse events is essential.

Epidemiology

• Immunotherapy is now used in >50 cancer types
• Approvals expanding rapidly; ICIs are standard of care in melanoma, NSCLC, renal cell, urothelial, head and neck, Hodgkin lymphoma, and many others
• Response rates vary: 15-60% depending on tumour type and biomarker status

Aetiology

• Not applicable (treatment modality)

Pathophysiology

• Tumours evade immune destruction by upregulating inhibitory checkpoints (PD-L1, CTLA-4)
• PD-1/PD-L1 pathway: PD-L1 on tumour cells binds PD-1 on T-cells, causing T-cell exhaustion
• CTLA-4 pathway: CTLA-4 competes with CD28 for B7 binding on APCs, reducing T-cell activation
• ICIs release the 'brakes' on the immune system, allowing T-cells to attack tumour cells
• CAR-T cells: T-cells genetically modified to express chimeric antigen receptor targeting specific tumour antigen (e.g. CD19); infused back into the patient
• Cytokine release syndrome (CRS): major toxicity of CAR-T therapy; managed with tocilizumab (anti-IL-6)

Indications

• Melanoma: pembrolizumab/nivolumab ± ipilimumab (adjuvant and metastatic)
• NSCLC: pembrolizumab (first-line if PD-L1 ≥50%); combinations with chemotherapy
• Renal cell carcinoma: nivolumab + ipilimumab (first-line intermediate/poor risk)
• Urothelial cancer: atezolizumab, pembrolizumab
• Hodgkin lymphoma: nivolumab, pembrolizumab (relapsed/refractory)
• MSI-H/dMMR tumours: pembrolizumab (tumour-agnostic indication)

Immune-Related Adverse Events (irAEs)

• Dermatitis (most common; 30-40%): rash, pruritus, vitiligo
• Colitis (15-20%): diarrhoea, abdominal pain, bloody stool
• Hepatitis (5-10%): elevated transaminases
• Pneumonitis (3-5%): cough, dyspnoea; potentially fatal
• Endocrinopathies (10-20%): thyroiditis (hypo/hyperthyroid), hypophysitis, adrenal insufficiency, type 1 diabetes
• Neurological (rare): myasthenia gravis, Guillain-Barré, encephalitis

Red Flags

• New-onset diarrhoea (>4 stools/day over baseline): colitis
• Dyspnoea with new infiltrates on CXR: pneumonitis
• Severe fatigue, hypotension, hyponatraemia: adrenal crisis
• Visual disturbance, headache: hypophysitis
• Rapid deterioration with muscle weakness: myasthenia/myositis

Bedside

• Observations (temperature, HR, BP, SpO2)
• Stool chart if diarrhoea
• Glucose monitoring if new diabetes suspected

Bloods

• Baseline and pre-cycle: FBC, U&Es, LFTs, TFTs, glucose, cortisol
• If irAE suspected: LFTs (hepatitis), TFTs (thyroiditis), cortisol and ACTH (adrenal/hypophysitis), lipase (pancreatitis), troponin and CK (myocarditis/myositis)
• Anti-nuclear antibodies if autoimmune cause suspected

Imaging

• CT chest: pneumonitis assessment
• MRI brain (pituitary protocol): if hypophysitis suspected
• CT abdomen: colitis assessment (wall thickening)

Special Tests

• PD-L1 immunohistochemistry: predictive biomarker (tumour proportion score, TPS)
• MSI/MMR testing: dMMR/MSI-H predicts response to pembrolizumab
• Tumour mutational burden (TMB): emerging biomarker
• Colonoscopy: for severe colitis (biopsy for histological confirmation)
• Bronchoscopy + BAL: for pneumonitis

Non-pharmacological

• Patient education about irAEs: provide alert card
• Regular monitoring with blood tests before each cycle
• Low threshold for investigation of new symptoms
• Specialist oncology review for any Grade ≥2 irAE

Pharmacological

• Grade 1 irAE: continue ICI, symptomatic treatment, close monitoring
• Grade 2 irAE: hold ICI; prednisolone 0.5-1mg/kg/day; taper over 4-6 weeks
• Grade 3 irAE: hold ICI; prednisolone 1-2mg/kg/day (or IV methylprednisolone 1-2mg/kg); specialist input
• Grade 4 irAE: permanently discontinue ICI; IV methylprednisolone 1-2mg/kg; consider infliximab 5mg/kg (colitis) or mycophenolate 1g BD (hepatitis)
• Endocrinopathies: often require permanent hormone replacement (levothyroxine, hydrocortisone) rather than immunosuppression
• CRS (CAR-T): tocilizumab 8mg/kg IV; dexamethasone if refractory

Surgical/Interventional

• Rarely required; colectomy for refractory colitis with perforation

Referral Criteria

• Any suspected irAE: discuss with oncology team
• Grade ≥3 irAE: inpatient management under oncology
• Endocrine irAEs: endocrinology input
• Pneumonitis: respiratory input
• Neurological irAEs: urgent neurology review

• ICIs have transformed outcomes in several cancers:
  • Metastatic melanoma: 5-year survival improved from 5% to 40-50% with ICIs
  • Advanced NSCLC (PD-L1 ≥50%): 5-year survival 25-30% with pembrolizumab
• Durable responses: some patients maintain response for years after stopping treatment
• irAEs: most are manageable with steroids; rare fatalities (0.3-1.3%), most commonly myocarditis and pneumonitis
• CAR-T for DLBCL: complete response rate 40-60%; long-term remission in 30-40%

irAE Grading and Management

Key Checkpoint Inhibitors (UK Approved)

Key Facts

Radiotherapy is a cornerstone of cancer treatment, using ionising radiation to cause lethal DNA damage in cancer cells. Understanding the principles of radiobiology, fractionation, and treatment planning is essential for postgraduate medical exams.

Epidemiology

• Approximately 50% of cancer patients receive radiotherapy
• Contributes to 40% of all cancer cures (second only to surgery)
• Used with curative intent in approximately 20% of patients and palliative intent in 30%

Aetiology

• Not applicable (treatment modality)

Pathophysiology

• Direct action: ionising radiation directly damages DNA (double-strand breaks are the key lethal lesion)
• Indirect action: radiation generates free radicals (from water radiolysis) that damage DNA; enhanced by oxygen (oxygen effect)
• Differential sensitivity: tumour cells have impaired DNA repair mechanisms compared to normal tissue
• 4 Rs of radiobiology: Repair (sublethal damage repair in normal tissue), Reassortment (redistribution of cells into radiosensitive phases), Reoxygenation (previously hypoxic tumour cells become oxygenated), Repopulation (accelerated repopulation during treatment)
• Linear-quadratic model: describes relationship between radiation dose and cell kill (α/β ratio); high α/β (e.g. 10 for most tumours) = more sensitive to fractionation; low α/β (e.g. 3 for late-responding tissues) = more sensitive to dose per fraction

Indications for Radiotherapy

• Curative: as primary treatment (cervical, head & neck, prostate) or adjuvant (breast, rectal, brain)
• Palliative: bone metastases (pain relief), brain metastases, SVCO, spinal cord compression, haemostasis
• Emergency: SVCO, spinal cord compression (urgent RT within 24 hours)

Acute Side Effects (during and up to 6 weeks post-RT)

• Skin: erythema, desquamation, pigmentation
• Mucositis: oral, oesophageal, rectal (depending on site)
• Fatigue: most common; affects 80-90% of patients
• Nausea/vomiting: if abdominal/pelvic RT
• Bone marrow suppression: if large fields

Late Side Effects (months to years)

• Fibrosis (lung, bowel, subcutaneous tissue)
• Stricture (oesophageal, rectal, ureteric)
• Secondary malignancy (typically 10-20 years later)
• Lymphoedema
• Infertility
• Cardiac toxicity (if heart in field)
• Radiation myelopathy (spinal cord)

Red Flags

• Spinal cord compression: urgent RT needed within 24 hours
• Radiation pneumonitis: cough, dyspnoea 2-6 months post-RT
• Radiation enteritis: severe diarrhoea, bleeding
• Osteoradionecrosis of jaw: pain, exposed bone (dental assessment before head & neck RT)

Bedside

• Clinical assessment of treatment site
• Skin assessment (CTCAE grading)
• Swallowing assessment if head & neck RT

Bloods

• FBC (myelosuppression if large fields)
• U&Es, LFTs (baseline)
• TFTs (if neck irradiated - hypothyroidism risk)

Imaging

• CT simulation: planning scan for treatment field design
• MRI fusion: improved target delineation (brain, pelvis)
• PET-CT: for target volume definition and response assessment
• Follow-up imaging: response assessment per cancer type

Special Tests

• DVH (dose-volume histogram): evaluates dose distribution to target and organs at risk
• Pulmonary function tests: before lung RT
• Audiometry: if cochlea in field
• Dental assessment: before head & neck RT (prevent osteoradionecrosis)

Non-pharmacological

• Patient education about expected side effects and timeline
• Skin care: gentle washing, aqueous cream, avoid sun exposure
• Nutritional support: dietitian input for head & neck / GI RT
• Oral care: fluoride trays, saliva substitutes
• Psychological support

Pharmacological

• Skin reactions: emollients (aqueous cream), moderate potency steroid cream (betamethasone 0.1%) if symptomatic
• Mucositis: benzydamine mouthwash, gelclair, systemic analgesia (opioids if severe)
• Nausea: ondansetron 8mg, dexamethasone 4mg
• Radiation pneumonitis: prednisolone 40-60mg tapering over 4-8 weeks
• Radiation proctitis: sucralfate enemas, topical steroids
• Amifostine: radioprotectant (limited use; reduces xerostomia in head & neck RT)

Surgical/Interventional

• Fiducial marker placement for image-guided RT
• Brachytherapy applicator insertion
• SpaceOAR hydrogel injection (rectal spacer for prostate RT)

Referral Criteria

• All radiotherapy prescribed by clinical oncologist within MDT
• Emergency RT: spinal cord compression, SVCO (immediate referral)
• Late radiation toxicity: specialist management

• Curative RT: 5-year local control rates depend on cancer type (e.g. cervical 80-90%, prostate 85-95%, early laryngeal 90%)
• Palliative RT for bone metastases: pain response in 60-80% (8 Gy single fraction as effective as 20 Gy in 5 per NCRI Bone Pain Trial)
• Late toxicity risk: generally <5-10% for serious complications with modern techniques
• Secondary malignancy risk: approximately 1-2% at 10-20 years
• IMRT and proton therapy reduce late toxicity compared to conventional techniques

Advanced Radiotherapy Techniques

Landmark Radiotherapy Trials

Key Facts

Targeted therapy represents a paradigm shift in oncology, enabling treatment directed at specific molecular abnormalities driving individual cancers. This approach underlies precision/personalised medicine.

Epidemiology

• Targeted agents now form part of standard treatment for the majority of common cancers
• Molecular profiling is increasingly performed at diagnosis to guide therapy selection
• Next-generation sequencing panels identify actionable mutations in 30-50% of advanced cancers

Aetiology

• Not applicable (treatment modality)

Pathophysiology

• Tyrosine kinase inhibitors (TKIs): small molecules that inhibit intracellular kinase domains (competitive or non-competitive ATP binding site inhibition)
• Monoclonal antibodies: bind extracellular targets (receptors, ligands); mechanisms include direct signalling blockade, ADCC (antibody-dependent cellular cytotoxicity), complement activation
• PARP inhibitors: block poly(ADP-ribose) polymerase, preventing single-strand break repair; in BRCA-deficient cells (impaired HRR), this leads to synthetic lethality
• CDK inhibitors: block cyclin-dependent kinases 4/6, preventing cell cycle progression from G1 to S phase
• Resistance mechanisms: secondary mutations (T790M in EGFR), bypass pathway activation, target amplification

Key Indications

• CML: imatinib, dasatinib, nilotinib (BCR-ABL TKIs)
• HER2+ breast cancer: trastuzumab, pertuzumab, T-DXd (trastuzumab deruxtecan)
• EGFR-mutant NSCLC: osimertinib
• ALK-rearranged NSCLC: alectinib, lorlatinib
• BRAF-mutant melanoma: dabrafenib + trametinib
• BRCA-mutant cancers: olaparib (ovarian, breast, prostate, pancreatic)
• HR+/HER2- breast cancer: CDK4/6 inhibitors + endocrine therapy
• RCC: sunitinib, pazopanib, cabozantinib (VEGFR TKIs)
• GIST: imatinib (KIT/PDGFRA mutations)

Common Side Effects by Drug Class

• TKIs: diarrhoea, rash (acneiform with EGFR inhibitors), fatigue, hypertension (VEGFR inhibitors)
• Anti-HER2: cardiotoxicity (reduced LVEF), infusion reactions
• PARP inhibitors: myelosuppression (anaemia, thrombocytopenia), nausea, fatigue
• CDK4/6 inhibitors: neutropenia, diarrhoea (abemaciclib), QT prolongation (ribociclib)
• BRAF/MEK inhibitors: pyrexia, rash, photosensitivity, cutaneous SCC (BRAF alone)

Red Flags

• Cardiac symptoms with trastuzumab (dyspnoea, oedema): check LVEF
• Severe diarrhoea with TKIs (dehydration risk)
• Interstitial lung disease with EGFR TKIs (rare but fatal)
• Hepatotoxicity with any targeted agent (monitor LFTs)
• Secondary cutaneous malignancy with BRAF inhibitors (SCC/keratoacanthoma)

Bedside

• Observations, clinical assessment
• ECG (QT interval for ribociclib, sunitinib)

Bloods

• FBC (myelosuppression with PARP inhibitors, CDK inhibitors)
• LFTs (hepatotoxicity)
• TFTs (sunitinib causes hypothyroidism)
• BNP/NT-proBNP if cardiac symptoms

Imaging

• Echocardiogram: baseline and regular monitoring with trastuzumab (every 3 months)
• CT response assessment: typically every 2-3 months

Special Tests

• Molecular profiling (NGS panel): identify targetable mutations before treatment
• FISH/IHC: HER2 status in breast/gastric cancer
• PCR: BCR-ABL transcript monitoring in CML
• Liquid biopsy (ctDNA): monitor resistance mutations (e.g. EGFR T790M)

Non-pharmacological

• Pre-treatment molecular profiling to confirm target
• Patient education about expected side effects
• Cardiac monitoring plan for cardiotoxic agents
• Fertility counselling where appropriate

Pharmacological

• Drug-specific management of side effects:
  • EGFR rash: prophylactic doxycycline 100mg OD, topical steroids
  • Trastuzumab cardiotoxicity: hold if LVEF drops >10 percentage points; consider ACE inhibitor/beta-blocker
  • VEGFR TKI hypertension: amlodipine 5-10mg or ramipril 2.5-10mg
  • PARP inhibitor anaemia: dose reduction, transfusion support
  • Diarrhoea: loperamide 4mg stat then 2mg after each loose stool (max 16mg/day)

Surgical/Interventional

• Excision of BRAF inhibitor-related cutaneous SCCs
• Interventional procedures for toxicity management (stenting, drainage)

Referral Criteria

• All targeted therapy prescribed by oncologists within MDT
• Molecular tumour board for complex cases
• Cardio-oncology referral for cardiac toxicity
• Clinical trial consideration for patients with actionable mutations

• CML with imatinib: 5-year survival >90% (previously 30%); transformed to chronic manageable disease
• HER2+ breast cancer: trastuzumab reduces mortality by 30-35%
• EGFR-mutant NSCLC: median OS with osimertinib approximately 38 months (FLAURA trial)
• BRAF-mutant melanoma: median OS with combined BRAF/MEK inhibition approximately 25-33 months
• BRCA-mutant ovarian cancer with olaparib: 70% reduction in risk of progression (SOLO-1)
• Resistance inevitably develops in most metastatic settings; duration of response varies

Key Targeted Therapy Agents and Indications

Resistance Mechanisms

Key Facts

Oncological emergencies encompass a range of life-threatening conditions arising from the cancer itself or its treatment. Rapid recognition and protocolised management are essential to prevent death and permanent disability.

