Nausea & Vomiting in Advanced Cancer Patients
Nausea and vomiting affects about half of advanced cancer patients. It is best managed if the mechanism involved is known. Treat the reversible causes. Diet manipulation and psychosocial support are as important as drug therapy. Give oral maintenance doses after vomiting is controlled with parenteral or rectal administration of antiemetics. Subcutaneous administration can be given as bolus by carer via a butterfly needle left in situ or continuously via a syringe driver. Nausea and vomiting need to be well managed early to prevent subsequent conditioned vomiting. Assessment, pharmaceutical and non-pharmaceutical management are discussed.
Nausea and vomiting is quite common in advanced cancer patients, affecting 40-70% of them and is more severe in AIDS patients.1,2 It is independent of the primary site of the cancer. It is often multifactorial in origin and is best managed if the mechanism involved is known.3
Conscious patients complain of it voluntarily. Patients with impaired consciousness may be found to be listless, withdrawn, disinterested in surrounding, sweaty and pale.
As with pain, the first step in helping the vomiting patient is to identify the cause.
Vomiting centre (VC) is activated by impulses coming in from the chemoreceptor trigger zone (CTZ), the gut and pharynx, the vestibular apparatus, the intracranial lesion and higher centres.
The CTZ detects blood borne chemicals such as toxins from cancer, infection, liver failure and constipation as well as calcium, ketosis, urea and drugs e.g. opioids, cytotoxics, antibiotics, digoxin. Low doses of morphine are more emetogenic than high doses owing to the emetic and antiemetic effect of opioids.4 However, nausea usually improves after several days of opioid therapy.
Table 1 shows the gastrointestinal (GI) causes of nausea and vomiting. It is more severe in high intestinal obstruction. In low intestinal obstruction, there is more distension and the vomitus tends to be faeculent.
Table 1: Gastrointestinal causes of nausea and vomiting
|
Pharyngeal irritation by copious sputum, excessive cough and candidiasis. Gastric irritation by drug, food, gastritis, peptic ulceration Gastric stasis in the presence of hepatomegaly, ascites, peptic ulceration, pancreatic carcinoma.5 Squash stomach syndrome in hepatomegaly, gross ascites. Gut wall irritation by chemotherapy, radiotherapy and drugs e.g. antibiotics, NSAIDs, aspirin. Intestinal obstruction - constipation in elderly people is a common cause Biliary obstruction & hepatic distension. |
Nausea and vomiting caused by vestibular problem is worse with movement. There are also vertigo, pallor and sweating.
Patients with intracranial lesions present with behavioural change, cranial nerve signs and fundal sign.
Nausea and vomiting may be caused by signals coming from the higher centre. Memory, sights, smells or tastes of something which has previously associated with vomiting can induce conditioned nausea and vomiting. Anxiety and stress can also cause nausea and vomiting.
In advanced cancer patients, nausea and vomiting is often multifactorial in origin. Intestinal tumour, use of narcotics, presence of infection and travelling all contribute to it.
Assess the severity of nausea and vomiting and its association with movement or any event or procedure. Ask about the patient’s mood and interpretation about the cause and significance of nausea and vomiting.
The nature and extent of the cancer help in suggesting the cause of nausea and vomiting. Intra-abdominal cancer can cause intestinal obstruction. Pelvic cancers cause post-renal uraemia by obstructing ureters.3 Hypercalcaemia is more common in myeloma, cancer of breast and bronchus.
Past operation can cause adhesion with bowel obstruction. The current medication may be emetogenic.
Constipation and colicky abdominal pain indicate intestinal obstruction. Presence of vertigo suggests vestibular problem. Gastric stasis presents with large amount of vomitus, oesophageal reflux, epigastric fullness, early satiation and hiccups. Hypercalcaemia also presents with drowsiness, confusion, constipation, dehydration and polyuria. This is a reversible condition that is often missed. Ask for any aggravating factors such as sight and smell of food or movement of head.
Large amount of vomitus suggests outlet obstruction. Small amount of vomitus with grossly distended stomach suggests floppy stomach syndrome. Vomiting small of amount of food and fluid taken within the last hour suggests regurgitation.
