{"title": "Chapter 14: Oncology and Palliative Care", "flashcards": [{"q": "What is the WHO analgesic ladder and how does it apply to cancer pain?", "a": "Three-step ladder: Step 1 (mild pain): non-opioid analgesia (paracetamol, NSAIDs) ± adjuvant; Step 2 (moderate pain): weak opioid (codeine, tramadol, low-dose strong opioid) ± non-opioid ± adjuvant; Step 3 (severe pain): strong opioid (morphine, oxycodone, fentanyl, hydromorphone) ± non-opioid ± adjuvant. Start at appropriate step for pain severity. Reassess regularly. Prescribe laxatives with all opioids; anti-emetic for first 1–2 weeks."}, {"q": "What is the definition of malignant spinal cord compression (MSCC) and the emergency management?", "a": "MSCC: compression of the dural sac and its contents (spinal cord or cauda equina) by tumour. Back pain is the most common presenting symptom (often precedes neurological signs by weeks). Management: dexamethasone 8 mg IV/oral stat then 16 mg/day; urgent MRI whole spine within 24 hours; clinical oncology/spinal surgery review within 24 hours; radiotherapy or surgery depending on tumour type, stability, and prognosis."}, {"q": "Name three paraneoplastic syndromes and their associated malignancies.", "a": "SIADH (lung cancer, brain tumours); hypercalcaemia from PTHrP secretion (squamous cell lung cancer, renal cell, breast); Cushing's syndrome from ectopic ACTH (small cell lung cancer, carcinoid); Lambert-Eaton myasthenic syndrome (small cell lung cancer — antibodies to presynaptic VGCC); DIC (AML-M3, mucin-secreting adenocarcinomas); hypertrophic pulmonary osteoarthropathy (lung cancer)."}, {"q": "What is the difference between disease-free survival (DFS) and overall survival (OS) as clinical trial endpoints?", "a": "DFS: time from randomisation to first event (disease recurrence or death from any cause) — measures treatment efficacy in preventing recurrence; used in adjuvant trials. OS: time from randomisation to death from any cause — the gold-standard endpoint directly measuring benefit in survival. Progression-free survival (PFS): time to tumour progression or death — used as surrogate endpoint in advanced cancer trials where OS requires longer follow-up."}, {"q": "What are the indications for Granulocyte Colony-Stimulating Factor (G-CSF) prophylaxis in chemotherapy?", "a": "G-CSF (filgrastim, lenograstim, pegfilgrastim) prophylaxis is recommended when the risk of febrile neutropaenia (FN) is ≥20% based on chemotherapy regimen, OR ≥10% if the patient has additional risk factors (age >65, poor performance status, previous FN, bone marrow involvement, active infection, comorbidities). It reduces FN incidence, hospitalisation, and treatment delays."}, {"q": "Define the principles of advance care planning (ACP) and DNAR orders.", "a": "ACP is a process of discussion between patients, families, and healthcare professionals about future care preferences, values, and goals — particularly for end-of-life care. DNAR (Do Not Attempt Resuscitation) is a specific decision about CPR, separate from other treatment decisions. It should be: based on clinical judgement and patient wishes; documented clearly; reviewed regularly; communicated across care settings. A DNAR does not mean withdrawal of other active treatment."}, {"q": "What is the mechanism of action of immune checkpoint inhibitors?", "a": "ICIs block inhibitory immune checkpoints on T cells: anti-PD-1 (pembrolizumab, nivolumab) blocks PD-1 on T cells, preventing PD-L1/PD-L2 engagement that suppresses T-cell activation; anti-PD-L1 (atezolizumab, durvalumab) blocks PD-L1 on tumour/immune cells; anti-CTLA-4 (ipilimumab) blocks CTLA-4 on T cells, preventing regulatory T-cell dominance. ICIs restore anti-tumour T-cell activity and cause immune-related adverse events."}, {"q": "Name four immune-related adverse events (irAEs) from checkpoint inhibitor therapy.", "a": "Immune-related colitis (most common GI toxicity — grades 1–4; steroid-responsive); immune-related pneumonitis (fatigue, cough, dyspnoea — can be fatal; steroids); immune-related hepatitis (AST/ALT rise — steroids ± mycophenolate); immune-related endocrinopathy (hypophysitis, adrenal insufficiency, hypothyroidism, DM1 — replacement therapy ± steroids); dermatitis (rash, vitiligo); nephritis; arthritis; myocarditis."