Epidemiology

• Neutropenic sepsis complicates approximately 15-25% of chemotherapy cycles (varies by regimen)
• MSCC affects 5-10% of cancer patients
• SVCO occurs in 2-4% of lung cancer patients
• Hypercalcaemia of malignancy affects 10-30% of cancer patients during their illness
• TLS most common with haematological malignancies (Burkitt lymphoma, ALL)

Aetiology

• Neutropenic sepsis: chemotherapy-induced bone marrow suppression
• MSCC: vertebral metastases with epidural compression (lung, breast, prostate most common)
• SVCO: mediastinal tumour compression/invasion (lung cancer 70%, lymphoma 15%)
• Hypercalcaemia: PTHrP secretion (humoral), osteolytic metastases, calcitriol production
• TLS: rapid tumour cell lysis releasing intracellular contents

Pathophysiology

• Neutropenic sepsis: impaired innate immunity allows overwhelming bacterial infection

• SVCO: obstruction of SVC → venous congestion in head, neck, arms, upper thorax
• Hypercalcaemia: PTHrP activates osteoclasts; excess calcium → renal impairment, cardiac arrhythmias, neurological dysfunction
• TLS: massive release of potassium, phosphate, uric acid, nucleic acids → renal failure, cardiac arrhythmias

Neutropenic Sepsis

• Fever ≥38°C (or ≥37.5°C sustained for >1 hour) in patient receiving chemotherapy
• May lack typical infection signs due to neutropenia
• Hypotension, tachycardia, rigors

Spinal Cord Compression

• Back pain (90%, often precedes neurology by weeks)
• Limb weakness (progressive)
• Sensory level
• Bladder/bowel dysfunction (late sign; poor prognostic indicator)

SVCO

• Facial and arm swelling
• Distended neck and chest wall veins
• Dyspnoea, stridor
• Headache worse on bending forward

Hypercalcaemia

• 'Stones, bones, groans, moans': renal stones, bone pain, abdominal pain, confusion
• Polyuria, polydipsia, dehydration
• Constipation, nausea
• Cardiac: shortened QT, arrhythmias

Red Flags

• Any temperature ≥38°C within 6 weeks of chemotherapy: assume neutropenic sepsis until proven otherwise
• New back pain in cancer patient: assume MSCC until excluded
• Rapid deterioration in conscious level: brain metastases, hypercalcaemia, or hyponatraemia

Bedside

• ABCDE assessment
• Observations: HR, BP, temperature, SpO2, RR
• Blood glucose
• ECG (hyperkalaemia, hypercalcaemia)
• Neurological examination (MSCC)

Bloods

• FBC (neutrophil count)
• U&Es (potassium, calcium, phosphate, urate, creatinine)
• LFTs, CRP, lactate
• Blood cultures (peripheral and from central line if present)
• Coagulation screen
• Blood gas

Imaging

• MSCC: MRI whole spine within 24 hours (NICE NG149)
• SVCO: CT chest with contrast (CT venogram)
• Brain metastases: CT head ± MRI brain
• CXR: baseline for sepsis assessment

Special Tests

• Urine culture, sputum culture (sepsis source)
• Adjusted calcium calculation: Corrected Ca = measured Ca + 0.02 × (40 - albumin)
• PTHrP: if humoral hypercalcaemia suspected

Non-pharmacological

• Sepsis 6 bundle implementation
• Spinal precautions (log-roll) if MSCC suspected
• IV fluid resuscitation

Pharmacological

• Neutropenic sepsis: IV piperacillin-tazobactam 4.5g TDS (or local protocol) within 1 hour of presentation (NICE NG151); add vancomycin if line infection suspected
• MSCC: dexamethasone 16mg IV stat then 16mg OD; PPI cover; specialist opinion within 24 hours
• SVCO: dexamethasone 16mg IV stat; anticoagulation if thrombosis; urgent oncology referral
• Hypercalcaemia: IV 0.9% saline 3-4L/24h rehydration → zoledronic acid 4mg IV over 15 minutes (onset 2-4 days; duration 3-4 weeks); denosumab 120mg SC if refractory
• TLS: aggressive IV hydration (3L/m²/day); rasburicase 0.2mg/kg IV (converts uric acid to allantoin; avoid in G6PD deficiency); allopurinol 300mg OD (prophylaxis); correct hyperkalaemia (calcium gluconate, insulin-dextrose, salbutamol nebuliser)
• Brain metastases: dexamethasone 16mg IV → 4mg QDS tapering; anticonvulsants if seizures (levetiracetam 250-500mg BD)

Surgical/Interventional

• MSCC: surgical decompression (if operable, single level, good performance status) ± RT; or RT alone
• SVCO: SVC stenting (interventional radiology) for rapid symptom relief
• Cardiac tamponade: pericardiocentesis (USS-guided)
• Obstructive uropathy: nephrostomy or ureteric stent

Referral Criteria

• All oncological emergencies: immediate oncology/acute medicine assessment
• MSCC: MSCC coordinator (every cancer network has one)
• Neutropenic sepsis: oncology assessment unit or A&E
• TLS: haematology/oncology + HDU/ITU if severe

• Neutropenic sepsis: mortality 5-10% with prompt treatment; up to 50% if delayed
• MSCC: ambulatory status at treatment predicts outcome; >80% remain ambulatory if mobile at diagnosis; <10% regain ambulation if paraplegic
• SVCO: depends on underlying cause; stenting provides rapid relief in >90%
• Hypercalcaemia: responds to treatment in >90%; median survival after first episode approximately 3-4 months (reflects advanced disease)
• TLS: mortality 5-15% with treatment; prevention is key

Oncological Emergency Management Summary

Cairo-Bishop TLS Classification

Key Facts

Neutropenic sepsis is the most common life-threatening complication of cancer chemotherapy. It requires immediate empirical antibiotic treatment, as the immunocompromised state allows rapid progression to septic shock and death.

Epidemiology

• Complicates 15-25% of chemotherapy cycles (varies by regimen and patient factors)
• Higher risk with haematological malignancies than solid tumours
• Neutrophil nadir typically occurs 7-14 days after chemotherapy
• Annual incidence in UK cancer patients receiving chemotherapy: approximately 20,000 episodes

Aetiology

• Sources of infection: GI tract (translocation of gut flora), skin (central venous catheter), respiratory tract, urinary tract
• Often no source identified (30-50% of episodes)
• Risk factors: previous neutropenic sepsis, poor performance status, advanced disease, mucositis, central venous catheter, comorbidities (diabetes, COPD, renal impairment)

Pathophysiology

• Neutrophils are the first line of defence against bacterial and fungal infections
• With counts <0.5 × 10⁹/L, risk of serious infection increases exponentially
• <0.1 × 10⁹/L: highest risk; unable to mount inflammatory response (classic signs of infection may be absent)
• Rapid bacterial proliferation can lead to septicaemia, multi-organ dysfunction, and death within hours

Typical Presentation

• Fever ≥38°C (single reading) or ≥37.5°C sustained for >1 hour
• Patient receiving chemotherapy within the last 6 weeks
• May have rigors, sweats, tachycardia
• Signs of sepsis: hypotension, confusion, tachypnoea, oliguria

Atypical Presentation

• Hypothermia (<36°C) may indicate severe sepsis
• Absence of typical inflammatory signs (no erythema, no pus formation) due to neutropenia
• Non-specific symptoms: fatigue, malaise, myalgia

Red Flags

• Systolic BP <90 mmHg
• Temperature >39°C or <36°C
• Heart rate >130/min
• Respiratory rate >25/min
• SpO2 <91%
• Altered mental status
• Lactate >2 mmol/L
• New onset of organ dysfunction

Bedside

• ABCDE assessment
• Full observations including NEWS2 score
• Examine all potential sites: oral cavity, central line exit site, lungs, abdomen, perianal area, skin
• Do NOT perform digital rectal examination (risk of bacteraemia through damaged mucosa)

Bloods

• Blood cultures: at least 2 sets (peripheral + each lumen of central line); BEFORE antibiotics if possible but do NOT delay antibiotics
• FBC (confirm neutropenia)
• U&Es, creatinine (renal function for dose adjustment)
• LFTs
• CRP, lactate
• Coagulation screen (DIC screen if unwell)
• Blood gas

Imaging

• CXR: baseline, even if no respiratory symptoms
• CT if source unclear and patient not improving
• HRCT chest if invasive fungal infection suspected

Special Tests

• MSU, stool cultures (if diarrhoea), sputum culture, wound swabs
• CMV PCR, galactomannan, β-D-glucan if prolonged neutropenia (>7 days) and not responding to antibiotics
• Central line tip culture if line removed

Non-pharmacological

• Immediate assessment using Sepsis 6 bundle
• IV access (large bore)
• Fluid resuscitation with IV crystalloid
• Oxygen to maintain SpO2 ≥94%
• Strict hand hygiene and reverse barrier nursing
• Consider HDU/ITU if haemodynamically unstable

Pharmacological

• Empirical antibiotics within 1 hour (NICE NG151):
  • First-line: piperacillin-tazobactam 4.5g IV TDS (most common UK protocol)
  • Penicillin allergy: meropenem 1g IV TDS
  • Add vancomycin 15-20mg/kg IV BD if: suspected line infection, skin/soft tissue infection, MRSA colonisation, haemodynamic instability
  • Add gentamicin 5-7mg/kg IV if: septic shock (local protocol)
• Escalation: if no improvement at 48 hours, consider broadening spectrum (add antifungal: caspofungin 70mg IV loading then 50mg OD, or liposomal amphotericin B if neutropenia >7 days)
• G-CSF: therapeutic use in established neutropenic sepsis (controversial; consider if prolonged neutropenia expected)
• Step down: to oral antibiotics (co-amoxiclav 625mg TDS + ciprofloxacin 500mg BD) if MASCC ≥21, afebrile >48 hours, and improving

Surgical/Interventional

• Central line removal: if tunnel infection, exit site infection not responding, or persistent bacteraemia
• Drainage of any collections

Referral Criteria

• All suspected neutropenic sepsis: immediate acute oncology or A&E assessment
• Escalation to ITU if: refractory hypotension, multi-organ failure, respiratory failure
• Discussion with microbiology for resistant organisms or failure to respond

• With prompt treatment: mortality 5-10%
• If antibiotics delayed >6 hours: mortality rises to 30-50%
• MASCC score ≥21: low risk (predicted mortality <5%); suitable for early discharge/oral therapy
• MASCC score <21: high risk (mortality 10-36%); requires inpatient IV antibiotics
• Most episodes resolve within 5-7 days
• Prolonged neutropenia (>7 days): increased risk of invasive fungal infection (aspergillosis, candidiasis)

MASCC Risk Index

Neutropenic Sepsis Antibiotic Escalation

Key Facts

Tumour lysis syndrome is an oncological emergency resulting from the rapid release of intracellular contents following tumour cell destruction. Prevention, early detection, and aggressive management are essential to avoid life-threatening complications.

Epidemiology

• Incidence: 5-20% in high-risk haematological malignancies
• Rare in solid tumours (<1%) but reported in bulky/rapidly responsive disease (SCLC, germ cell tumours)
• Usually occurs within 12-72 hours of initiating treatment
• Can occasionally occur spontaneously in rapidly proliferating tumours

Aetiology

• High-risk: Burkitt lymphoma, ALL, high-grade NHL, CLL with bulky disease/high WCC
• Moderate-risk: AML, intermediate-grade NHL, CML in blast crisis
• Low-risk: most solid tumours, indolent lymphomas
• Risk factors: high tumour burden, high proliferative rate, high LDH, renal impairment, dehydration

Pathophysiology

• Rapid cell lysis releases intracellular potassium, phosphate, and nucleic acids
• Nucleic acid metabolism produces uric acid (via xanthine oxidase)

• Hypocalcaemia → tetany, seizures, cardiac arrhythmias

Metabolic Derangements

• Hyperkalaemia: muscle weakness, ECG changes (peaked T waves, widened QRS), cardiac arrhythmias
• Hyperuricaemia: flank pain, oliguria, haematuria (uric acid nephropathy)
• Hyperphosphataemia: often asymptomatic; contributes to renal failure
• Hypocalcaemia: muscle cramps, tetany (Chvostek/Trousseau sign), seizures, prolonged QT

Acute Kidney Injury

• Oliguria or anuria
• Rising creatinine
• Fluid overload

Red Flags

• Potassium >6.0 mmol/L with ECG changes
• Symptomatic hypocalcaemia (seizures, tetany)
• Anuria or rapidly rising creatinine
• Cardiac arrhythmias

Bedside

• ECG (hyperkalaemia changes: peaked T waves, prolonged PR, widened QRS, sine wave)
• Fluid balance chart (strict input/output)
• Blood pressure, observations
• Urinalysis

Bloods

• U&Es: potassium, creatinine (monitor every 6-8 hours in high-risk)
• Calcium and phosphate: monitor every 6-8 hours
• Uric acid: monitor every 6-8 hours
• LDH: marker of cell turnover
• Blood gas: acidosis (lactic acidosis from tissue ischaemia)
• FBC (WCC, platelets)

Imaging

• Renal USS: exclude obstruction if AKI
• CXR: fluid overload assessment

Special Tests

• Urine uric acid/creatinine ratio: >1.0 suggests uric acid nephropathy
• G6PD assay: BEFORE rasburicase administration (contraindicated in G6PD deficiency)

Non-pharmacological

• Aggressive IV hydration: 3L/m²/day (0.9% saline); aim urine output >2 mL/kg/hour
• Cardiac monitoring (telemetry)
• Strict fluid balance
• Avoid potassium in IV fluids
• Consider ICU admission for severe TLS
• Renal replacement therapy (haemodialysis/haemofiltration) if: refractory hyperkalaemia, volume overload, severe AKI

Pharmacological

• Prevention (high risk): rasburicase 0.2mg/kg IV single dose (can repeat); aggressive hydration
• Prevention (moderate risk): allopurinol 300mg PO OD (start 24-48h before treatment); hydration
• Hyperkalaemia management:
  • Calcium gluconate 10% 10mL IV over 10 minutes (cardiac protection)
  • Insulin 10 units + 50mL 50% glucose IV (shift potassium intracellularly)
  • Salbutamol 10-20mg nebulised
  • Calcium resonium 15-30g PO or PR (slow onset)
• Hyperphosphataemia: phosphate binders (aluminium hydroxide 500mg TDS, sevelamer)
• Hypocalcaemia: only treat if symptomatic (seizures, tetany); IV calcium gluconate 10% 10-20mL over 10 minutes; avoid calcium if hyperphosphataemia present (precipitation risk)
• Hyperuricaemia: rasburicase 0.2mg/kg IV if not already given; allopurinol for mild cases
• Alkalinisation of urine is NO longer routinely recommended (may worsen calcium phosphate precipitation)

Surgical/Interventional

• Haemodialysis/haemofiltration: for refractory hyperkalaemia (>6.5 despite medical treatment), severe AKI (oliguria/anuria), volume overload, severe metabolic acidosis
• Nephrostomy if obstructive component

Referral Criteria

• All high-risk patients: haematology/oncology and renal team awareness before starting treatment
• Established TLS: renal team review
• ICU if multi-organ dysfunction

• With prevention and prompt treatment: mortality <5%
• Without treatment: mortality up to 50-80% (particularly with renal failure and hyperkalaemia)
• AKI requiring dialysis: approximately 5-10% of TLS cases
• Most metabolic derangements resolve within 5-7 days with appropriate treatment
• Long-term renal impairment is uncommon if managed promptly

Cairo-Bishop TLS Classification

TLS Risk Stratification

Key Facts

Metastatic spinal cord compression is an oncological emergency that requires immediate recognition and treatment to prevent irreversible neurological damage. Delay in diagnosis and treatment is the most important modifiable factor.

