Cancer and nausea

Cancer and nausea are associated in about fifty percent of people affected by a malignant neoplasm (cancer). This may be as a result of the cancer itself, or as an effect of the treatment such as chemotherapy, radiation therapy, or other medication such as opiates used for pain relief. While seventy to eighty percent of people undergoing chemotherapy experience nausea and/or vomiting, they may also occur in people not receiving treatment, mostly as a result of the disease involving the gastrointestinal tract or other metabolic disorders such as hypercalcaemia and renal failure or as a result of anxiety. Nausea and vomiting are considered by affected people to be the most burdening adverse reactions to cytostatics and are often severe enough to lead to a termination of therapy.

A painting from 1681 depicting a person affected by nausea and vomiting

The vomiting reflex (also called emesis) is thought to have evolved in many animal species as a protective mechanism against ingested toxins. In humans, the vomiting response may be preceded by an unpleasant sensation termed nausea, but nausea may also occur without vomiting. The central nervous system is the primary site where a number of emetic stimuli (input) are received, processed and efferent signals (output) are generated as a response and sent to various effector organs or tissues, leading to processes that eventually end in vomiting. The detection of emetic stimuli, the central processing by the brain and the resulting response by organs and tissues which lead to nausea and vomiting are referred to as the emetic pathway or emetic arch.

Definitions

Nausea may be defined as an unpleasant sensation of the need to vomit, which is often accompanied by symptoms such as skin pallor, cold sweat, salivation, and tachycardia. Vomiting is the forceful ejection of stomach contents through the mouth.

Associated medical conditions

Some medical conditions which arise as a result of cancer or as a complication of its treatment are known to be associated with a high risk of nausea and/or vomiting. These include malignant bowel obstruction (MBO), chemotherapy induced nausea and vomiting (CINV), radiotherapy induced nausea and vomiting (RINV) and anticipatory nausea and vomiting (ANV).

Malignant bowel obstruction (MBO)

Main article: Bowel obstruction

Malignant obstruction of the gastrointestinal tract is a common complication of advanced caner, especially in patients with bowel or gynaecological cancer. These include colorectal cancer, ovarian cancer, breast cancer and melanoma. Three percent of all advanced cancers lead to malignant bowel obstruction and 25 to 50 percent of patients with ovarian cancer experience at least one episode of malignant bowel obstruction. The mechanisms of action which may lead to nausea in MBO include mechanical compression of the gut, motility disorders, gastrointestinal secretion accumulation, decreased gastrointestinal absorption, and inflammation. Bowel obstruction and the resulting nausea may also occur as a result of anti-cancer therapy such as radiation, or adhesion after surgery. Some constipating drugs used in cancer therapy such as opioids may cause a slowing of peristalsis of the gut, which may lead to a functional bowel obstruction.

Chemotherapy induced nausea and vomiting (CINV)

Main article: Chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting is one of the most feared side effects of chemotherapy and is associated with a significant deterioration in quality of life. CINV is classified into three categories:

• early onset (occurring within 24 hours of initial exposure to chemotherapy
• delayed onset (occurring 24 hours to several days after treatment)
• anticipatory (triggered by taste, odor sight, thoughts, or anxiety)

There are several risk factors which are used to predict the occurrence and severity of CINV including sex and age, with females, younger people and people who have a high pretreatment expectation of nausea being at a higher risk, while people with a history of high alcohol consumption being at a lower risk. Other person-related variables, such as chemotherapy dose, rate and route of administration also play a role in the degree of CINV experienced by a person. By far the most important factor which determines the degree of CINV is the emetogenic potential of the chemotherapeutic agents used. Chemotherapeutic agents are classified into four groups according to their degree of emetogenicity: high, moderate, low and minimal.

List of intravenous antineoplastic agents with high emetogenicity (>90%)
Cisplatin
Mechlorethamine
Streptozotocin
Cyclophosphamide>1500 mg/m2
Carmustine
Dacarbazine
Anthracycline

List of oral antineoplastic agents with high emetogenicity (>90%)
Hexamethylmelamine
Procarbazine

List of intravenous antineoplastic agents with moderate emetogenicity (30-90%)
Oxaliplatin
Cytarabine >1 gm/m2
Carboplatin
Ifosfamide
Cyclophosphamide <1500 mg/m2
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Irinotecan
Azacitidine
Bendamustine
Clofarabine
Alemtuzumab

List of oral antineoplastic agents with moderate emetogenicity (30-90%)
Cyclophosphamide
Temozolomide
Vinorelbine
Imatinib

The European Society of Medical Oncology (ESMO)and the Multinational Association of Supportive Care in Cancer (MASCC) in 2010 as well as the American Society of Clinical Oncology (ASCO)(2011) recommend a prophylaxis to prevent acute vomiting and nausea following chemotherapy with high emetic risk drugs by using a three-drug regimen including a 5-HT3 receptor antagonist, dexamethasone and aprepitant (a Neurokinin-1 antagonist) given before chemotherapy.