}, {"q": "What is the definition of febrile neutropaenia and the immediate management?", "a": "Febrile neutropaenia: temperature >38°C and neutrophils <0.5 × 10⁹/L (or <1.0 × 10⁹/L and predicted to fall). Medical emergency. Management: MASCC risk score for low/high risk stratification; blood cultures (peripheral and central line if CVAD); urine, sputum cultures; CXR; start empirical broad-spectrum antibiotics within 1 hour (piperacillin-tazobactam IV). G-CSF for high-risk. Antifungal if fever persists >96 hours."}, {"q": "What is the significance of tumour mutational burden (TMB) in cancer immunotherapy?", "a": "TMB measures the number of somatic mutations per megabase of tumour genome. High TMB (>10 mut/Mb — threshold varies) correlates with higher neoantigen production, increasing immunogenicity and likelihood of response to immune checkpoint inhibitors. TMB-high status is an FDA-approved biomarker for pembrolizumab in solid tumours (TMB ≥10 mut/Mb). PD-L1 expression and microsatellite instability (MSI-H/dMMR) are also predictive biomarkers."}], "quiz": [{"q": "What is the most appropriate analgesic route when a patient with advanced cancer can no longer swallow oral opioids?", "opts": ["Intramuscular injections every 4 hours", "Continuous subcutaneous infusion via syringe driver (e.g. diamorphine or morphine) with PRN breakthrough doses", "IV opioids only", "Withhold opioids until patient can swallow"], "ans": 1, "exp": "Subcutaneous syringe driver providing continuous 24h infusion of opioid (diamorphine, morphine, or hydromorphone) is the standard route when oral route is lost. Conversion: oral morphine to SC diamorphine divide by 3 (e.g. oral morphine 30 mg/24h = SC diamorphine 10 mg/24h). PRN SC breakthrough doses (1/6th of 24h total dose) prescribed for pain not controlled by the syringe driver."}, {"q": "Which cancer is most associated with BRCA1 and BRCA2 mutations?", "opts": ["Colorectal cancer", "Breast, ovarian, fallopian tube, peritoneal, and pancreatic cancers; BRCA2 also prostate cancer", "Lung cancer", "Cervical cancer"], "ans": 1, "exp": "BRCA1/2 (tumour suppressor genes involved in homologous recombination repair) mutations confer lifetime risks of breast cancer (~70% by age 80 in BRCA1 carriers) and ovarian cancer (~44% BRCA1, ~17% BRCA2). BRCA2 mutations also increase risk of male breast, prostate, and pancreatic cancers. PARP inhibitors exploit synthetic lethality in BRCA-mutant tumours."}, {"q": "What is the gold-standard investigation for staging colorectal cancer?", "opts": ["PET-CT only", "CT chest/abdomen/pelvis (CT-CAP) for systemic staging + MRI pelvis for rectal cancer local staging", "Barium enema", "Colonoscopy with biopsy (diagnosis only, not staging)"], "ans": 1, "exp": "Staging colorectal cancer: CT-CAP assesses for distant metastases (liver, lung, peritoneal). For rectal cancer, high-resolution MRI pelvis is mandatory for locoregional staging (T and N stage, circumferential resection margin, extramural vascular invasion — EMVi — predicts systemic recurrence). FDG-PET CT is used selectively for equivocal lesions or before major resection."}, {"q": "What is the mechanism of platinum-based chemotherapy agents (cisplatin, carboplatin)?", "opts": ["Antimetabolite — folate antagonism", "Formation of intra-strand DNA crosslinks (primarily at GG dinucleotides), blocking DNA replication and transcription, triggering apoptosis", "Topoisomerase I inhibition", "Microtubule stabilisation"], "ans": 1, "exp": "Cisplatin and carboplatin form platinum-DNA adducts — predominantly intrastrand crosslinks at adjacent guanine residues — which distort the DNA double helix, blocking replication and transcription. Cells trigger apoptosis via p53 and mismatch repair pathways. Cisplatin toxicities: nephrotoxicity (requires pre-hydration), ototoxicity, peripheral neuropathy. Carboplatin: less nephrotoxic, myelosuppression dominant."}, {"q": "What is the first-line systemic treatment for HER2-positive metastatic breast cancer?", "opts": ["Tamoxifen alone", "Pertuzumab + trastuzumab + taxane chemotherapy (CLEOPATRA regimen)", "Endocrine therapy alone", "Anti-PD-1 checkpoint inhibitor"], "ans": 1, "exp": "CLEOPATRA trial established pertuzumab + trastuzumab + docetaxel as first-line standard for HER2-positive metastatic breast cancer, demonstrating improved OS (57 months vs 41 months vs trastuzumab + docetaxel alone). Both pertuzumab and trastuzumab target HER2 at different epitopes, preventing homo/heterodimerisation and activating ADCC."