If vomiting occurs immediately after food, it may be psychogenic or due to prepyloric ulcer. Motility disorder or postvagotomy causes nausea or vomiting 1-2 hrs after food or repeated vomiting. If vomiting occurs more than twelve hours after food, obstruction or atony may be the cause. Raised intracranial pressure causes vomiting in the morning before eating.
Faeculent vomitus suggests obstruction of lower intestine, peritonitis with ileus or gastrocolic fistula.
The purpose of physical examination is to find the cause of nausea and vomiting as well as the result of vomiting such as malnutrition, dehydration and electrolyte imbalance.
Assess the general activity of the patient. Look for jaundice, ankle oedema, pallor, puffiness or dehydration, skin changes of uraemia, confusion as well as emotional and behavioural abnormalities.
Look for candidiasis, dehydration and signs of malnutrition such as glossitis and angular stomatitis.
Feel for a loaded colon of constipation and do a digital rectal examination. Look for ascites. Gastric or bowel distension occurs GI obstruction. Presence of hepatomegaly, gross ascites or enlarged tumour mass suggests squashed stomach syndrome. Auscultate for bowel motility.
Assess if there is any gait or balance abnormality if the patient is ambulant. Examine for cranial nerve signs and eye signs such as nystagmus and fundal change for intracranial abnormality.
Investigation is indicated only if the result is useful for management such as for finding the cause or monitoring the consequence of vomiting.
Blood test helps in confirming if electrolyte imbalance, uraemia, hepatic failure or hypercalcaemia is the cause of vomiting. Plain abdominal x-ray helps in diagnosing the presence of and the site of intestinal obstruction. It can also show the extent of loaded colon in constipation. Chest x-ray confirms the presence of aspiration pneumonia or rib fracture. Skull x-ray can show signs of increased intracranial pressure. CT scan is essential for diagnosing intracranial tumour.
Always try to treat the reversible causes. Avoid irritating drugs such as non-steroidal anti-inflammatory drugs (NSAIDs). If they must be used, replace them with less irritating alternatives or change the route of administration to rectal or parenteral administration.
Most advanced cancer patients having intestinal obstruction do not need operative intervention. They may be having widespread peritoneal secondaries, multiple level obstructions, short life expectancy and may be too weak to tolerate operation. Operation is indicated only if the obstruction is due to non-malignant cause such as adhesion, single level obstruction and the patient has reasonable quality and quantity of life after operation.
Attempts to understand the underlying aetiology of symptoms are sometimes unsuccessful, or treatment is often desirable before diagnosis is made, hence an empirical approach may be used.
Relaxation, guided imagery, systematic desensitisation and distraction have been shown to be effective in reducing nausea, and to a lesser extent, vomiting.6 Acupunture has been shown to be effective against cytotoxic-drug-induced emesis.7
Avoid unpleasant sounds and stressful discussions around meal time. Accompany the patient during meals. Avoid strong smells and odours such as garlic and onion. Well ventilate the kitchen. Keep the mouth clean and fresh. Rest can reduce vestibular stimulation.
Fast if vomiting is severe. Table 2 shows some tips of eating in managing nausea and vomiting.
Table 2: Types of food and eating behaviours that are recommended and to be avoided.
|
Recommended |
Avoid |
|
· Small frequent liquid or soft foods eaten slowly · Eaten at preferred time at leisure. · Attractive foods chosen by patient · Suck ice chips or sip cold clear fluid slowly, such as apple juice, lemonade, ginger ale. · Low fat foods, e.g. white bread, mashed potatoes, savoury foods, rice water. · Sour foods are better tolerated, squeeze a little lemon juice into food. · Trial of alcohol before meals. |
· Sweet, salty, greasy or spicy foods · Foods with strong flavour or odour e.g. onion, garlic. · Smoking · Strong tea and coffee. · Hot food. |
Its use is uncomfortable and can cause nasal and oesophageal ulceration as well as regurgitation with aspiration. It should be avoided except in certain situations. It can be used for reducing gastric distension in total gastric outflow obstruction if conservation medical management is not adequate or in preparation of surgical correction. In floppy stomach syndrome, it reduces distressful distension and prevents release of large amount of gastric content at the time of death, which is a great distress to the carers. It can be removed after aspiration of fluid and gas.