Epidemiology

• Affects 5-10% of cancer patients
• Accounts for approximately 4,000 cases per year in England and Wales
• Most common primary cancers: lung (25%), breast (20%), prostate (15%), myeloma (10%), lymphoma (5%), renal (5%)
• Thoracic spine: 60-70%; lumbosacral: 20-30%; cervical: 10%

Aetiology

• Vertebral metastases with posterior expansion into the epidural space (85%)
• Direct epidural extension without bony involvement (10%)
• Paravertebral tumour extending through neural foramina (5%)
• Pathological vertebral collapse causing cord compression

Pathophysiology

• Tumour in epidural space compresses the spinal cord

• If untreated: irreversible infarction and permanent neurological damage
• Speed of onset influences prognosis: gradual onset (better) vs rapid (worse)
• Dexamethasone reduces vasogenic oedema, providing temporary neuroprotection

Early Symptoms

• Back pain (90%): localised, progressive, worse on coughing/straining/lying flat
• Pain may precede neurological symptoms by weeks to months
• Radicular pain (nerve root distribution)
• Band-like pain around trunk

Progressive Neurological Deficit

• Motor weakness (60-85%): upper motor neuron pattern below level of compression
• Sensory loss (40-90%): sensory level; may start distally and ascend
• Bladder/bowel dysfunction (40-60%): late sign; poor prognostic indicator; urinary retention, overflow incontinence
• Autonomic dysfunction: postural hypotension

Red Flags

• New back pain in a known cancer patient (assume MSCC until excluded)
• Progressive limb weakness
• Sensory level on examination
• Urinary retention or new-onset incontinence
• Bilateral radiculopathy
• Saddle anaesthesia (cauda equina)

Bedside

• Full neurological examination (motor, sensory level, reflexes, tone, plantar response)
• Bladder assessment (post-void residual; catheterise if retention)
• Straight leg raising, anal tone
• Spinal tenderness to percussion

Bloods

• FBC, U&Es, LFTs, bone profile (calcium)
• Myeloma screen: protein electrophoresis, immunoglobulins, Bence-Jones protein
• PSA (if prostate cancer suspected)
• CRP, ESR (infection vs malignancy)

Imaging

• MRI whole spine (with gadolinium): gold standard; must image entire spine (10-38% have multiple levels of compression)
• Requested urgently: within 24 hours if suspected on clinical grounds (NICE NG149)
• Plain X-rays: may show vertebral collapse but low sensitivity (<60%); do NOT rely on negative X-rays
• CT spine: if MRI contraindicated (pacemaker)

Special Tests

• CT-guided biopsy: if no known primary and tissue diagnosis needed
• Bone scan: assess extent of skeletal metastases

Non-pharmacological

• Spinal precautions: log-roll, flat bed rest if neurological deficit
• Nurse on pressure-relieving mattress
• VTE prophylaxis (LMWH; high DVT risk due to immobility)
• Urgent contact MSCC coordinator (each cancer network has one)

Pharmacological

• Dexamethasone 16mg IV/PO stat, then 16mg OD (reduce and taper after definitive treatment over 5-7 days)
• PPI cover (omeprazole 20mg OD)
• Blood glucose monitoring (steroid-induced hyperglycaemia)
• Analgesia: paracetamol ± opioids (morphine titrated); avoid NSAIDs if renal impairment
• Laxatives: senna 15mg ON, movicol 1 sachet OD (prevent constipation)
• Catheterisation if urinary retention

Surgical/Interventional

• Radiotherapy: most common definitive treatment; 20 Gy in 5 fractions or 30 Gy in 10 fractions; start within 24 hours
• Surgery (direct decompressive surgery + post-op RT): for selected patients meeting criteria:
  • Single or oligometastatic level of compression
  • Good performance status (ECOG 0-2)
  • Expected survival >3 months
  • Spinal instability (SINS score ≥7)
  • Progressive neurological deficit during RT
• Patchell trial evidence: surgery + RT maintained ambulation in 84% vs 57% with RT alone
• Vertebroplasty/kyphoplasty: for pain from vertebral collapse without cord compression

Referral Criteria

• Any suspected MSCC: contact MSCC coordinator immediately (NICE NG149)
• Urgent MRI within 24 hours
• Oncology and spinal surgery joint review
• Rehabilitation input: physiotherapy, occupational therapy early

• Ambulatory at treatment: >80% remain ambulatory after treatment
• Paraparetic at treatment: 30-40% regain ambulation
• Paraplegic >24-48 hours: <5-10% regain ambulation (often irreversible)
• Median survival after MSCC: approximately 3-6 months (varies by primary cancer and overall disease burden)
• Prostate and breast cancer: better survival (median 9-12 months)
• Lung cancer: worse survival (median 3-4 months)
• Bladder dysfunction at presentation: poor prognostic indicator for functional recovery

MSCC Management Pathway (NICE NG149)

Spinal Instability Neoplastic Score (SINS)

Key Facts

SVCO is the obstruction of blood flow through the superior vena cava, causing venous congestion in the head, neck, upper limbs, and upper thorax. It is most commonly caused by malignancy but has an important differential of thrombotic and non-malignant causes.

Epidemiology

• Approximately 3-4% of patients with lung cancer develop SVCO
• Incidence of non-malignant SVCO increasing due to more central venous catheter and pacemaker use
• Male predominance (reflects lung cancer demographics)

Aetiology

• Malignant (85%):
  • Lung cancer: 70% (SCLC most common, followed by NSCLC)
  • Lymphoma: 15% (particularly NHL, mediastinal)
  • Other: thymoma, germ cell tumour, metastatic disease
• Non-malignant (15%):
  • Central venous catheter-related thrombosis
  • Pacemaker leads
  • Fibrosing mediastinitis
  • Retrosternal goitre
  • Aortic aneurysm

Pathophysiology

• External compression by mediastinal mass or invasion of SVC wall
• Intraluminal thrombosis (may be superimposed on compression)
• SVC is thin-walled, low-pressure vessel surrounded by rigid structures (sternum, trachea, bronchi, aorta, lymph nodes)
• Obstruction causes venous hypertension in the head, neck, and upper extremities
• Collateral venous circulation develops over days-weeks (azygos, internal mammary, subcutaneous)
• Cerebral oedema (rare): raised intracranial pressure in severe acute obstruction

Typical Presentation

• Facial swelling and plethora (worse in morning, improves with upright posture)
• Periorbital oedema
• Upper limb swelling (bilateral)
• Distended neck veins (non-pulsatile)
• Visible chest wall collateral veins
• Dyspnoea
• Headache (worse on bending forward, lying flat, or straining)

Severe Symptoms

• Stridor (tracheal compression)
• Hoarseness (recurrent laryngeal nerve involvement)
• Dysphagia (oesophageal compression)
• Confusion, visual disturbance (cerebral oedema)

Red Flags

• Stridor or airway compromise
• Altered consciousness (cerebral oedema)
• Papilloedema
• Rapid onset (more likely thrombosis or aggressive tumour)
• Known central venous catheter (thrombosis)

Bedside

• Observations (HR, BP, SpO2, RR)
• Examine for collateral veins, JVP, facial swelling
• Pemberton's sign
• Pulse oximetry

Bloods

• FBC, U&Es, LFTs, calcium, LDH
• Tumour markers (AFP, βhCG if germ cell tumour suspected)
• Coagulation screen (thrombosis assessment)
• Blood gas if respiratory symptoms

Imaging

• CT chest with IV contrast (CT venogram): investigation of choice; shows site and extent of obstruction, identifies underlying cause, guides stent placement
• CXR: mediastinal widening, right paratracheal mass (abnormal in 80%)
• CT head: if cerebral oedema suspected

Special Tests

• Tissue diagnosis: essential before treatment if no prior histology
  • CT-guided biopsy of mediastinal mass
  • Bronchoscopy with biopsy
  • Lymph node biopsy (cervical/supraclavicular)
  • Sputum cytology
• Venography: rarely needed; CT venogram usually sufficient

Non-pharmacological

• Elevate head of bed (30-45°)
• Avoid IV access in upper limbs if possible (poor venous return)
• Avoid constricting clothing

Pharmacological

• Dexamethasone 16mg IV stat then 8mg BD: reduces peritumoral oedema; particularly effective in lymphoma/thymoma
• PPI cover (omeprazole 20mg OD)
• Anticoagulation: if thrombotic component identified; LMWH initially
• Definitive treatment based on histology:
  • SCLC: chemotherapy (cisplatin/carboplatin + etoposide); rapid response expected
  • Lymphoma: chemotherapy ± steroids (R-CHOP for DLBCL)
  • NSCLC: radiotherapy or chemoradiotherapy

Surgical/Interventional

• SVC stenting: provides rapid symptom relief (within 24-48 hours in >90%)
  • Indicated for: severe symptoms, poor response to medical treatment, bridge to definitive therapy
  • Performed by interventional radiology under fluoroscopic guidance
• Radiotherapy: palliative (8-12 Gy in 1-2 fractions for rapid relief, or 20-30 Gy in 5-10 fractions)

Referral Criteria

• All suspected SVCO: urgent oncology referral
• Airway compromise: immediate anaesthetic/ENT assessment
• Stenting: interventional radiology referral
• Unknown histology: urgent tissue diagnosis required

• Depends on underlying cause and treatment response
• SCLC with SVCO: median survival approximately 6-12 months (chemosensitive)
• NSCLC with SVCO: median survival approximately 3-6 months
• Lymphoma with SVCO: good prognosis if chemosensitive (>50% 5-year survival for some subtypes)
• SVC stenting: symptom relief in >90% within 48-72 hours; re-occlusion rate 10-15%
• Non-malignant SVCO: good prognosis with anticoagulation and/or stenting

SVCO Management Algorithm

Causes of SVCO by Frequency

Key Facts

Hypercalcaemia is the most common metabolic emergency in oncology and is often a sign of advanced disease. Prompt recognition and treatment are essential to prevent life-threatening cardiac arrhythmias, renal failure, and coma.

Epidemiology

• Affects 10-30% of cancer patients during their illness
• Most common with: squamous cell carcinomas (lung, head & neck), breast cancer, renal cell carcinoma, myeloma
• Often indicates advanced disease with poor prognosis

Aetiology

• Humoral hypercalcaemia (80%): PTHrP (parathyroid hormone-related peptide) secretion by tumour
  • Most common: squamous cell lung cancer, renal cell, breast, bladder, ovarian
• Osteolytic metastases (20%): local osteoclast activation by cytokines (RANKL, IL-6)
  • Breast cancer, myeloma
• Calcitriol-mediated (<1%): ectopic 1,25(OH)₂D production
  • Lymphoma (particularly Hodgkin)
• Ectopic PTH production: extremely rare

Pathophysiology

• PTHrP mimics PTH at the PTH receptor: increases osteoclastic bone resorption, increases renal calcium reabsorption, increases phosphate excretion
• Osteolytic metastases: tumour cells in bone produce cytokines that activate osteoclasts (vicious cycle of bone destruction)

• Calcium affects cardiac conduction (shortened QT), neurological function (confusion), and GI motility (constipation)

Mild Hypercalcaemia (2.6-3.0 mmol/L)

• Often asymptomatic
• Mild fatigue, constipation
• Polyuria, polydipsia

Moderate Hypercalcaemia (3.0-3.5 mmol/L)

• Nausea, vomiting, anorexia
• Constipation, abdominal pain
• Confusion, drowsiness
• Dehydration
• Muscle weakness

Severe Hypercalcaemia (>3.5 mmol/L)

• Obtundation, coma
• Cardiac arrhythmias (shortened QT, bradycardia, heart block)
• Renal failure
• Pancreatitis
• Cardiac arrest

Red Flags

• Corrected calcium >3.5 mmol/L
• Altered conscious level
• ECG changes (shortened QT, wide QRS, arrhythmias)
• Renal failure (oliguria)
• Severe dehydration

Bedside

• ECG: shortened QT interval, wide QRS, arrhythmias
• Fluid balance chart
• Observations including GCS

Bloods

• Corrected calcium (adjusted for albumin) or ionised calcium
• Phosphate: low in PTHrP-mediated (PTH-like effect), variable in osteolytic
• PTH: suppressed in malignancy (distinguishes from primary hyperparathyroidism where PTH is raised/inappropriately normal)
• PTHrP: elevated in humoral hypercalcaemia
• U&Es (renal function; dehydration)
• Albumin (for calcium correction)
• ALP (bone metastases; often raised)
• Vitamin D (25(OH)D and 1,25(OH)₂D)
• Myeloma screen: protein electrophoresis, Bence-Jones protein, immunoglobulins

Imaging

• CXR (primary lung cancer, lymphadenopathy)
• Bone scan or skeletal survey (myeloma; osteolytic metastases)
• CT if staging/primary unknown