}, {"q": "What is the definition of refractory cachexia in cancer?", "opts": ["Weight loss >5% over 6 months", "A state where weight loss cannot be reversed by nutritional support due to advanced metabolic changes associated with active progressive disease; life expectancy <3 months; anabolic potential limited", "Any involuntary weight loss in cancer", "Cachexia only in GI cancers"], "ans": 1, "exp": "Cachexia is defined by the International Consensus as weight loss >5% in 12 months (or BMI <20 + any weight loss >2%) with an underlying illness. Pre-cachexia → cachexia → refractory cachexia. Refractory cachexia: very short life expectancy, active treatment no longer possible or appropriate, severe metabolic changes. Focus shifts to symptom management and quality of life rather than nutritional interventions."}, {"q": "Which molecular target does imatinib act on in chronic myeloid leukaemia?", "opts": ["CD20", "BCR-ABL1 tyrosine kinase — competitively inhibits ATP binding to the ABL kinase domain, blocking constitutive kinase activity", "EGFR", "VEGFR"], "ans": 1, "exp": "Imatinib (Gleevec) is a selective tyrosine kinase inhibitor that binds to the ATP-binding site of BCR-ABL1, c-KIT, and PDGFR, blocking their catalytic activity. In CML (t(9;22) BCR-ABL1), imatinib normalises haematopoiesis, achieving complete cytogenetic response (CCyR) in >85% at 12 months. Major molecular response (MMR — BCR-ABL1/ABL <0.1% IS) is the treatment goal."}, {"q": "What is the DNAR decision-making process under the Mental Capacity Act 2005?", "opts": ["The physician alone decides", "If the patient has capacity: discuss with patient and respect their decision; if lacking capacity: decision is made in patient's best interests, involving those close to them, any existing ADRT (advance decision), and LPA (lasting power of attorney for health and welfare)", "Family makes the final decision", "Only a court can authorise a DNAR"], "ans": 1, "exp": "MCA 2005: if a patient lacks mental capacity, the treating clinician makes a best-interests decision about attempting CPR, consulting those close to the patient (family, carers), reviewing any advance decision to refuse treatment (ADRT — legally binding if valid and applicable), and any LPA with authority to refuse CPR. The treating clinician makes the final clinical decision; family cannot demand or refuse CPR on behalf of an incapacitated adult."}, {"q": "What is the most common reason for undertreating pain in cancer patients?", "opts": ["Pain is not a feature of most cancers", "Fear of opioid addiction and respiratory depression among clinicians and patients — leading to under-prescribing of appropriate strong opioids", "Lack of analgesic options", "Strong opioids are not available in most countries"], "ans": 1, "exp": "Opiophobia — fear of addiction, tolerance, respiratory depression, or shortening life — among both clinicians and patients leads to under-treatment of cancer pain globally. When opioids are appropriately titrated to pain, psychological dependence is rare; physical dependence is expected but manageable. Respiratory depression at analgesic doses is uncommon when opioids are titrated carefully."}, {"q": "Which tumour marker is most specific for hepatocellular carcinoma (HCC)?", "opts": ["CEA", "Alpha-fetoprotein (AFP) — elevated in ~70% of HCC; level >400 ng/mL is highly specific; used for surveillance in cirrhotic patients (6-monthly AFP + liver ultrasound per EASL guidelines)", "CA 19-9", "CA 125"], "ans": 1, "exp": "AFP is the most widely used tumour marker for HCC, though it lacks sensitivity (normal in ~30% of HCC). AFP >400 ng/mL in a cirrhotic patient with a hypervascular hepatic lesion on CT/MRI is diagnostic without biopsy (EASL criteria). Other markers: AFP-L3, DCP (des-gamma-carboxyprothrombin/PIVKA-II) improve specificity. Multiphase MRI/CT with arterial enhancement and washout is the radiological diagnostic standard."}, {"q": "What is the mechanism of action of bevacizumab?", "opts": ["Anti-EGFR monoclonal antibody", "Humanised anti-VEGF-A monoclonal antibody that binds and neutralises VEGF-A, preventing its interaction with VEGFR-1 and VEGFR-2 on endothelial cells — inhibiting tumour angiogenesis, reducing vascular permeability, and 'normalising' tumour vasculature to improve chemotherapy delivery", "Anti-PD-1 checkpoint inhibitor", "Anti-HER2 antibody"], "ans": 1, "exp": "Bevacizumab (Avastin) targets the VEGF-A ligand rather than its receptor, preventing all VEGFR interactions. Used in: metastatic colorectal cancer (FOLFOX/FOLFIRI + bevacizumab), non-squamous NSCLC, ovarian, cervical, and glioblastoma. Side effects: hypertension (most common — treat with antihypertensives), proteinuria (monitor ACR), impaired wound healing (withhold 4–6 weeks perioperatively), arterial thromboembolism, GI perforation, haemorrhage (contraindicated in squamous NSCLC — haemoptysis risk)."