If vomiting persists in high obstruction such as gastric outlet obstruction with aggressive drug treatment and if the patient cannot tolerate repeated nasogastric tube suction, consider venting gastrostomy to be performed under local anaesthesia.8
Use drugs at the earliest suggestion of nausea to prevent development of conditioned symptoms. Start with the most appropriate drug depending on the apparent mechanism of vomiting. High dose of one agent should be attempted before switching to another agent. Use a combination if necessary, but avoid using more than one drug with the same type of action at the same time. Regular dosage should be given to prevent and control symptoms.
Table 3 shows the suggested drug management for the different causes of nausea and vomiting.
Table 3: Drug management for different causes of nausea and vomiting.
|
Cause |
Management |
Chemoreceptor Trigger Zone |
(high in dopamine and 5HT3 receptors) |
|
· Drug: Opioids*, chemotherapy Toxin: from cancer cells, constipation, infection, uraemia, liver failure, post-radiotherapy tissue breakdown. |
· Haloperidol, metoclopramide +/- promethazine 5HT3 antagonists for chemotherapy or radiotherapy induced vomiting |
|
· Hypercalcaemia |
· Very resistant to antiemetics, try to lower Ca and rehydrate. |
Vomiting Centre |
(high in histamine, muscarinic cholinergic and 5HT3 receptors) |
|
· Radiotherapy of head and neck |
· Promethazine, hyoscine, hydroxyzine, cyclizine · Prochlorperazine, chlorpromazine · Ibuprofen and steroid9 |
Gut problem |
|
|
· Stomach irritation |
· Antacid, H2 antagonist, sucrafate, proton pump inhibitors |
|
· Squash Stomach Syndrome & gastric stasis |
· Domperidone, metoclopramide, Cisapride, add dimethicone for gastric stasis |
|
· Bowel obstruction, biliary obstruction, hepatic distension, peritoneal carcinomatosis |
· Hyoscine, promethazine, dimenhydrinate, dexamethasone |
|
· Gut wall irritation from ° drugs such as antibiotic, NSAIDs.
° chemotherapy or radiotherapy |
· Treat gastritis, modify medication, · Use suppository or parenteral medication · Metoclopramide, domperidone · 5HT3 receptor antagonist: ondansetron, tropisetron |
Vestibular apparatus |
|
|
· Motion sickness, ear problem, 8th nerve tumour, labyrinthitis, · Drugs: aspirin, opioids |
· Dimenhydrinate, cyclizine, betahistine, hydroxyzine, promethazine, hyoscine, prochlorperazine |
Intracranial lesion |
|
|
· Tumour in brain & meninges · Increased intracranial pressure |
· Dexamethasone, promethazine, Haloperidol, cyclizine, dimenhydrinate |
Conditioned Nausea and Vomiting |
|
|
· Event or procedure that has previously associated with vomiting |
· Benzodiazepine & antiemetics started the night before procedure |
* Morphine induced vomiting may result from a combination of stimulation of CTZ, delayed gastric emptying and constipation.
If a clear aetiology of vomiting cannot be established, try a step-wise approach. Start with metoclopramide unless it is contraindicated, for example in gastric outlet or bowel obstruction. If it is not effective, change to a butyrophenone such as haloperidol. If it is still not effective add an antihistamine, e.g. cyclizine.
If the patient cannot tolerate oral medication, try phenothiazine suppository (prochlorperazine) or subcutaneous haloperidol or metoclopramide.
Antiemetics tend to suppress vomiting better than nausea, which needs a higher dosage. Refer palliative care specialist if nausea is still difficult to control.
Table 4 shows the dosage for the commonly used antiemetics. If the patient cannot tolerate oral medication, the drug can be given parenterally as bolus subcutaneous injection via a butterfly needle left in situ or subcutaneous infusion via syringe driver. Rectal absorption is erratic. Use suppository before subcutaneous administration is established. After control of vomiting, the drugs can be given orally for maintenance.
