Side effects of systemic cancer therapy - nausea
Red flags
- Headache, papilloedema, focal deficit, morning nausea -> raised ICP / brain metastases
- Colicky pain, distension, absolute constipation, tinkling or absent bowel sounds -> malignant bowel obstruction
- Confusion, polyuria, constipation, dehydration -> hypercalcaemia of malignancy
- Postural hypotension, hyponatraemia, hyperkalaemia, unexplained weight loss -> adrenal insufficiency (checkpoint inhibitor hypophysitis, steroid withdrawal, adrenal metastases)
- Neck stiffness, cranial nerve palsy -> leptomeningeal disease
- Fever + neutropenia -> neutropenic sepsis takes priority over any antiemetic
- Haematemesis, melaena, severe abdominal pain -> perforation, ulcer, ischaemia
- Anuria, rapidly rising creatinine -> obstructive uropathy, TLS
Differential by mechanism
Nausea in cancer is multifactorial. Identify the dominant pathway - it selects the drug.
The four inputs to the vomiting centre
| Pathway | Receptors | Typical trigger |
|---|---|---|
| Chemoreceptor trigger zone (area postrema, outside BBB) | D2, 5-HT3, NK1 | Chemotherapy, opioids, uraemia, hypercalcaemia, hyponatraemia, sepsis, drugs |
| Vagal / GI afferents | 5-HT3, D2 | Mucosal injury, gastric stasis, constipation, obstruction, hepatic capsule stretch |
| Vestibular | H1, muscarinic | Motion, opioid-induced, skull base or posterior fossa disease |
| Cortical / higher centre | GABA, 5-HT | Anxiety, anticipatory nausea, pain, fear, smells, raised ICP |
By mechanism
- Chemotherapy-induced - acute (<24 h, mainly 5-HT3), delayed (24-120 h, mainly substance P/NK1), anticipatory (conditioned, before the dose), breakthrough, refractory
- Radiotherapy-induced - abdominal, whole-body, hemibody fields
- Opioid-induced - CTZ + vestibular + gastric stasis; usually settles in 5-7 days
- Metabolic - hypercalcaemia, hyponatraemia, uraemia, hepatic failure, adrenal insufficiency
- Structural - bowel obstruction, gastric outlet obstruction, gastroparesis, ascites, hepatomegaly
- CNS - brain metastases, leptomeningeal disease, raised ICP
- Drugs - opioids, antibiotics, NSAIDs, digoxin, SSRIs, anticonvulsants
- Other - constipation (commonest reversible cause), oral candidiasis, mucositis, gastritis, infection, pain, anxiety
Focused history
- Timing relative to chemotherapy - before (anticipatory), <24 h (acute), 24-120 h (delayed)
- What regimen, what cycle, what happened last cycle - *poor control in cycle 1 is the strongest predictor of nausea in every subsequent cycle*
- What antiemetics were prescribed, taken, and did they help - and were the delayed-phase ones actually taken at home?
- Nausea vs vomiting vs retching - nausea without vomiting suggests metabolic or cortical cause
- Vomit character - undigested food (obstruction/gastroparesis), faeculent (distal obstruction), bile, blood
- Relation to movement (vestibular), meals (gastric stasis), posture, smells
- Bowel habit and time since last motion - constipation is the commonest reversible cause
- Full drug list including opioids, recent dose escalations, steroid changes
- Headache, visual change, weakness
- Oral intake, weight, thirst, urine output
- Anxiety, prior nausea in pregnancy or motion sickness (predict poor control)
- Alcohol history (heavy prior use predicts BETTER control)
Focused examination
- Volume status - postural BP, mucous membranes, JVP, skin turgor
- Weight
- Abdomen - distension, tenderness, mass, hepatomegaly, ascites, succussion splash (gastric outlet obstruction), bowel sounds
- PR examination - faecal loading, impaction
- Mouth - candidiasis, mucositis, dentition
- Neurology - fundoscopy for papilloedema, cranial nerves, focal signs, gait
- Signs of sepsis and neutropenia
- Skin - hyperpigmentation (adrenal insufficiency)
Investigation strategy
First pass in everyone
- UEC, corrected calcium, magnesium, phosphate, glucose, LFT, FBE, CRP
- *Corrected calcium is the test most often forgotten and most often the answer*
- Cultures if febrile
Directed
- Morning cortisol +/- TSH - if on checkpoint inhibitors, recent steroid cessation, or hyponatraemia
- Abdominal x-ray - constipation, obstruction
- CT abdomen/pelvis if obstruction, ascites or new mass suspected
- CT or MRI brain if headache, focal signs, papilloedema, or unexplained persistent vomiting
- Drug levels (digoxin, lithium, phenytoin); beta-hCG in women of childbearing age
- Gastric emptying study rarely needed
Do not investigate uncomplicated, expected, well-controlled chemotherapy-induced nausea.