Special Tests

• Urine calcium:creatinine ratio (to exclude familial hypocalciuric hypercalcaemia)

Non-pharmacological

• Aggressive IV rehydration: 0.9% saline 3-4L over first 24 hours (most important initial step)
• Mobilise if possible (immobility worsens hypercalcaemia)
• Stop offending drugs (thiazides, calcium supplements, vitamin D supplements)
• Strict fluid balance and urine output monitoring
• Cardiac monitoring if calcium >3.5 mmol/L

Pharmacological

• Zoledronic acid 4mg IV over 15 minutes (onset 2-4 days; peak effect 7 days; duration 3-4 weeks)
  • Caution: dose adjust for eGFR 30-60; avoid if eGFR <30
• Pamidronate 60-90mg IV over 2-4 hours: alternative bisphosphonate
• Denosumab 120mg SC: for bisphosphonate-refractory cases or renal impairment; onset 4-10 days; monitor for hypocalcaemia
• Calcitonin 4-8 units/kg SC/IM 12-hourly: rapid onset (hours) but tachyphylaxis within 48 hours; useful as bridge
• Prednisolone 40-60mg OD: for lymphoma/myeloma-related hypercalcaemia (vitamin D-mediated or steroid-responsive tumours)
• Loop diuretics (furosemide 20-40mg IV): ONLY after adequate rehydration and if fluid overload; not routine
• Definitive: treat underlying malignancy (chemotherapy, hormonal therapy, radiotherapy)

Surgical/Interventional

• Haemodialysis: for life-threatening hypercalcaemia refractory to medical treatment (Ca >4.5 mmol/L or with renal failure)

Referral Criteria

• Moderate-severe hypercalcaemia: acute medical/oncology admission
• Corrected calcium >3.5 mmol/L: consider HDU/ITU monitoring
• Refractory hypercalcaemia: discuss with endocrinology and oncology
• If underlying malignancy unknown: urgent investigation for primary

• Median survival after first episode: approximately 3-4 months (indicates advanced disease)
• Response to bisphosphonates: normalisation of calcium in 60-90% within 7 days
• Recurrence is common: repeat bisphosphonate/denosumab as needed
• Patients with hypercalcaemia responding to cancer treatment have better prognosis
• Myeloma patients may have better outcomes as the hypercalcaemia is more treatment-responsive

Severity Classification

Mechanism of Hypercalcaemia by Cancer Type

Key Facts

Lung cancer remains the leading cause of cancer death worldwide and in the UK. Advances in molecular profiling, targeted therapy, and immunotherapy have significantly improved outcomes for selected patients.

Epidemiology

• UK incidence: approximately 48,500 new cases per year (3rd most common cancer)
• Mortality: approximately 35,000 deaths per year (leading cause of cancer death)
• Peak incidence: 70-74 years
• Male:female ratio approaching 1:1 (increasing in women)
• 5-year survival: approximately 15-16% overall; 55-60% for Stage I
• NHS Targeted Lung Health Check programme being rolled out for early detection

Aetiology

• Smoking (85-90%): dose-response relationship; risk proportional to pack-years; risk declines after cessation but never returns to baseline
• Passive smoking: 20-30% increased risk
• Occupational exposure: asbestos (synergistic with smoking), radon, arsenic, chromium, nickel
• Air pollution: estimated to contribute to 1-2% of lung cancers
• Genetic: family history increases risk 1.5-2×; EGFR mutations more common in non-smokers/East Asian populations
• Pre-existing lung disease: COPD, pulmonary fibrosis

Pathophysiology

• Adenocarcinoma (40%): peripheral location; most common subtype; common in non-smokers; glandular differentiation; EGFR, ALK, KRAS mutations
• Squamous cell carcinoma (25-30%): central location, cavitating; strongly associated with smoking; may produce PTHrP (hypercalcaemia)
• Large cell carcinoma (10%): poorly differentiated; often peripheral
• Small cell lung cancer (15%): central, rapidly growing, early metastasis; neuroendocrine origin; strongly associated with smoking; paraneoplastic syndromes common (SIADH, Lambert-Eaton, Cushing)

Local Symptoms

• Persistent cough (most common presenting symptom)
• Haemoptysis
• Dyspnoea
• Chest pain (pleuritic or dull ache)
• Recurrent pneumonia (post-obstructive)

Local Invasion

• Hoarseness (recurrent laryngeal nerve palsy)
• Dysphagia (oesophageal compression)
• SVCO (facial swelling, distended veins)
• Pancoast tumour: shoulder/arm pain, Horner syndrome (miosis, ptosis, anhidrosis), T1 weakness
• Phrenic nerve palsy (raised hemidiaphragm)

Paraneoplastic Syndromes

• SIADH (hyponatraemia) - SCLC
• Ectopic ACTH (Cushing) - SCLC
• Lambert-Eaton myasthenic syndrome - SCLC
• Hypercalcaemia (PTHrP) - squamous cell
• Hypertrophic pulmonary osteoarthropathy (HPOA) - clubbing, periostitis

Red Flags

• Haemoptysis at any age
• Persistent cough >3 weeks with risk factors
• Unexplained weight loss with chest symptoms
• New hoarseness with smoking history
• Recurrent pneumonia in same location

Bedside

• CXR: first-line investigation (lesion visible in ~75%); hilar mass, peripheral nodule, pleural effusion, collapse, mediastinal widening
• Sputum cytology: low sensitivity (~30%) but specific if positive
• Pulse oximetry

Bloods

• FBC, U&Es (Na⁺ for SIADH), LFTs, calcium, LDH, albumin
• Tumour markers: not routinely used for diagnosis

Imaging

• CT chest/abdomen/adrenals with contrast: staging; characterise primary lesion and assess lymph nodes, liver, adrenals
• PET-CT: staging and assessment of mediastinal lymph nodes; guides biopsy site
• MRI brain: if SCLC or NSCLC Stage IB+ (brain metastasis screening)
• Bone scan: if bone pain or raised ALP

Special Tests

• Tissue biopsy for histological diagnosis:
  • CT-guided percutaneous biopsy (peripheral lesions)
  • Bronchoscopy ± EBUS (endobronchial USS-guided biopsy) for central lesions and mediastinal lymph nodes
  • Thoracoscopy (VATS) for pleural disease
• Molecular profiling (NSCLC, non-squamous): EGFR mutations, ALK rearrangement, ROS1 rearrangement, BRAF V600E, KRAS G12C, PD-L1 expression (TPS), NTRK fusions
• Pulmonary function tests: pre-operative assessment (FEV1, TLCO); predict postoperative lung function

Non-pharmacological

• MDT discussion (thoracic surgery, medical oncology, clinical oncology, radiology, pathology, respiratory medicine, CNS)
• Smoking cessation
• Pulmonary rehabilitation (pre-operative)
• Psychological support

Pharmacological

• Early-stage NSCLC (Stage I-II):
  • Surgery (lobectomy) + adjuvant chemotherapy if Stage IB-IIIA (cisplatin-based, e.g. cisplatin + vinorelbine × 4 cycles)
  • Adjuvant osimertinib for resected EGFR-mutant NSCLC (ADAURA trial)
  • Adjuvant atezolizumab for resected PD-L1+ NSCLC (IMpower010)
• Locally advanced NSCLC (Stage III):
  • Concurrent chemoradiotherapy (cisplatin + etoposide or cisplatin + vinorelbine + 60-66 Gy RT) → durvalumab maintenance (PACIFIC trial)
• Advanced NSCLC (Stage IV):
  • PD-L1 ≥50%, no actionable mutation: pembrolizumab monotherapy (KEYNOTE-024)
  • PD-L1 <50%, no mutation: pembrolizumab + carboplatin + pemetrexed (KEYNOTE-189)
  • EGFR mutation: osimertinib (FLAURA trial)
  • ALK rearrangement: alectinib (ALEX trial)
  • BRAF V600E: dabrafenib + trametinib
  • KRAS G12C: sotorasib (CodeBreaK 100)
• SCLC:
  • Limited stage: cisplatin 80mg/m² + etoposide 100mg/m² × 4 cycles + concurrent thoracic RT (45 Gy); prophylactic cranial irradiation (PCI) if response
  • Extensive stage: carboplatin + etoposide + durvalumab × 4 cycles → durvalumab maintenance (CASPIAN trial); PCI if response

Surgical/Interventional

• Lobectomy (preferred) or pneumonectomy: curative for early-stage NSCLC
• VATS (video-assisted thoracoscopic surgery): minimally invasive; preferred approach
• SABR/SBRT: for medically inoperable early-stage NSCLC (e.g. 54 Gy in 3 fractions)
• Endobronchial interventions: stenting, debulking, laser for airway obstruction
• Pleural procedures: talc pleurodesis for malignant effusion, IPC insertion

Referral Criteria

• Suspected lung cancer: urgent 2-week wait referral per NICE NG12
• All confirmed: MDT discussion before any treatment
• Molecular testing results: to determine targeted therapy eligibility
• Palliative care: early involvement recommended (improves quality of life and survival)

• Overall 5-year survival: 15-16% (all stages combined)
• Stage IA: 80-90% 5-year survival
• Stage IB: 68%
• Stage II: 50-60%
• Stage IIIA: 25-35%
• Stage IIIB-C: 10-15%
• Stage IV: 5-10% (improving with immunotherapy and targeted therapy)
• SCLC limited stage: median survival 15-20 months; 5-year survival 10-15%
• SCLC extensive stage: median survival 10-12 months; rare long-term survivors

Lung Cancer TNM Staging (8th Edition Summary)

Key Landmark Trials

Key Facts

Breast cancer is the most common cancer in the UK and a leading cause of cancer mortality in women. Treatment is increasingly personalised based on molecular subtype, stage, and genomic profiling.

Epidemiology

• UK incidence: approximately 56,000 new cases per year (most common cancer overall)
• Mortality: approximately 11,500 deaths per year
• Lifetime risk: 1 in 7 women; 1 in 870 men
• Peak incidence: 60-64 years
• 5-year survival: approximately 85-90% (improvement due to screening and better treatments)

Aetiology

• Hormonal factors: early menarche, late menopause, nulliparity, late first pregnancy (>30), HRT (combined > oestrogen-only), OCP (small increased risk while taking)
• Genetic: BRCA1 (60-80% lifetime risk, typically TNBC), BRCA2 (40-60%, typically ER+), TP53 (Li-Fraumeni), PALB2, CHEK2, ATM
• Lifestyle: obesity (postmenopausal), alcohol (dose-dependent, 7% increase per unit/day), physical inactivity
• Previous: previous breast cancer, atypical ductal hyperplasia, LCIS, chest wall irradiation
• Protective: breastfeeding, multiparity, physical activity, late menarche

Pathophysiology

• Ductal carcinoma in situ (DCIS): pre-invasive; proliferation within ducts; 30-50% progress to invasive cancer over 10-20 years
• Invasive ductal carcinoma (NST): 75-80% of invasive cancers
• Invasive lobular carcinoma: 10-15%; diffuse infiltration pattern; may be bilateral
• Special types: mucinous, tubular, medullary, papillary (generally better prognosis)

Typical Presentation

• Painless breast lump (most common)
• Detected on screening mammography (20-30% of diagnoses)
• Breast skin changes: peau d'orange, dimpling, tethering
• Nipple changes: inversion, discharge (bloody), Paget's disease (eczematous change over nipple/areola)
• Axillary lump (lymphadenopathy)

Advanced Disease

• Bone pain (most common site of metastasis)
• Dyspnoea (pleural effusion, lung metastases)
• Jaundice, abdominal pain (liver metastases)
• Headache, neurological symptoms (brain metastases)

Red Flags

• Hard, irregular, fixed breast lump
• Bloody nipple discharge (unilateral)
• Skin tethering or peau d'orange
• Axillary lymphadenopathy
• Inflammatory breast cancer (rapidly enlarging, erythematous, warm breast)
• Male breast lump

Bedside

• Triple assessment (NICE NG101):
  1. Clinical examination
  2. Imaging (mammography ± USS)
  3. Core biopsy (14G needle)
• Examine both breasts, axillae, supraclavicular fossae

Bloods

• FBC, U&Es, LFTs, calcium, ALP (baseline; staging if advanced)
• Tumour markers: CA 15-3 (monitoring, not diagnosis)

Imaging

• Mammography: first-line for women ≥40; screening detects 6-8 cancers per 1,000 women screened
• Breast USS: first-line for women <40 (dense breast tissue); USS-guided core biopsy
• MRI breast: for lobular carcinoma, BRCA carriers, implants, neoadjuvant response assessment
• CT chest/abdomen/pelvis + bone scan or PET-CT: for staging in advanced/symptomatic disease

Special Tests

• Core biopsy (14G): histological diagnosis, ER/PR status, HER2 status (IHC/FISH), Ki67
• Oncotype DX / EndoPredict / Prosigna: genomic assays for ER+/HER2-/node-negative to guide adjuvant chemotherapy benefit
• Sentinel lymph node biopsy: staging of axilla (avoids full clearance if negative)
• BRCA testing: all <50, TNBC, bilateral, male, or family history meeting criteria

Non-pharmacological

• MDT discussion
• Psychological support and breast care nurse specialist
• Fertility preservation counselling (before chemotherapy)
• Genetic counselling for BRCA carriers

Pharmacological

• Endocrine therapy (ER+):
  • Premenopausal: tamoxifen 20mg OD for 5-10 years (± GnRH agonist)
  • Postmenopausal: aromatase inhibitor (anastrozole 1mg, letrozole 2.5mg, or exemestane 25mg) for 5-10 years
  • CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) added for metastatic HR+/HER2-
• Anti-HER2 therapy (HER2+):
  • Adjuvant: trastuzumab 6mg/kg IV 3-weekly for 1 year + chemotherapy (docetaxel + carboplatin)
  • Neoadjuvant: trastuzumab + pertuzumab + chemotherapy (NeoSphere, PEONY trials)
  • Metastatic: trastuzumab deruxtecan (T-DXd) (DESTINY-Breast03)
• Chemotherapy:
  • Neoadjuvant or adjuvant: FEC-D (fluorouracil, epirubicin, cyclophosphamide → docetaxel) or dose-dense AC-T
  • Guided by genomic assays in ER+/HER2-/node-negative (TAILORx, RxPONDER trials)
• TNBC:
  • Neoadjuvant: pembrolizumab + chemotherapy (KEYNOTE-522)
  • BRCA-mutated: olaparib (OlympiAD) or talazoparib
  • Metastatic: sacituzumab govitecan (ASCENT trial)
• Bisphosphonates: zoledronic acid adjuvant in postmenopausal (AZURE, ABCSG-12) - reduces bone recurrence

Surgical/Interventional

• Breast-conserving surgery (wide local excision) + adjuvant radiotherapy: preferred for early-stage (equivalent survival to mastectomy)
• Mastectomy ± immediate reconstruction: for multicentric disease, large tumour:breast ratio, patient preference
• Sentinel lymph node biopsy (SLNB): staging; if positive → axillary clearance or axillary radiotherapy
• Neoadjuvant chemotherapy: to downstage tumour enabling BCS
• Risk-reducing mastectomy: for BRCA carriers (reduces risk by 90%)
• Adjuvant radiotherapy: whole breast after BCS; chest wall after mastectomy if high risk; boost to tumour bed

Referral Criteria

• Breast lump in woman ≥30: urgent 2-week wait referral (NICE NG12)
• Breast lump in woman <30 with concerning features: urgent referral
• Skin changes, nipple changes: urgent referral
• Family history meeting criteria: genetics referral (NICE CG164)

• Overall 5-year survival: 85-90%
• Stage I: >95% 5-year survival
• Stage II: 80-90%
• Stage III: 50-70%
• Stage IV: 25% (improving with modern therapies)
• ER+ tumours: better short-term prognosis but can recur late (up to 20 years)
• HER2+ with trastuzumab: significantly improved (50% reduction in recurrence)
• TNBC: worst short-term prognosis; lower rate of late recurrence
• Oncotype DX low recurrence score: excellent prognosis with endocrine therapy alone (no chemotherapy benefit)

Molecular Subtypes and Treatment

Key Breast Cancer Trials

Key Facts

Colorectal cancer is common and highly preventable through screening. The adenoma-carcinoma sequence provides a window for early detection and polypectomy. Treatment is multimodal, with surgery for early disease and systemic therapy for advanced disease.