Table 4: Commonly used antiemetics and their dosages.
|
Drugs |
Oral |
SC, IM, IV, PR |
|
|
|
|
|
0.5 – 1.5mg nocte - tds |
0.5 – 1.5mg nocte - tds sci, or total daily dose via syringe driver. |
|
Phenothiazine |
|
|
|
5mg 1-2 tablets tds |
12.5mg q8-12h imi or 25mg q8-12h as suppository. |
|
|
Chlorpromazine (Largactil) |
25mg q8-12h |
50mg q8-12h imi or 100mg q12h as suppository. |
Antihistamines |
|
|
|
25mg nocte-tds |
|
|
|
25mg bd-tds |
25mg bd-tds imi 200mg/day subcutaneously via syringe driver. |
|
|
50mg q8h |
25mg q8-12h sci, increase to 50mg tds if necessary |
|
|
50mg q4-6h |
|
|
|
25-50mg tds |
|
|
Anticholinergic |
|
|
|
Hyoscine Butylbromide (Buscopan) |
||
|
|
0.2-0.4mg tds sci or 0.2-0.8mg/24h via syringe driver |
|
Gut prokinetics |
|
|
|
10mg q6h |
10mg q4h sci or ivi to gain control, then 10mg q6h po or sci or 30mg/24h sc via syringe driver. increase to 60mg/24h in resistant cases. |
|
|
10mg tds |
|
|
|
Cisapride (Prepulsid) |
10 - 20mg bd-tds |
|
|
5HT3 receptor antagonists |
|
|
|
Ondansetron (Zofran) |
4,8mg tablet bd-tds, 4,8mg in a wafer form to be used on the tongue. |
4,8mg bd-tds slow iv in 15min or 24mg/24hr via syringe driver. |
|
Tropisetron (Navoban) |
5mg once daily, |
5mg iv once daily, |
Analogue of Somatostatin |
|
|
Haloperidol has a higher dopamine receptor affinity and hence more extrapyramidal side effects than other commonly used anti-emetics. It inhibits CTZ and may cause agitation and restlessness (akathesia) in high doses. Its half-life is 16 hours.
They have action in dopamine, histamine, muscarinic anticholinergic receptors. However they are less effective than butyrophenones. They are used in vomiting due to GI obstruction, steroid-resistant raised intracranial pressure and in combination with other classes of antiemetics.
Prochlorperazine has unpredictable oral absorption and cannot be given subcutaneously. It is most useful for vestibular causes of nausea and vomiting. Occasionally, patients with central causes of vomiting, such as from medication, will respond to it when metoclopramide is not effective. Chlorpromazine is more sedative and hypotensive than prochlorperazine.
They act on the vomiting centre and the vestibular centre. Cyclizine is more effective and less sedative than Promethazine which also has antihistamine and anticholinergic effects. Promethazine theoclate is effective for morning nausea if given at bedtime.
They predominantly have central actions on the vomiting centre and vestibular centre. They also reduce secretion and colic in bowel obstruction. They can cause dry mouth and urinary retention.
Hyoscine Butylbromide acts peripherally and has less central side effect such as sedation and delirium than Hyoscine Hydrobromide that can cause confusion. However, the latter can be given in combination with other drugs in a syringe driver. They are useful for reducing gastrointestinal secretions and vomiting in bowel obstruction.
They are good for chronic nausea due to delayed gastric emptying caused by dysfunction of autonomic nervous system, which is a paraneoplastic manifestation of advanced cancer. They can cause spasm in patients of gastric outlet obstruction and bowel obstruction.
Metoclopramide has both peripheral upper gastrointestinal and central (CTZ) antiemetic effect. It is useful for chemotherapy induced vomiting in very high dose (1-10 mg/kg) far in excess of the dose required to block dopamine D2 receptors. In these dosages, it is acting via non-specific blockade of 5-HT3 receptors.10
Domperidone and Cisapride are less effective then metoclopramide as anti-emetic. Domperidone stimulates upper bowel activity and cisapride acts on the whole gastrointestinal tract. They do not cross blood brain barrier and have no extrapyramidal side effect. Cisapride raises lower esophageal sphincter tone, raises gastric and intestinal peristalsis throughout the gastrointestinal tract and improve constipation. It is effective for gastric stasis or compression.