Management
A. Treat the cause first
- Relieve constipation, correct calcium and sodium, treat candidiasis, review opioid dose, treat pain and anxiety
- Dexamethasone for raised ICP; NG decompression and surgical/palliative review for obstruction
B. Match the drug to the receptor - the organising principle
| Pathway | Agent |
|---|---|
| CTZ / chemotherapy, drugs, metabolic | Metoclopramide, haloperidol, ondansetron, aprepitant |
| Gastric stasis / GI | Metoclopramide (prokinetic), domperidone |
| Vestibular / movement-related | Prochlorperazine, cyclizine, hyoscine |
| Cortical / anxiety, anticipatory | Lorazepam |
| Raised ICP | Dexamethasone + cyclizine |
| Broad/unclear or refractory | Olanzapine (broad receptor coverage) |
C. Chemotherapy-induced nausea
- Prophylaxis by emetogenic risk, given before every cycle - see vomiting with cancer therapy for the full regimen
- Delayed nausea (24-120 h) is driven by substance P -> NK1 antagonist (aprepitant/fosaprepitant/netupitant) + dexamethasone
- 5-HT3 antagonists work poorly in the delayed phase - a common prescribing error
- Olanzapine 5-10 mg nocte added to standard prophylaxis substantially improves nausea control (the largest recent gain), especially the nausea rather than vomiting endpoint
- Breakthrough: add an agent from a different class, give regularly rather than PRN, consider parenteral/subcutaneous route
D. Anticipatory nausea
- *A conditioned response, not a pharmacological effect* - so standard antiemetics do not work
- Benzodiazepine: lorazepam 0.5-2 mg orally the night before and the morning of chemotherapy
- Behavioural therapy, relaxation, hypnosis, systematic desensitisation
- Prevention is the real treatment: control emesis completely from cycle 1
E. Supportive
- Small frequent bland meals, cold food, avoid strong smells, ginger, oral care
- Dietitian input; consider IV fluids and electrolyte replacement
- Cannabinoids (nabilone) - modest evidence, reserved for refractory cases
Traps
- Treating "chemo nausea" without checking calcium, sodium and bowels
- Using a 5-HT3 antagonist for delayed-phase nausea - the wrong receptor for that phase, and it worsens the constipation that is fuelling the nausea
- Prescribing antiemetics PRN in established nausea - give them regularly
- Metoclopramide in complete bowel obstruction - prokinetics with a mechanical obstruction cause colic and perforation risk
- Missing adrenal insufficiency in a patient on checkpoint inhibitors, or after abrupt steroid cessation
- Attributing morning headache and vomiting to chemotherapy rather than brain metastases
- Forgetting that ondansetron causes constipation and QT prolongation
- Metoclopramide and prochlorperazine cause acute dystonia and akathisia, especially in young patients - the restlessness is often mistaken for anxiety
- Assuming the patient took the take-home delayed-phase antiemetics - ask specifically
- Not asking about anticipatory nausea, which the patient may find embarrassing to mention
Talk track
- "Nausea and vomiting are separate problems - which is bothering you more?"
- "Is it there before you even come in for treatment, or only afterwards?"
- "Show me the tablets you were given to take home - which ones did you actually take, and when?"
- "When did your bowels last open?"
- "We can almost always control this. It matters that we get on top of it from the first cycle, because the body learns the pattern."
- Explaining anticipatory nausea: "Your body has learned to associate this place with feeling sick. That's not something you're imagining, and it responds to a different kind of medication."
- "Nausea is one of the symptoms patients say most affects their quality of life - please tell us rather than putting up with it."
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