}, {"q": "What is the significance of microsatellite instability (MSI) in colorectal cancer?", "opts": ["It predicts resistance to immunotherapy", "MSI-H/dMMR CRC (Lynch syndrome or sporadic MLH1 methylation) indicates defective mismatch repair, creating high mutational burden and neoantigen load; predicts excellent response to anti-PD-1 checkpoint inhibitors (pembrolizumab — KEYNOTE-177 trial — now first-line for MSI-H metastatic CRC) and worse response to 5-FU alone in adjuvant setting", "It has no clinical significance", "It only occurs in rectal cancer"], "ans": 1, "exp": "MSI testing (PCR or IHC for MMR proteins — MLH1, MSH2, MSH6, PMS2) is mandatory for all new CRC diagnoses. MSI-H = deficient MMR = high TMB → excellent immunotherapy response. MSS (microsatellite stable) = proficient MMR → poor immunotherapy response. Germline testing should be offered if MSI-H is due to Lynch syndrome (absent MLH1/MSH2/MSH6 by IHC without somatic MLH1 promoter methylation). Lynch syndrome carries 40–80% lifetime CRC risk + extracolonic cancer risk."}, {"q": "What is the palliative approach to managing malignant bowel obstruction?", "opts": ["Emergency laparotomy for all patients", "Octreotide (somatostatin analogue — reduces GI secretions and peristalsis), dexamethasone (reduces perineal oedema), antiemetics (cyclizine/haloperidol/levomepromazine via syringe driver), hyoscine butylbromide (antispasmodic); surgical intervention selected for patients with good performance status and surgically reversible obstruction", "Nasogastric tube drainage alone", "IV fluids only"], "ans": 1, "exp": "Malignant bowel obstruction in advanced cancer is often managed medically in palliative settings: octreotide reduces secretions and vomiting (superior to hyoscine for secretory control); dexamethasone reduces tumour oedema (8 mg OD IV/SC for 5–7 days trial); antiemetics via CSCI. A nasogastric tube provides temporary relief for distressing vomiting. A venting gastrostomy reduces symptoms in proximal obstruction. Surgical bypass selected only in patients with good prognosis and surgically correctable anatomy."}, {"q": "What is the RECIST criterion for partial response to oncological treatment?", "opts": ["Any decrease in tumour size", "≥30% decrease in sum of target lesion diameters (compared to baseline sum) — at least 4 weeks apart; Complete Response (CR): disappearance of all target lesions; Progressive Disease (PD): ≥20% increase in sum or new lesions; Stable Disease (SD): neither CR/PR nor PD", "50% decrease in tumour volume", "≥10% reduction in tumour marker"], "ans": 1, "exp": "RECIST 1.1 (Response Evaluation Criteria in Solid Tumours): target lesions are measurable lesions (longest diameter ≥10 mm on CT, ≥20 mm on CXR, ≥15 mm lymph nodes short axis). Responses: CR (all target lesions gone + any lymph nodes <10 mm); PR (≥30% decrease); SD; PD (≥20% increase or new lesion). Used in clinical trials to standardise response assessment and as secondary endpoint in regulatory submissions."}, {"q": "What is the role of bisphosphonates in bone metastases?", "opts": ["They shrink metastatic deposits", "Inhibit osteoclast activity (via mevalonate pathway inhibition), reducing bone resorption, preventing skeletal-related events (SREs — pathological fractures, cord compression, hypercalcaemia, bone pain requiring radiotherapy), and reducing bone pain; IV zoledronic acid or oral ibandronate/clodronate for breast and prostate cancer bone metastases", "They increase bone formation", "They are only used for osteoporosis"], "ans": 1, "exp": "Zoledronic acid (IV 4 mg q4-weekly) or denosumab (anti-RANKL SC q4-weekly) reduce SREs in bone-metastatic solid tumours. Denosumab is superior to zoledronic acid for SRE prevention but carries higher ONJ risk and rebound effect on discontinuation. Both require calcium and vitamin D supplementation and dental review before initiation (osteonecrosis of the jaw — ONJ — risk, particularly with tooth extraction during treatment)."