Epidemiology

• UK incidence: approximately 42,900 new cases per year (4th most common cancer)
• Mortality: approximately 16,500 deaths per year (2nd most common cause of cancer death)
• Peak incidence: 70-79 years
• Male:female ratio approximately 1.2:1
• 5-year survival: approximately 60% overall; >90% for Stage I
• Incidence declining in screening-age population due to polypectomy at screening

Aetiology

• Sporadic (75-80%): accumulation of somatic mutations; risk factors include age, red/processed meat, obesity, alcohol, smoking, physical inactivity
• Hereditary:
  • Lynch syndrome (HNPCC): 3-5% of CRC; autosomal dominant; MMR mutations (MLH1, MSH2, MSH6, PMS2); 80% lifetime CRC risk
  • FAP (familial adenomatous polyposis): <1%; APC gene mutation; >100 polyps by age 20; near 100% CRC risk without prophylactic colectomy
  • MUTYH-associated polyposis: autosomal recessive; attenuated polyposis
• Inflammatory bowel disease: UC (8-10× risk after 20 years of pancolitis); Crohn's colitis

Pathophysiology

• Microsatellite instability (MSI) pathway: defective MMR → accumulation of mutations at microsatellite repeats; sporadic (MLH1 promoter methylation) or hereditary (Lynch syndrome)

Right-Sided Colon Cancer

• Iron deficiency anaemia (insidious blood loss)
• Vague abdominal pain
• Palpable right iliac fossa mass
• Weight loss
• Often presents late (large bowel calibre allows growth without obstruction)

Left-Sided Colon Cancer

• Change in bowel habit (increasing constipation or alternating)
• Rectal bleeding (mixed with stool)
• Colicky abdominal pain
• Tenesmus
• May present as large bowel obstruction

Rectal Cancer

• Fresh rectal bleeding
• Mucus per rectum
• Tenesmus
• Sense of incomplete evacuation
• Palpable on digital rectal examination

Red Flags

• Unexplained iron deficiency anaemia (any age)
• Rectal bleeding with change in bowel habit
• Abdominal mass
• Large bowel obstruction
• New-onset symptoms >50 years with weight loss

Bedside

• Digital rectal examination (essential; palpable low rectal tumours)
• Abdominal examination (mass, hepatomegaly)
• FIT (faecal immunochemical test): quantitative; >10 mcg Hb/g faeces is positive

Bloods

• FBC (iron deficiency anaemia)
• U&Es, LFTs (liver metastases)
• CEA: baseline (not diagnostic; prognostic and monitoring)
• Iron studies (ferritin, transferrin saturation)

Imaging

• Colonoscopy: gold standard for diagnosis; allows biopsy and polypectomy
• CT colonography (virtual colonoscopy): alternative if colonoscopy incomplete or patient unfit
• CT chest/abdomen/pelvis: staging
• MRI pelvis: local staging for rectal cancer (T and N staging, CRM involvement)
• PET-CT: if potentially resectable metastatic disease

Special Tests

• Histopathology: adenocarcinoma subtype, grade, lymphovascular invasion
• MMR immunohistochemistry / MSI testing: all CRC (Lynch screening and treatment implications)
• RAS (KRAS/NRAS) and BRAF mutation testing: for metastatic disease (guides targeted therapy)
• Staging laparoscopy: if peritoneal disease suspected

Non-pharmacological

• MDT discussion
• Enhanced recovery after surgery (ERAS) protocol
• Stoma care specialist nurse if stoma formed
• Psychological support

Pharmacological

• Adjuvant chemotherapy (Stage III, selected Stage II with high-risk features):
  • FOLFOX (5-FU + leucovorin + oxaliplatin) × 6 months (MOSAIC trial) or 3 months (IDEA trial for low-risk Stage III)
  • Capecitabine monotherapy (alternative for Stage III; X-ACT trial)
• Neoadjuvant (rectal cancer):
  • Long-course chemoradiotherapy (capecitabine + 45-50.4 Gy RT over 5 weeks) then surgery at 6-8 weeks
  • Short-course RT (25 Gy in 5 fractions) then surgery at 1 week or delayed
  • Total neoadjuvant therapy (TNT): chemotherapy + RT before surgery (RAPIDO, PRODIGE 23 trials)
• Metastatic CRC:
  • RAS wild-type, left-sided: FOLFOX/FOLFIRI + cetuximab (anti-EGFR)
  • RAS wild-type, right-sided: FOLFOX/FOLFIRI + bevacizumab (anti-VEGF)
  • RAS mutant: FOLFOX/FOLFIRI + bevacizumab
  • MSI-H/dMMR: pembrolizumab first-line (KEYNOTE-177)
  • BRAF V600E: encorafenib + cetuximab (BEACON trial)

Surgical/Interventional

• Right hemicolectomy: caecal and ascending colon tumours
• Left hemicolectomy: descending colon tumours
• Sigmoid colectomy: sigmoid tumours
• Anterior resection: upper/mid rectal tumours
• Abdominoperineal resection (APR): low rectal tumours (permanent colostomy)
• TME (total mesorectal excision): standard for rectal cancer surgery
• Liver resection: potentially curative for isolated liver metastases (20-40% 5-year survival)
• Lung metastasectomy: selected cases
• Emergency surgery: obstruction (stenting as bridge to surgery or Hartmann's procedure), perforation

Referral Criteria

• NICE NG12 2-week wait criteria
• Positive FIT: urgent colonoscopy
• All confirmed CRC: MDT discussion
• Family history meeting criteria: genetics referral and surveillance colonoscopy

• Overall 5-year survival: 60%
• Stage I (Dukes A): >90%
• Stage II (Dukes B): 80%
• Stage III (Dukes C): 65% (with adjuvant chemotherapy)
• Stage IV (Dukes D): 10-15% (higher with resectable metastatic disease: 30-40%)
• MSI-H tumours: better prognosis at Stage II; respond well to immunotherapy at Stage IV
• CEA surveillance: rising CEA after treatment indicates recurrence
• Follow-up: CT surveillance, CEA monitoring, colonoscopy at 1 and 3 years post-surgery

Dukes vs TNM Staging

NHS Bowel Cancer Screening Programme

Key Facts

Prostate cancer has a wide spectrum of biological behaviour, from indolent disease requiring only monitoring to aggressive metastatic disease. Understanding risk stratification and appropriate treatment selection is crucial.

Epidemiology

• UK incidence: approximately 52,300 new cases per year (most common cancer in men)
• Mortality: approximately 12,000 deaths per year (2nd most common cause of cancer death in men)
• Peak incidence: 75-79 years
• Lifetime risk: 1 in 8 men
• 5-year survival: approximately 87% overall; >95% for localised disease

Aetiology

• Age: strongest risk factor; rare before 50; median age at diagnosis 72
• Ethnicity: Black men have 2× higher risk; earlier onset
• Family history: first-degree relative with prostate cancer doubles risk; BRCA2 carriers 3-5× risk
• Genetic: BRCA2, HOXB13, Lynch syndrome
• Protective: 5-alpha reductase inhibitors (finasteride, dutasteride) reduce incidence by 25% but may select for higher-grade tumours

Pathophysiology

• Adenocarcinoma (>95%): arises from prostatic epithelial cells, typically in the peripheral zone

• Multifocal in approximately 85% of cases

• Castration-resistant prostate cancer (CRPC): disease progresses despite castrate testosterone levels; may still be AR-driven

Early Disease (Often Asymptomatic)

• Detected on PSA testing or incidental finding
• May have LUTS (frequency, hesitancy, nocturia) but these more commonly due to BPH
• Hard, irregular nodule on DRE

Locally Advanced Disease

• Haematuria, haematospermia
• Obstructive symptoms: acute urinary retention
• Perineal pain
• Erectile dysfunction
• Lower limb oedema (lymphatic/venous obstruction)

Metastatic Disease

• Bone pain (axial skeleton; sclerotic metastases)
• Pathological fractures
• Spinal cord compression
• Weight loss, fatigue, anorexia
• Anaemia

Red Flags

• Hard irregular prostate on DRE
• Rapidly rising PSA (PSA velocity >0.75 ng/mL/year)
• New bone pain with raised PSA
• Lower limb weakness in man with prostate cancer (MSCC)
• PSA >100 ng/mL (almost always metastatic)

Bedside

• Digital rectal examination (DRE): assess prostate size, shape, consistency, nodules
• Urinalysis (exclude UTI)

Bloods

• PSA: age-adjusted reference ranges (50-59: <3, 60-69: <4, >70: <5 ng/mL); also check if symptoms or abnormal DRE
• FBC (anaemia in advanced disease)
• U&Es, ALP (bone metastases), LDH

Imaging

• mpMRI prostate: first-line before biopsy (NICE NG131); PI-RADS 1-2 (negative) avoids biopsy; PI-RADS 3-5 → targeted biopsy
• TRUS biopsy or MRI-targeted transperineal biopsy: histological diagnosis; at least 12 cores
• CT chest/abdomen/pelvis and bone scan: staging for intermediate/high-risk disease
• PSMA PET-CT: superior staging for high-risk disease; detects small volume metastases

Special Tests

• Gleason grading: pathologist grades tumour architecture (Grade Groups 1-5)
• Genomic tests: Oncotype DX GPS, Prolaris (risk stratification for active surveillance candidates)
• BRCA2/ATM testing: for metastatic disease (PARP inhibitor eligibility)
• Bone density (DEXA): before long-term ADT

Non-pharmacological

• Active surveillance: for low-risk disease (Grade Group 1, PSA <10, ≤T2a); regular PSA, mpMRI, and re-biopsy; ProtecT trial supports safety
• Watchful waiting: for men with limited life expectancy; treat symptoms only

Pharmacological

• Androgen deprivation therapy (ADT):
  • GnRH agonists: goserelin 3.6mg SC monthly or 10.8mg 3-monthly; triptorelin, leuprorelin
  • GnRH antagonist: degarelix 240mg SC loading → 80mg monthly (no testosterone flare)
  • Anti-androgens: bicalutamide 50mg OD (combined androgen blockade) or 150mg monotherapy
• Radical RT ± ADT: EBRT (78 Gy in 39 fractions or hypofractionated) ± 6 months ADT (intermediate-risk) or 2-3 years ADT (high-risk; STAMPEDE trial)
• Metastatic hormone-sensitive prostate cancer (mHSPC):
  • ADT + docetaxel (STAMPEDE/CHAARTED) or
  • ADT + abiraterone 1000mg OD + prednisolone 5mg OD (STAMPEDE/LATITUDE) or
  • ADT + enzalutamide 160mg OD (ENZAMET) or
  • ADT + apalutamide (TITAN)
• Castration-resistant prostate cancer (CRPC):
  • Abiraterone + prednisolone (COU-AA-301/302)
  • Enzalutamide (PREVAIL/AFFIRM)
  • Docetaxel 75mg/m² 3-weekly
  • Cabazitaxel (post-docetaxel; TROPIC trial)
  • Olaparib (BRCA1/2 or ATM mutated; PROfound trial)
  • Lutetium-177 PSMA (PSMA-expressing; VISION trial)
  • Radium-223 (bone-only metastases; ALSYMPCA trial)

Surgical/Interventional

• Radical prostatectomy (open, laparoscopic, or robot-assisted): for localised disease; cure rate >90% for organ-confined disease
• Brachytherapy (low-dose rate or high-dose rate): alternative for low/intermediate risk
• Pelvic lymph node dissection: at time of radical prostatectomy for intermediate/high-risk
• TURP: for obstructive symptoms (palliative)
• Orchidectomy (bilateral): surgical castration; rapid, permanent; rarely performed now

Referral Criteria

• Abnormal DRE or raised PSA: urgent 2-week wait urology referral
• Confirmed prostate cancer: MDT discussion
• BRCA carrier or strong family history: genetics referral and early PSA screening (from age 40)
• Advanced disease: oncology referral

• Overall 5-year survival: 87% (one of the highest of any cancer)
• Localised disease: >95% 10-year survival with active surveillance, surgery, or RT (ProtecT trial)
• Locally advanced: 80-85% with multimodal treatment
• Metastatic hormone-sensitive: median survival 4-6 years with intensified treatment (ADT + docetaxel or abiraterone)
• Castration-resistant metastatic: median survival 2-3 years with modern sequential therapies
• Bone metastases: managed but significantly impacts QoL (pain, fractures, MSCC)

Risk Stratification (NICE NG131)

Key Prostate Cancer Trials

Key Facts

This entry covers ovarian cancer from the oncology perspective, focusing on systemic treatment principles. Ovarian cancer remains the most lethal gynaecological malignancy, largely because it presents at advanced stage. BRCA testing and PARP inhibitors have significantly altered the treatment landscape.