Acting on CTZ, vomiting centre and the gut, they are particularly effective for nausea and vomiting caused by radiotherapy and chemotherapy.11.12
Ondansetron and Tropisetron have a pro-kinetic activity and are not indicated in bowel obstruction.13 They have additive effect when used with other drugs that act on the CTZ, such as haloperidol. However, they can cause constipation and are very expensive.11,12
Octreotide reduces gastrointestinal motility and inhibits secretion of the pancreas, stomach, and intestine. It facilitates the absorption of water and electrolytes in the bowel lumen. It has negligible side effect but is very expensive.13
They exert an anti-emetic effect when used alone although their mechanism of action is not fully understood. Dexamethasone has synergistic effect with metoclopramide, 5HT3 antagonist14 and prochlorperazine. It has particular value in the treatment of nausea and vomiting caused by increased intracranial pressure, bowel obstruction, liver distension and squashed stomach syndrome by shrinking tumour temporarily. It also helps in relieving nausea of hypercalcaemia and enhances appetite. Megestrol acetate has both antiemetic and appetite stimulating properties.15
1. Always try to identify and treat the reversible causes.
2. The pharmaceutical therapy would be more effective if the drug is prescribed specifically for the known mechanism of nausea and vomiting.
3. Use drugs at the earliest suggestion of nausea may prevent development of conditioned symptoms.
4. Non-drug therapy is as important as drug management.
5. If the patient cannot tolerate oral administration, use parenteral or rectal route until vomiting is controlled.
6. Rectal absorption may be erratic. Subcutaneous administration is more reliable.
7. Subcutaenous bolus injection can be given by family via butterfly needle left in situ.
8. Use a combination of antiemetics if necessary, but avoid using more than one drug with the same type of action.
1. Grond S, Zech D, Diefenbach C, Bishcoff A, Prevalence and pattern of symptoms in patients with cancer pain: a prospective evaluation of 1635 patients referred to a pain clinic, J Pain Symptom Manage 1994; 9:372-82.
2. Dunlop GM, A study of the relative frequency and importance of gastrointestinal symptoms, and weakness in patients with far advanced cancer. Palliat Med, 1989; 4:37-43.
3. Regnard C, Cormisky M, Nausea and vomiting in advanced cancer, Palli Med, 1992; 6:146-51.
4. Blancquaert JP, LeFebvre, Willems JL. Emetic and antiemetic effects of opioids in the dog. European J of Rheumatology, 1986; 128:143-50
5. Barkin JS. Pancreatic carcinoma is associated with delayed gastric emptying. Digestive Diseases Science, 1986; 31:265-7
6. Devine E, Westlake S, The effects of psychoeducational care provided to adults with cancer: meta-analysis of 116 studies. Oncology Nursing Forum, 1995; 22(9):1369-1381.
7. Dundee JW, Yang J. Prolongation of the anti-emetic action of P6 acupuncture by acupressure in patients having cancer chemotherapy. J Royal Soc Med, 1991; 83:360-2.
8. Ashby MA, Game PA, Devitt P, et al., Percutaneous gastrostomy as a venting procedure in palliative care. Palliat Med, 1991; 5:147-150.
9. Young RW. Mechanisms and treatment of radiation induced nausea and vomiting. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith DG, eds. Nausea and Vomiting: Mechanisms and treatment. Berlin: Springer-Verlag, 1986:94-109.
10. Milne RJ, Heel RC, Ondansetron: therapeutic use as an anti-emetic. Drugs, 1991; 41:574-95.
11. Grunberg SM, Hesketh PJ, Control of chemotherapy-induced emesis. N Engl J Med, 1993; 329:1790-6.
12. Perez Ea, Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol 1995; 13:1036-43.
13. Riley J, Fallon MT, Octreotide in terminal malignant obstruction of the gastrointestinal tract, Euro J Palliat Care, 1994; 1:20-22.
14. Smith DB. Ondansetron plus dexamethasone: effective prophylaxis for patients receiving cytotoxic chemotherapy. B J Cancer, 1990:61:323-4.
15. Loprinzi CL. Controlled trial of megestrol acetate for the treatment of cancer, anorexia and cachexia. J National Cancer Institute, 1990;82:1127-32.