}, {"q": "What is 'early palliative care' and what does it involve?", "opts": ["Hospice care at end of life only", "Integrating palliative care alongside curative/life-prolonging treatment from diagnosis of serious illness; focuses on symptom management, advance care planning, psychosocial support, and goals of care discussions — shown to improve quality of life and survival (NEJM Temel 2010 — early PC improved median OS by 2.7 months in metastatic NSCLC)", "Only end-of-life sedation", "Only spiritual care"], "ans": 1, "exp": "Temel 2010 landmark trial: early palliative care integrated with oncology from metastatic NSCLC diagnosis improved QoL (FACT-L), reduced aggressive end-of-life care, and unexpectedly improved median OS (11.6 vs 8.9 months) vs standard oncology alone — possibly from reduced symptom burden and depression improving functional status. WHO recommends PC from diagnosis of any life-limiting illness regardless of prognosis or anticancer treatment."}, {"q": "What is the most common site of metastatic spread for colorectal cancer?", "opts": ["Lung", "Liver (via portal venous drainage — 50% of CRC patients will develop liver metastases; 20–30% at presentation)", "Brain", "Bone"], "ans": 1, "exp": "Colorectal cancer drains via the portal venous system to the liver — the most common site of metastasis (50% eventually; 15–25% synchronous at diagnosis). Pulmonary metastases are second most common (via systemic circulation). Peritoneal metastases occur in ~10%. Resection of limited liver metastases (≤3–4 lesions, no extrahepatic disease) achieves 5-year OS ~35–40% — making staging CT and multidisciplinary liver MDT essential."}, {"q": "What is the mechanism of anthracycline-induced cardiotoxicity?", "opts": ["Only occurs with IV administration", "Free radical generation and reactive oxygen species (ROS) production from iron-anthracycline complexes → mitochondrial damage → cardiomyocyte apoptosis and oxidative stress; cumulative dose-dependent (doxorubicin threshold ~400–550 mg/m²); manifests as systolic dysfunction (reduced LVEF) months-years after treatment; dexrazoxane (iron chelator) partially protective", "COX-2 inhibition in cardiac tissue", "QT prolongation only"], "ans": 1, "exp": "Anthracyclines (doxorubicin, epirubicin, daunorubicin) cause cardiotoxicity via topoisomerase II-beta inhibition in cardiomyocytes (which cannot regenerate) and ROS production. Risk factors: cumulative dose, prior mediastinal radiation, pre-existing cardiac disease, young age (paediatric patients), older age, female sex. Monitoring: baseline and serial echocardiography or MUGA scan. Liposomal formulations (Caelyx) reduce cardiotoxicity without reducing antitumour efficacy."}, {"q": "What is the recommended adjuvant treatment for stage III colon cancer (node-positive)?", "opts": ["Observation only", "CAPOX (capecitabine + oxaliplatin) for 3–6 months or FOLFOX for 6 months — reduces 3-year disease-free survival event rate by ~20% relative risk reduction compared to observation", "Bevacizumab alone", "Radiotherapy to the abdomen"], "ans": 1, "exp": "Stage III colon cancer (any T, N1–N2, M0 — lymph node positive) benefits from adjuvant chemotherapy. MOSAIC trial: FOLFOX (5-FU + leucovorin + oxaliplatin) × 12 cycles vs 5-FU/LV alone — reduced recurrence by 23% relative. XELOXA: CAPOX non-inferior to FOLFOX. Duration: 3 months CAPOX (IDEA collaboration — adequate for low-risk Stage III T1–3/N1); 6 months preferred for high-risk (T4/N2). Anti-EGFR and bevacizumab have no role in adjuvant Stage III."}, {"q": "What is palliative sedation and when is it appropriate?", "opts": ["Deliberate hastening of death", "Proportionate sedation using medications (midazolam, levomepromazine, phenobarbitone) to reduce consciousness sufficiently to relieve refractory suffering in imminently dying patients where all other symptom management options have been exhausted — distinct from euthanasia (intention is symptom relief, not death)", "Only appropriate for pain", "Requires court approval"], "ans": 1, "exp": "Palliative sedation: continuous deep sedation (CDS) is ethically justified under the doctrine of double effect and proportionality for refractory symptoms (pain, dyspnoea, agitation, existential distress) in imminently dying patients. Requires: informed consent or documented best-interests decision; review that symptoms are genuinely refractory; MDT and family communication; careful titration (lowest effective dose). It does not shorten survival when correctly used. Distinct from euthanasia (legal in some jurisdictions, illegal in UK)."}]}