Epidemiology

• UK incidence: approximately 7,500 new cases per year
• Mortality: approximately 4,100 deaths per year
• Peak incidence: 60-64 years
• Lifetime risk: 1.8% overall; 40-60% with BRCA1; 10-30% with BRCA2

Aetiology

• As per gynaecological ovarian cancer entry: sporadic (85-90%), hereditary (10-15%)
• BRCA1, BRCA2, Lynch syndrome
• Protective: COC use, multiparity, breastfeeding, tubal ligation

Pathophysiology

• HGSC arises from serous tubal intraepithelial carcinoma (STIC) in the fallopian tube fimbriae
• Universal TP53 mutations; 50% have homologous recombination deficiency (HRD)
• Transcoelomic spread: peritoneal deposits, omental cake
• BRCA-deficient tumours: impaired DNA repair → sensitivity to platinum and PARP inhibitors (synthetic lethality)

Symptoms

• Persistent bloating, early satiety, pelvic/abdominal pain, urinary urgency/frequency
• Ascites, palpable mass, pleural effusion
• Weight loss, fatigue
• Change in bowel habit

Red Flags

• Persistent symptoms ≥12 times/month, new onset, in women ≥50
• Ascites with pelvic mass
• CA-125 ≥35 IU/mL
• Family history of BRCA-associated cancers

Bedside

• Abdominal examination: ascites, palpable mass
• Pelvic examination

Bloods

• CA-125, HE4, FBC, U&Es, LFTs, albumin
• CEA, CA19-9 (if GI primary suspected)
• AFP, βhCG, LDH (young women: germ cell tumours)

Imaging

• Pelvic USS, CT CAP, PET-CT for staging
• MRI for indeterminate lesions

Special Tests

• RMI calculation
• Tissue biopsy (CT-guided or ascitic cytology)
• BRCA1/2 and HRD testing on tumour
• MMR/MSI testing

Non-pharmacological

• MDT discussion at specialist gynaecological oncology centre
• Genetic counselling for BRCA carriers and families
• Nutritional and psychological support

Pharmacological

• First-line: carboplatin AUC5 + paclitaxel 175mg/m² q3w × 6 cycles
• Bevacizumab 15mg/kg q3w: added for Stage IIIB-IV; continued as maintenance
• PARP inhibitor maintenance:
  • Olaparib 300mg BD: for BRCA-mutated (SOLO-1: 70% risk reduction)
  • Niraparib 200-300mg OD: for all comers after platinum response (PRIMA)

• Platinum-sensitive relapse (>6 months): rechallenge with platinum doublet ± bevacizumab; PARP maintenance
• Platinum-resistant relapse (<6 months): pegylated liposomal doxorubicin, weekly paclitaxel, topotecan, gemcitabine

Surgical/Interventional

• Primary debulking surgery: total hysterectomy + BSO + omentectomy + appendicectomy + peritoneal biopsies + lymphadenectomy; aim complete cytoreduction
• Interval debulking: after NACT if primary surgery not feasible
• Fertility-sparing surgery: unilateral salpingo-oophorectomy for Stage IA, Grade 1 in young women
• Risk-reducing BSO: for BRCA1 (by age 35-40) and BRCA2 (by age 40-45)

Referral Criteria

• RMI >250: urgent specialist referral
• Confirmed ovarian cancer: specialist gynaecological oncology centre
• All patients: BRCA testing
• BRCA carriers: genetics referral for family cascade testing

• Overall 5-year survival: 45%
• Stage I: 90%; Stage II: 60-70%; Stage III: 25-30%; Stage IV: 10-15%
• Complete cytoreduction: strongest surgical prognostic factor
• BRCA-mutated: paradoxically better prognosis (platinum and PARP sensitivity)
• PARP inhibitor era: significantly prolonged PFS and emerging OS benefits
• Most patients with advanced disease relapse within 18-24 months
• CA-125 monitoring: rising levels may indicate relapse (but early treatment of asymptomatic relapse does not improve OS per MRC OV05/EORTC 55955)

Key Ovarian Cancer Trials

FIGO Staging Summary

Key Facts

This entry covers cervical cancer from the oncology treatment perspective. Cervical cancer is highly preventable through vaccination and screening. Treatment is stage-dependent, with concurrent chemoradiotherapy being standard for locally advanced disease.

Epidemiology

• UK incidence: approximately 3,200 cases per year
• Mortality: approximately 850 deaths per year
• Peak incidence: 30-34 years
• Declining incidence due to screening and expected to decline further with HPV vaccination

Aetiology

• Persistent high-risk HPV infection (types 16, 18 most important)
• Risk factors: early sexual debut, multiple partners, immunosuppression, smoking, long-term COC

Pathophysiology

• Squamous cell carcinoma (70-80%): arises from transformation zone
• Adenocarcinoma (20-25%): arises from endocervical glandular cells
• HPV E6/E7 oncoproteins inactivate p53/Rb

Early Disease

• Postcoital bleeding, intermenstrual bleeding
• Vaginal discharge (blood-stained/watery)
• Often asymptomatic (detected on screening)

Advanced Disease

• Pelvic pain, leg oedema, renal failure (ureteric obstruction)
• Haematuria, rectal bleeding (local invasion)
• Fistulae (vesicovaginal, rectovaginal) in very advanced/recurrent disease

Red Flags

• Visible cervical lesion on speculum
• Postcoital bleeding in any age group
• Unexplained renal failure in a woman

Bedside

• Speculum and bimanual/rectal examination

Bloods

• FBC, U&Es (renal function), LFTs
• SCC antigen (squamous marker)

Imaging

• MRI pelvis: local staging
• CT CAP: distant staging
• PET-CT: increasingly used for staging and response assessment

Special Tests

• Cervical biopsy: histological confirmation
• EUA: clinical staging
• Cystoscopy/sigmoidoscopy if bladder/rectal involvement suspected

Non-pharmacological

• MDT discussion
• Fertility counselling for young women
• Psychological support

Pharmacological

• Early-stage (IA-IB1): surgery ± adjuvant RT if high-risk features (positive margins, LVI, deep invasion)
• Locally advanced (IB2-IVA): concurrent chemoradiotherapy:
  • Cisplatin 40mg/m² IV weekly × 5-6 cycles
  • EBRT 45-50 Gy in 25 fractions
  • Intracavitary brachytherapy (total equivalent dose >80 Gy to point A)
  • Treatment completed within 56 days (prolongation worsens outcomes)
• Metastatic/recurrent:
  • Pembrolizumab + cisplatin/carboplatin + paclitaxel ± bevacizumab (KEYNOTE-826)
  • Tisotumab vedotin (antibody-drug conjugate targeting tissue factor; innovaTV 204)
• Adjuvant RT ± concurrent cisplatin: after radical hysterectomy with high-risk features (Sedlis criteria, Peters criteria)

Surgical/Interventional

• Cone biopsy / simple hysterectomy: Stage IA1 without LVI
• Radical hysterectomy (Wertheim) + pelvic lymphadenectomy: Stage IA2-IB1 (open approach preferred after LACC trial)
• Radical trachelectomy: fertility-sparing for Stage IA2-IB1 (tumour <2cm)
• Pelvic exenteration: central recurrence after RT (anterior, posterior, or total)
• Sentinel lymph node mapping: emerging for early-stage

Referral Criteria

• Visible cervical lesion: urgent 2-week wait
• Confirmed cervical cancer: specialist gynaecological oncology centre
• All women: HPV vaccination recommended for prevention

• Overall 5-year survival: 60-65%
• Stage IA: 95%
• Stage IB: 80-85%
• Stage II: 60-70%
• Stage III: 30-40%
• Stage IV: 15-20%
• Concurrent chemoradiotherapy reduces risk of death by 30-40% compared to RT alone
• HPV vaccination expected to make cervical cancer a rare disease in coming decades

Treatment by FIGO Stage

Key Trials

Key Facts

Testicular cancer is one of the great success stories of modern oncology, with cure rates exceeding 95% even in metastatic disease. Cisplatin-based combination chemotherapy and multidisciplinary management are key to these outcomes.

Epidemiology

• UK incidence: approximately 2,400 new cases per year
• Peak incidence: 25-35 years
• Incidence has been rising over the past 50 years (reason unclear)
• Caucasian men have highest incidence worldwide
• Mortality: approximately 60 deaths per year in the UK (reflects high cure rate)

Aetiology

• Cryptorchidism: strongest risk factor (4-8× risk; not eliminated by orchidopexy but allows better surveillance)
• Previous testicular cancer: 2-5% risk of contralateral tumour
• Family history: first-degree relative 4-8× risk
• Klinefelter syndrome (47,XXY): increased risk of mediastinal germ cell tumours
• Testicular microlithiasis: controversial risk factor; surveillance if symptomatic
• Germ cell neoplasia in situ (GCNIS): precursor lesion; 50% progress to invasive cancer within 5 years

Pathophysiology

• Seminoma: uniform cells resembling primordial germ cells; radiosensitive; slower growth; good prognosis
• Non-seminomatous germ cell tumours (NSGCT): includes embryonal carcinoma (aggressive), yolk sac tumour (AFP production), choriocarcinoma (βhCG, haematogenous spread), teratoma (mature/immature)
• Mixed germ cell tumours: contain both seminomatous and non-seminomatous elements; treated as NSGCT
• Spread: lymphatic to retroperitoneal lymph nodes (para-aortic) → haematogenous to lungs, liver, brain, bone
• Excellent chemosensitivity due to high mitotic rate and intact apoptotic pathways

Typical Presentation

• Painless testicular swelling or lump (most common)
• Sensation of heaviness in scrotum
• Dull ache in testis, groin, or lower abdomen
• Detected incidentally after trauma

Advanced Disease

• Back pain (retroperitoneal lymphadenopathy)
• Dyspnoea, cough (pulmonary metastases)
• Gynaecomastia (βhCG-producing tumours)
• Neck mass (supraclavicular lymphadenopathy)

Red Flags

• Any new testicular lump in a young man
• Rapidly enlarging testis
• Gynaecomastia in young man
• Unexplained back pain in young man with testicular abnormality
• Elevated AFP or βhCG

Bedside

• Testicular examination (size, consistency, tenderness, transillumination)
• Abdominal examination (retroperitoneal mass)
• Supraclavicular lymph nodes

Bloods

• Tumour markers (pre-orchidectomy):
  • AFP: raised in yolk sac tumour and embryonal carcinoma; NEVER raised in pure seminoma
  • βhCG: raised in choriocarcinoma and 10-20% of seminomas
  • LDH: non-specific; reflects tumour burden
• FBC, U&Es, LFTs
• Semen analysis and sperm banking: BEFORE orchidectomy/chemotherapy

Imaging

• Scrotal USS: first-line; hypoechoic intratesticular mass is cancer until proven otherwise
• CT chest/abdomen/pelvis: staging (retroperitoneal lymph nodes, pulmonary metastases)
• MRI brain: if choriocarcinoma (high risk of brain metastases) or neurological symptoms

Special Tests

• Serial tumour markers: post-orchidectomy; half-lives: AFP 5-7 days, βhCG 24-36 hours
• Histopathology after orchidectomy: definitive diagnosis, subtype classification
• PET-CT: role in post-chemotherapy assessment of residual seminoma masses (>3cm)

Non-pharmacological

• Sperm banking BEFORE orchidectomy (30-50% of men have impaired spermatogenesis at diagnosis)
• Testicular prosthesis option
• Psychological support
• Long-term follow-up (late effects of treatment)

Pharmacological

• Stage I seminoma (post-orchidectomy options):
  • Active surveillance (98-99% cure; relapse 15-20%, salvaged with treatment)
  • Single-dose carboplatin AUC7 (reduces relapse to 5%)
  • Adjuvant radiotherapy to para-aortic nodes (20 Gy; reduces relapse to <5%)
• Stage I NSGCT (post-orchidectomy options):
  • Active surveillance (70-80% cure without further treatment; 30% relapse)
  • Adjuvant BEP × 1 cycle (reduces relapse to <3%)
• Metastatic seminoma and NSGCT:
  • BEP: bleomycin 30,000 IU days 1, 8, 15 + etoposide 100mg/m² days 1-5 + cisplatin 20mg/m² days 1-5; q21 days
  • Good prognosis: 3 cycles BEP (or 4 × EP if bleomycin contraindicated)
  • Intermediate/poor prognosis: 4 cycles BEP
  • Bleomycin pulmonary toxicity: monitor PFTs; stop if TLCO falls >25%
• Post-chemotherapy residual mass:
  • NSGCT: retroperitoneal lymph node dissection (RPLND) if residual mass >1cm
  • Seminoma: PET-CT at 6 weeks; surgery only if PET-avid and >3cm
• Salvage chemotherapy: TIP (paclitaxel + ifosfamide + cisplatin) or high-dose chemotherapy with autologous stem cell rescue

Surgical/Interventional

• Radical inguinal orchidectomy: diagnostic and therapeutic; approach through inguinal incision (NOT trans-scrotal)
• RPLND: post-chemotherapy for residual NSGCT masses; nerve-sparing technique to preserve ejaculation
• Metastasectomy: resection of residual pulmonary or other metastases

Referral Criteria

• Any testicular lump in a young man: urgent USS within 2 weeks
• Confirmed testicular cancer: urgent referral to specialist supra-network centre
• All patients: sperm banking before any treatment
• Follow-up: long-term surveillance for relapse and late effects

• Overall cure rate: >95%
• Stage I: 99% cure rate with surveillance and salvage treatment
• Good prognosis metastatic (IGCCCG): 92% 5-year survival
• Intermediate prognosis: 80% 5-year survival
• Poor prognosis: 48% 5-year survival
• Long-term effects of treatment: cardiovascular disease (2× risk), secondary malignancy, nephrotoxicity, ototoxicity (cisplatin), pulmonary toxicity (bleomycin), infertility, metabolic syndrome
• Late relapse (>2 years): occurs in 2-3%; often chemo-resistant; surgery is primary treatment

IGCCCG Prognostic Classification

Tumour Marker Interpretation

Key Facts

RCC is notable for its resistance to chemotherapy and radiotherapy, but the introduction of targeted therapies and immunotherapy has significantly improved outcomes in advanced disease.

Epidemiology

• Approximately 13,300 new cases/year in the UK
• Male:female ratio 2:1
• Peak incidence age 60-70 years
• Incidence rising (partly due to increased incidental detection)

Aetiology

• Smoking: strongest modifiable risk factor (2× risk)
• Obesity: 2× risk (especially in women)
• Hypertension: independent risk factor
• Von Hippel-Lindau (VHL) syndrome: autosomal dominant; bilateral/multifocal clear cell RCC
• Acquired cystic kidney disease: in dialysis patients (50× risk)
• Family history: 2-4× risk with first-degree relative

Pathophysiology

• Papillary RCC (10-15%): types 1 and 2; MET pathway activation
• Chromophobe RCC (5%): better prognosis
• RCC characteristically extends into the renal vein and IVC (tumour thrombus)
• Metastatic spread: lung (75%), bone, liver, brain, contralateral kidney

Classic Triad (only 10-15%)

• Haematuria (visible or non-visible)
• Loin/flank pain
• Palpable abdominal/loin mass

Other Features

• Incidental finding on imaging (>50% of cases)
• Unexplained weight loss
• Fever of unknown origin
• Varicocele (left-sided, does not disappear on lying down - left renal vein obstruction)
• Paraneoplastic syndromes (20-30%)

Paraneoplastic Syndromes

• Polycythaemia (EPO secretion)
• Hypercalcaemia (PTHrP)
• Hypertension (renin secretion)
• Stauffer syndrome (non-metastatic hepatic dysfunction; raised ALP, deranged LFTs)

Red Flags

• Visible haematuria in adults ≥45 (2-week wait referral)
• Non-visible haematuria with raised PSA or symptoms
• Palpable renal mass
• Left varicocele that does not decompress on lying flat

Bedside

• Urinalysis (haematuria)
• Blood pressure
• Abdominal examination

Bloods

• FBC (polycythaemia or anaemia), U&Es, LFTs, calcium, ALP, LDH
• ESR/CRP (may be raised as paraneoplastic)

Imaging

• CT chest/abdomen/pelvis with contrast: investigation of choice for diagnosis and staging
  • Renal mass with contrast enhancement is RCC until proven otherwise
• CT renal angiography: pre-operative vascular mapping for partial nephrectomy
• MRI: IVC tumour thrombus assessment, indeterminate lesions
• Bone scan/PET-CT: if bone metastases or advanced disease suspected

Special Tests

• Renal biopsy: not routinely required for solid enhancing masses (risk of seeding); used for small masses (<4cm) if active surveillance considered, or metastatic disease for histological confirmation
• Bosniak classification: for cystic renal lesions (I-IV; III-IV warrant surgery)
• Genetic testing if VHL or hereditary syndrome suspected

Non-pharmacological

• Active surveillance: for small renal masses (<4cm) in elderly/frail patients
• MDT discussion mandatory

Pharmacological

• Metastatic RCC - first-line:
  • Favourable/intermediate risk: nivolumab + ipilimumab (CheckMate-214) or pembrolizumab + axitinib (KEYNOTE-426)
  • Poor risk: nivolumab + ipilimumab
  • Alternative: cabozantinib monotherapy
• Second-line: nivolumab monotherapy (CheckMate-025), cabozantinib, lenvatinib + everolimus
• Adjuvant: pembrolizumab for high-risk RCC post-nephrectomy (KEYNOTE-564)
• Cytokine therapy (historical): IL-2, interferon-alpha (largely replaced)

Surgical/Interventional

• Partial nephrectomy: standard for T1a (<4cm) and selected T1b (4-7cm); nephron-sparing
• Radical nephrectomy: for larger/more advanced tumours (T2+, tumour thrombus)
• IVC thrombectomy: for tumour thrombus extending into IVC (may require cardiopulmonary bypass if atrial extension)
• Metastasectomy: selected patients with limited metastatic disease (oligometastatic)
• Ablation (cryotherapy/radiofrequency): small tumours in non-surgical candidates
• Cytoreductive nephrectomy: in metastatic RCC, role now more selective (CARMENA trial)

Referral Criteria

• Visible haematuria in ≥45: 2-week wait urology referral
• Suspicious renal mass on imaging: urgent urology referral
• All confirmed RCC: renal cancer MDT

• Stage I (T1): 5-year survival >90% (with surgery)
• Stage II (T2): 5-year survival 75-85%
• Stage III (T3/N1): 5-year survival 50-60%
• Stage IV (metastatic): 5-year survival 10-20% (improving with immunotherapy)
  • IMDC favourable risk: median OS >4 years
  • IMDC poor risk: median OS 12-18 months
• Median survival with untreated metastatic RCC: 6-12 months
• Spontaneous regression of metastases after nephrectomy: rare but documented (<1%)
• Late recurrence can occur >10 years after initial treatment

IMDC (Heng) Prognostic Criteria for Metastatic RCC

Bosniak Classification of Cystic Renal Masses

Key Facts

Bladder cancer has a high recurrence rate for superficial disease and requires lifelong cystoscopic surveillance. Muscle-invasive disease has a significantly worse prognosis.

Epidemiology

• Approximately 10,300 new cases/year in the UK
• Male:female ratio 3:1
• Median age at diagnosis: 73 years
• ~5,500 deaths/year

Aetiology

• Smoking: most important risk factor (50% of cases); 3× increased risk
• Occupational exposure: aromatic amines (rubber, dye, chemical industries) - latency 15-40 years
• Schistosomiasis (S. haematobium): squamous cell carcinoma in endemic areas (Egypt, Middle East)
• Pelvic radiotherapy: previous RT increases risk
• Cyclophosphamide: haemorrhagic cystitis → increased risk
• Chronic catheterisation/irritation: squamous cell carcinoma

Pathophysiology

• NMIBC (75%): confined to mucosa (Ta, CIS) or lamina propria (T1); high recurrence rate (50-70%)
• MIBC (25%): invades muscularis propria (T2) or beyond; higher metastatic potential
• Carcinoma in situ (CIS): flat, high-grade; high progression risk to muscle-invasive disease
• FGFR3 mutations: common in low-grade NMIBC (targeted by erdafitinib)
• P53 mutations: common in high-grade and muscle-invasive disease

Typical Presentation

• Painless visible (macroscopic) haematuria: most common (80-90%)
• Non-visible (microscopic) haematuria
• Lower urinary tract symptoms (frequency, urgency - especially with CIS)
• Recurrent UTIs

Advanced Disease

• Pelvic pain
• Flank pain (ureteric obstruction)
• Lower limb oedema (lymphatic/venous obstruction)
• Bone pain (metastases)
• Weight loss, fatigue

Red Flags

• Visible haematuria in any adult ≥45 (2-week wait referral)
• Non-visible haematuria with raised PSA, UTI symptoms, or recurrent UTIs ≥60
• Palpable suprapubic mass
• Hydronephrosis on imaging

Bedside

• Urinalysis (haematuria)
• DRE (exclude prostate pathology)
• Abdominal examination

Bloods

• FBC, U&Es, LFTs
• PSA (if indicated)

Imaging

• CT urogram: investigation of choice for visible haematuria (detects upper tract tumours)
• USS kidneys and bladder: alternative initial imaging
• CT chest/abdomen/pelvis: staging for MIBC
• MRI pelvis: local staging (T stage assessment)

Special Tests

• Flexible cystoscopy: gold standard for diagnosis; outpatient under local anaesthetic
• TURBT (transurethral resection of bladder tumour): diagnostic (provides tissue) and therapeutic for NMIBC
  • Must include detrusor muscle in specimen to assess muscle invasion
• Urine cytology: useful for high-grade and CIS (low sensitivity for low-grade)
• Re-TURBT: at 6 weeks for high-grade T1 or if detrusor muscle absent from initial specimen

Non-pharmacological

• Smoking cessation (reduces recurrence risk)
• Cystoscopic surveillance post-TURBT
• MDT discussion for all MIBC

Pharmacological

• NMIBC - low/intermediate risk: single dose intravesical mitomycin C 40mg at TURBT
• NMIBC - high risk (T1 high-grade, CIS): intravesical BCG (Bacillus Calmette-Guérin) induction (6 weekly instillations) + maintenance (3 weekly at 3, 6, 12 months)
• MIBC - neoadjuvant chemotherapy: gemcitabine + cisplatin × 3-4 cycles before radical cystectomy (improves 5-year survival by 5-8%)
• Metastatic/advanced: gemcitabine + cisplatin first-line; pembrolizumab or atezolizumab for PD-L1+ cisplatin-ineligible patients; avelumab maintenance after chemo (JAVELIN Bladder 100)
• FGFR-altered: erdafitinib (targeted therapy)
• Enfortumab vedotin (antibody-drug conjugate): for post-ICI/post-chemo advanced urothelial carcinoma

Surgical/Interventional

• TURBT: first-line for NMIBC (diagnostic and therapeutic)
• Radical cystectomy + urinary diversion: standard for MIBC (T2+)
  • Ileal conduit (Bricker) or neobladder reconstruction
  • Includes pelvic lymphadenectomy
• Radical radiotherapy (55Gy/20 fractions): bladder-preserving alternative for MIBC with concurrent chemo (mitomycin C + 5-FU, or gemcitabine)
• Palliative radiotherapy: for haemorrhage, pain
• Nephrostomy: for obstructive uropathy

Referral Criteria

• Visible haematuria ≥45: 2-week wait urology referral
• Non-visible haematuria ≥60 with dysuria or raised WCC: 2-week wait
• All MIBC: MDT discussion

• NMIBC (Ta low-grade): 5-year survival >90%; recurrence rate 50-70% (requires surveillance)
• T1 high-grade: 5-year survival 70-80%; progression to MIBC in 30-50% if inadequately treated
• CIS: high progression risk (50-70% without BCG); BCG response rate 70-80%
• MIBC (T2-T3): 5-year survival 40-60% with radical treatment
• Metastatic: median survival 12-15 months with chemotherapy; improving with immunotherapy
• Overall 5-year survival: approximately 50%
• Lifelong cystoscopic surveillance is required for NMIBC (check cystoscopy at 3 months, then scheduled intervals)

Bladder Cancer Staging (TNM)

Risk Stratification for NMIBC

Key Facts

Melanoma treatment has been revolutionised by immunotherapy and targeted therapy. Early detection remains critical for cure.

Epidemiology

• Fifth most common cancer in the UK (~16,700 new cases/year)
• ~2,300 deaths/year
• Incidence rising rapidly (UV exposure, sun-seeking behaviour)
• More common in fair-skinned populations
• Median age: 65 years; can affect younger adults

Aetiology

• UV radiation: most important environmental risk factor (intermittent intense exposure > chronic)
• Sunburn history: particularly childhood sunburns
• Fair skin, red/blonde hair, blue eyes (Fitzpatrick skin types I-II)
• Multiple naevi (>50 common naevi or >5 atypical naevi)
• Family history: 2× risk with first-degree relative
• Genetic: CDKN2A mutations (familial melanoma); BRAF, NRAS somatic mutations
• Previous melanoma: 3-5% risk of second primary
• Immunosuppression: transplant recipients have 3-5× risk

Pathophysiology

• Arises from malignant transformation of melanocytes (neural crest-derived)
• BRAF V600E mutation: constitutive activation of MAPK pathway (50% of cutaneous melanomas)
• NRAS mutations: 15-20%
• C-KIT mutations: mucosal and acral melanomas
• Subtypes: superficial spreading (70%), nodular (15-20%), lentigo maligna (5-10%), acral lentiginous (5%)
• Spread: lymphatic (regional nodes), haematogenous (lung, brain, liver, bone, skin)

ABCDE Criteria

• Asymmetry of shape
• Border irregularity
• Colour variation (multiple shades of brown, black, red, white, blue)
• Diameter >6mm
• Evolution (change in size, shape, colour, or new symptoms)

Subtypes

• Superficial spreading: most common; irregular border, colour variation, radial growth phase
• Nodular: rapidly growing dome-shaped/polypoid nodule; often amelanotic; worst prognosis (no radial growth phase)
• Lentigo maligna: on sun-damaged skin (face) in elderly; slow-growing
• Acral lentiginous: palms, soles, subungual; most common in dark-skinned individuals

Red Flags

• Rapidly changing pigmented lesion
• New pigmented lesion in an adult
• Amelanotic (non-pigmented) nodule that is growing
• Subungual pigmentation (Hutchinson's sign - periungual pigmentation suggests melanoma)
• Satellite lesions or in-transit metastases

Bedside

• Dermoscopy: essential for assessment of pigmented lesions (improves diagnostic accuracy by 30%)
• Full skin examination (check all sites including scalp, soles, nails, mucous membranes)
• Lymph node palpation (regional drainage basins)

Bloods

• LDH: elevated in metastatic melanoma (prognostic marker)
• FBC, U&Es, LFTs (baseline)
• S100B protein: monitoring marker in advanced disease

Imaging

• CT chest/abdomen/pelvis: staging for ≥stage IIB or symptomatic
• MRI brain: if neurological symptoms or stage III/IV
• PET-CT: for staging equivocal findings, recurrence detection
• USS of regional lymph nodes: if suspicious on examination

Special Tests

• Excision biopsy (full thickness, 2mm clinical margin): standard diagnostic procedure
  • Never shave biopsy or incisional biopsy of suspected melanoma (need full Breslow measurement)
• Sentinel lymph node biopsy (SLNB): offered for Breslow ≥0.8mm or <0.8mm with ulceration/high mitotic rate
  • Staging procedure; prognostic value (positive SLNB → stage III)
• BRAF mutation testing: all stage III/IV melanomas (guides targeted therapy)
• Gene expression profiling: emerging prognostic tools (DecisionDx-Melanoma)

Non-pharmacological

• Sun protection advice (sunscreen SPF 30+, protective clothing, avoid sunburn)
• Regular skin self-examination education
• Surveillance: clinical examination ± imaging per risk stratification

Pharmacological

• Adjuvant (stage III):
  • Nivolumab (CheckMate-238) or pembrolizumab (KEYNOTE-054) for 1 year
  • Dabrafenib + trametinib for BRAF-mutated (COMBI-AD)
• Metastatic (stage IV):
  • BRAF-mutated: dabrafenib 150mg BD + trametinib 2mg OD (COMBI-d/v trials)
  • BRAF wild-type or any: nivolumab 3mg/kg + ipilimumab 1mg/kg × 4 then nivolumab maintenance (CheckMate-067)
  • Alternative: pembrolizumab monotherapy
• Response rates: combination immunotherapy 50-60% ORR; BRAF-targeted 65-70% ORR but shorter duration

Surgical/Interventional

• Wide local excision (WLE): definitive primary treatment
  • In situ: 5mm margin
  • Breslow ≤1mm: 1cm margin
  • Breslow 1-2mm: 1-2cm margin
  • Breslow >2mm: 2cm margin
• SLNB: staging for ≥0.8mm Breslow
• Completion lymph node dissection (CLND): no longer routine for positive SLNB (DeCOG-SLT, MSLT-II trials)
• Metastasectomy: for oligometastatic disease (especially pulmonary, can be curative)
• Isolated limb perfusion: for in-transit metastases

Referral Criteria

• Suspected melanoma: 2-week wait referral to dermatology/skin cancer clinic
• All confirmed melanomas: skin cancer MDT
• Stage III/IV: medical oncology referral
• Family history/high risk: specialist dermatology surveillance

• Stage IA (≤0.8mm, no ulceration): 5-year survival >99%
• Stage IB (≤1mm with ulceration or 1-2mm without): 5-year survival >95%
• Stage II (>1mm with high-risk features): 5-year survival 70-90% (depending on thickness)
• Stage III (nodal involvement): 5-year survival 40-78% (depending on tumour burden)
• Stage IV (metastatic): 5-year survival ~50% with combination immunotherapy (from <10% pre-immunotherapy era)
• Overall 5-year survival: approximately 90% (reflecting majority early-stage diagnosis)
• Prognosis for metastatic disease has been transformed by immunotherapy

Breslow Thickness and Excision Margins

Key Trials in Melanoma

Key Facts

Head and neck cancer requires multidisciplinary management involving surgeons, oncologists, speech therapists, dietitians, and specialist nurses.

Epidemiology

• Approximately 12,400 new cases/year in the UK
• Male:female ratio 2:1 (narrowing)
• HPV-related oropharyngeal cancer incidence is rising rapidly in younger patients
• Tobacco and alcohol-related cancers declining

Aetiology

• Smoking: most important risk factor; dose-response relationship
• Alcohol: independent risk factor; synergistic with smoking
• HPV-16: responsible for 70-80% of oropharyngeal cancers in the UK (tonsil, base of tongue)
• Betel nut chewing: oral cavity cancer (South Asian populations)
• Poor oral hygiene: oral cavity cancer
• EBV: nasopharyngeal carcinoma

Pathophysiology

• 90% are squamous cell carcinoma

• HPV-positive: p16 overexpression (surrogate marker); better prognosis, younger patients, often non-smokers
• HPV-negative: TP53 mutations, associated with smoking/alcohol; worse prognosis
• Spread: local invasion, lymphatic (cervical nodes - 40% have nodal disease at presentation), distant metastases rare at diagnosis (lung, bone, liver)

By Site

• Oral cavity: non-healing ulcer (>3 weeks), white/red patch (leukoplakia/erythroplakia), loose teeth, difficulty chewing
• Oropharynx: sore throat, dysphagia, referred otalgia, neck lump (cystic - HPV+)
• Larynx: hoarseness (>3 weeks), stridor, dysphagia
• Hypopharynx: dysphagia, referred otalgia, weight loss, neck lump
• Nasopharynx: unilateral nasal obstruction, epistaxis, serous otitis media, cranial nerve palsies

Red Flags (NICE NG12)

• Unexplained neck lump persisting >3 weeks
• Hoarseness >3 weeks
• Oral ulcer not healing >3 weeks
• Persistent sore throat >3 weeks (especially with otalgia)
• Unexplained dysphagia
• Unilateral serous otitis media in an adult

Bedside

• Full ENT examination including flexible nasendoscopy
• Oral examination (inspection, palpation of tongue and floor of mouth)
• Neck palpation (cervical lymph nodes)

Bloods

• FBC, U&Es, LFTs, TFTs (baseline before treatment)
• EBV serology (if nasopharyngeal carcinoma suspected)

Imaging

• CT neck with contrast: initial staging (tumour extent, nodal disease)
• MRI: superior soft tissue detail (oral cavity, oropharynx, parapharyngeal space)
• PET-CT: staging for advanced disease; detection of unknown primary; post-treatment response assessment
• CT chest: exclude lung metastases or synchronous primary
• OPG (orthopantomogram): dental assessment before radiotherapy

Special Tests

• Biopsy: incisional biopsy, punch biopsy, or EUA with biopsy under GA
• Fine needle aspiration (FNA): for neck lumps (cytology)
• p16 IHC: surrogate marker for HPV in oropharyngeal carcinoma
• HPV DNA testing: confirmatory if p16 positive
• Panendoscopy (EUA): assessment of tumour extent, biopsy, exclude synchronous primary
• Speech and swallowing assessment: baseline before treatment

Non-pharmacological

• MDT discussion mandatory (surgeon, oncologist, SALT, dietitian, CNS, dental)
• Smoking and alcohol cessation
• Nutritional optimisation (PEG/RIG feeding may be needed during treatment)
• Dental assessment and extractions before radiotherapy (to prevent osteoradionecrosis)
• Speech and language therapy
• Psychological support

Pharmacological

• Concurrent chemoradiotherapy (locally advanced): cisplatin 100mg/m² on days 1, 22, 43 with 70Gy RT over 7 weeks
  • Alternative: weekly cisplatin 40mg/m²
  • If cisplatin contraindicated: cetuximab 400mg/m² loading then 250mg/m² weekly with RT (Bonner trial)
• Recurrent/metastatic: pembrolizumab + platinum + 5-FU (KEYNOTE-048) or cetuximab + platinum + 5-FU (EXTREME trial)
• Induction chemotherapy (TPF: docetaxel, cisplatin, 5-FU): in selected cases to reduce tumour volume before definitive treatment

Surgical/Interventional

• Primary surgery: for oral cavity cancers (preferred over RT for most oral cavity subsites) and selected early-stage laryngeal/oropharyngeal cancers
• Transoral robotic surgery (TORS) or transoral laser microsurgery (TLM): minimally invasive for oropharyngeal and laryngeal tumours
• Neck dissection: selective or radical for nodal disease (with primary surgery or after chemoRT if residual disease)
• Reconstruction: free tissue transfer (radial forearm flap, fibula, ALT flap) for defect reconstruction
• Total laryngectomy: for advanced laryngeal cancer or recurrence after RT; permanent tracheostomy

Referral Criteria

• Suspected head and neck cancer: 2-week wait referral (NICE NG12)
• All confirmed cancers: head and neck cancer MDT
• Unknown primary with neck lump: urgent ENT/MDT assessment

• Early-stage (I-II): 5-year survival 70-90% (site-dependent)
• Locally advanced (III-IVA): 5-year survival 40-60% with chemoRT
• Metastatic/recurrent: median survival 10-15 months (improving with immunotherapy)
• HPV-positive oropharyngeal: 5-year survival ~80% (significantly better than HPV-negative ~40%)
• Laryngeal cancer (early): 5-year survival >90% with voice preservation
• Overall 5-year survival: approximately 60%
• Late effects of treatment: xerostomia, dysphagia, osteoradionecrosis, hypothyroidism, carotid stenosis, second primary cancers

HPV-Positive vs HPV-Negative Oropharyngeal Cancer

Key Trials

Key Facts

Oesophageal cancer has a poor prognosis overall due to late presentation, but outcomes for operable disease have improved with modern neoadjuvant regimens.

Epidemiology

• ~9,300 new cases/year in the UK; ~7,900 deaths/year
• Male:female ratio 3:1 (adenocarcinoma); SCC more equal
• Adenocarcinoma incidence rising rapidly (now >50% of oesophageal cancers in the UK)
• Squamous cell carcinoma incidence declining (linked to reduced smoking)

Aetiology

• Adenocarcinoma: Barrett's oesophagus (10× risk), GORD, obesity, smoking
• SCC: smoking, alcohol (synergistic), hot drinks, caustic injury, Plummer-Vinson syndrome, achalasia, tylosis

Pathophysiology

• Oesophagus lacks serosa → early transmural spread and lymph node involvement
• Lymphatic drainage is longitudinal → skip metastases common

Typical Symptoms

• Progressive dysphagia: initially solids, then liquids (by the time dysphagia occurs, >50% of lumen is occluded)
• Weight loss (often >10%)
• Odynophagia (painful swallowing)
• Regurgitation
• Chest pain or epigastric pain
• Iron deficiency anaemia

Advanced Disease

• Hoarseness (recurrent laryngeal nerve involvement)
• Persistent cough or aspiration pneumonia (tracheo-oesophageal fistula)
• Hepatomegaly (liver metastases)
• Supraclavicular lymphadenopathy (Virchow's node - left)

Red Flags

• Progressive dysphagia (any age - urgent OGD)
• Unintentional weight loss >3kg
• Iron deficiency anaemia without obvious cause
• Dysphagia + weight loss + age ≥55
• New dyspepsia in patients ≥55 with alarm symptoms

Bedside

• BMI, nutritional assessment
• Abdominal examination (hepatomegaly, ascites)
• Cervical lymph node palpation (Virchow's)

Bloods

• FBC (anaemia), U&Es, LFTs, albumin (nutritional status)
• CEA (monitoring, not diagnostic)

Imaging

• OGD with biopsy: gold standard diagnostic investigation
• CT chest/abdomen/pelvis: TNM staging
• EUS (endoscopic ultrasound): T and N staging (depth of invasion)
• PET-CT: detects distant metastases, guides treatment decisions
• Staging laparoscopy: for GOJ tumours (peritoneal disease)

Special Tests

• Histopathology: SCC vs adenocarcinoma, differentiation grade
• HER2 testing: for GOJ adenocarcinoma (trastuzumab if HER2+, ToGA trial)
• PD-L1 CPS: guides immunotherapy use
• Nutritional assessment and dietitian review
• Swallowing assessment

Non-pharmacological

• MDT discussion mandatory (upper GI surgeon, oncologist, CNS, dietitian, SALT)
• Nutritional optimisation (supplementary feeds, consider feeding jejunostomy)
• Smoking and alcohol cessation
• Psychological support

Pharmacological

• Operable adenocarcinoma: perioperative FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) × 4 pre-op + 4 post-op (FLOT4 trial)
• Operable SCC: neoadjuvant CROSS regimen (carboplatin + paclitaxel + 41.4Gy RT) then surgery (CROSS trial)
• Inoperable locally advanced: definitive chemoradiotherapy (cisplatin + 5-FU + 50Gy)
• Metastatic adenocarcinoma: platinum + fluoropyrimidine ± trastuzumab if HER2+ (ToGA); nivolumab + chemo if PD-L1 CPS ≥5 (CheckMate-649)
• Metastatic SCC: platinum + 5-FU + pembrolizumab if PD-L1 CPS ≥10 (KEYNOTE-590)
• Adjuvant: nivolumab after neoadjuvant chemoRT if residual disease (CheckMate-577)

Surgical/Interventional

• Ivor Lewis oesophagectomy: right thoracotomy + laparotomy (mid/lower oesophagus)
• McKeown (3-stage) oesophagectomy: includes cervical anastomosis (upper oesophagus)
• Minimally invasive oesophagectomy: laparoscopic/thoracoscopic (reducing morbidity)
• Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD): for T1a (intramucosal) adenocarcinoma or high-grade dysplasia in Barrett's
• Radiofrequency ablation (RFA): for Barrett's with dysplasia (after EMR of visible lesions)
• Palliative stenting: for dysphagia in inoperable disease (self-expanding metal stent)
• Palliative RT: for dysphagia, bleeding

Referral Criteria

• Dysphagia at any age: urgent 2-week wait OGD
• Age ≥55 with unexplained weight loss and upper GI symptoms: 2-week wait
• All confirmed oesophageal cancers: upper GI cancer MDT

• Stage I: 5-year survival 60-80%
• Stage II-III (operable): 5-year survival 35-45% with neoadjuvant + surgery
• Stage IV (metastatic): median survival 8-12 months
• Overall 5-year survival: approximately 15-20%
• FLOT4 (adenocarcinoma): median OS 50 months with perioperative FLOT
• CROSS (SCC): 5-year OS 47% with neoadjuvant chemoRT + surgery
• Barrett's surveillance: early detection of dysplasia/cancer improves outcomes
• Operative mortality for oesophagectomy: 2-5% in high-volume centres

Barrett's Oesophagus Surveillance (BSG 2014)

Key Trials in Oesophageal Cancer

Key Facts

Gastric cancer has high mortality due to late presentation. H. pylori eradication is a key preventive strategy.

Epidemiology

• ~6,600 new cases/year in the UK; ~4,300 deaths/year
• Male:female ratio 2:1
• Incidence declining in the West (falling H. pylori prevalence); very common in East Asia
• Median age: 70 years

Aetiology

• Diet: smoked/salted foods, low fruit/vegetable intake
• Smoking: 1.5-2× risk
• Family history: 2-3× risk; hereditary diffuse gastric cancer (CDH1 mutation - prophylactic gastrectomy)
• Pernicious anaemia: atrophic gastritis → 2-3× risk
• Previous gastric surgery: bile reflux → increased risk after 15-20 years

Pathophysiology

• Diffuse type: poorly cohesive cells, signet ring morphology; CDH1 (E-cadherin) loss; infiltrative growth (linitis plastica)
• Spread: direct invasion (peritoneum), lymphatic (perigastric nodes), haematogenous (liver, lung), transcoelomic (peritoneal - Krukenberg tumours in ovaries, Sister Joseph's nodule at umbilicus)

Early Disease

• Often asymptomatic or vague dyspepsia
• Epigastric discomfort
• Early satiety, loss of appetite

Advanced Disease

• Progressive dysphagia (GOJ tumours)
• Weight loss (significant)
• Nausea and vomiting (if outlet obstruction)
• GI bleeding (haematemesis, melaena, iron deficiency anaemia)
• Palpable epigastric mass

Metastatic Signs

• Virchow's node (left supraclavicular - Troisier's sign)
• Sister Mary Joseph's nodule (periumbilical metastasis)
• Krukenberg tumour (ovarian metastases - bilateral)
• Blumer's shelf (palpable mass on rectal examination - pouch of Douglas deposits)
• Ascites (peritoneal carcinomatosis)

Red Flags

• Dysphagia (any age)
• Age ≥55 with weight loss and upper GI symptoms
• Iron deficiency anaemia in male or post-menopausal female
• Palpable epigastric mass
• Virchow's node

Bedside

• Abdominal examination
• Lymph node palpation (supraclavicular, periumbilical)
• DRE (Blumer's shelf)

Bloods

• FBC (anaemia), U&Es, LFTs, albumin
• CEA, CA 19-9 (monitoring, not diagnostic)

Imaging

• OGD with biopsy: gold standard (multiple biopsies from mass and surrounding mucosa)
• CT chest/abdomen/pelvis: TNM staging
• EUS: T and N staging
• PET-CT: detects occult metastases
• Staging laparoscopy + peritoneal washings: mandatory for potentially operable gastric cancer (detects peritoneal disease missed on CT in 20-30%)

Special Tests

• HER2 testing: all advanced gastric/GOJ adenocarcinomas
• PD-L1 CPS: guides immunotherapy eligibility
• MSI/dMMR testing: immunotherapy eligibility
• H. pylori testing and eradication

Non-pharmacological

• MDT discussion
• Nutritional support (dietitian, supplementary feeds)
• H. pylori eradication if positive
• Psychological support

Pharmacological

• Resectable disease: perioperative FLOT × 4 pre-op + 4 post-op (FLOT4 trial; superior to ECF/ECX)
• Metastatic - first-line: platinum + fluoropyrimidine (cisplatin or oxaliplatin + 5-FU or capecitabine)
  • HER2+: add trastuzumab (ToGA trial)
  • PD-L1 CPS ≥5: add nivolumab (CheckMate-649)
• Second-line: ramucirumab (anti-VEGFR2) + paclitaxel (RAINBOW trial)
• MSI-high metastatic: pembrolizumab
• MALT lymphoma (H. pylori-associated): H. pylori eradication can cure early-stage disease

Surgical/Interventional

• Subtotal gastrectomy: distal tumours (2/3 resection with D2 lymphadenectomy)
• Total gastrectomy: proximal/diffuse tumours (with Roux-en-Y reconstruction)
• D2 lymphadenectomy: standard in specialist centres (removes perigastric + coeliac axis nodes)
• Endoscopic resection (EMR/ESD): for T1a, well-differentiated, <2cm, no ulceration
• Palliative stenting: GOJ obstruction
• Palliative gastrectomy/bypass: in selected patients with bleeding or obstruction