Radiation therapy induced nausea and vomiting (RINV)

The incidence and severity of nausea and vomiting associated with radiation therapy depends on a number of factors including therapy related factors such as irradiated site, single and total dose, fractionation, irradiated volume and radiotherapy techniques. Also involved are person related factors such as gender, general health of the person, age, concurrent or recent chemotherapy, alcohol consumption, previous experience of nausea, vomiting, anxiety as well as the tumor stage. The emetogenic potential of radiotherapy is classified into high, moderate, low and minimal risk depending on the site of irradiation:

• High risk: total body irradiation (TBI) is associated with a high risk of RINV
• Moderate risk; radiation of the upper abdomen, half body irradiation and upper body irradiation
• Low risk: radiation of the cranium, spine, head and neck, lower thorax region and pelvis
• Minimal risk: radiation of extremities and breast

Anticipatory nausea and vomiting (ANV)

A common consequence of cancer treatment is the development of anticipatory nausea and vomiting. This kind of nausea is usually elicited by the re-exposure of the patients to the clinical context they need to attend to be treated. Approximately 20% of people undergoing chemotherapy are reported to develop anticipatory nausea and vomiting. Behavioral treatment techniques, such as systematic desensitization have been shown to be effective against ANV.

Complications

Nausea and vomiting may lead to further medical conditions and complications including dehydration, electrolyte imbalance, malnutrition, aspiration pneumonia, oesophageal tears, and a decrease in the ability to self care and quality of life.

Pathophysiology

Nausea and vomiting may have a number of causes in people with cancer. While more than one cause may exist in the same person stimulating symptoms via more than one pathway, the actual cause of nausea and vomiting may be unknown in some people. The underlying causes of nausea and vomiting may in some cases not be directly related to the cancer. The causes of nausea and vomiting can be grouped according to the mechanisms leading to the emetic reflex and the receptors involved. The causes may also be categorized as disease-related and treatment-related.

Central processing

The stimuli which lead to emesis are received and processed in the brain. It is thought that a number of loosely organized neuronal networks within the medulla oblongata probably interact to coordinate the emetic reflex. Some of the brain stem nuclei which have been identified as important in the coordination of the emetic reflex include the parvicellular reticular formation, the Bötzinger complex and the nucleus tractus solitarius. The nuclei coordinating emesis had formerly been referred to as the vomiting complex, but it is no longer thought to represent a single anatomical structure.

Input stimuli and pathways

Nausea and vomiting may be initiated by various stimuli, through different neuronal pathways. A stimulus may act on more than one pathway.

Toxic substances in the gastrointestinal tract

Toxic substances (including drugs which are used in the treatment of cancer) in the lumen of the gastrointestinal tract stimulate vagal afferent nerves in the gut mucosa which communicate to the nucleus tractus solitarius and the area postrema to initiate vomiting and nausea. A number of receptors on the terminal ends of the vagal afferent nerves have been identified as being involved in this process, including the 5-hydroxytryptamine3 (5-HT3), neurokinin-1, and cholecystokinin-1 receptors. Various local mediators located in enterochromaffin cells of the gut mucosa play a role in stimulating these receptors. Of these 5-hydroxytryptamine seems to play the dominating role. This pathway has been postulated to be the mechanism by which some anti-cancer drugs such as cisplatin induce emesis.

Toxic substances in the blood

Toxic substances which have been absorbed into the blood (including cytostatics) or endogenous toxic (waste) material released by body or cancer cells into the blood can be detected directly in the area postrema of the brain and trigger the emetic reflex. The area postrema is a structure located on the floor of the fourth ventricle around which the blood-brain barrier is permeable, thus allowing for the detection of humoral or pharmacological stimuli in the blood or cerebrospinal fluid. This structure contains receptors which form a chemoreceptor trigger zone. Some of the receptors and neurotransmitters involved in the regulation of this emetic pathway include dopamine type D2, serotonin types 2–4 (5HT2–4), histamine type 1(H1), and acetylcholine (muscarinic receptors type 1 to 5, M1–5). Some other receptors such as substance P, cannabinoid type 1 (CB1) and the endogenous opioids may also be involved.

Pathological conditions of the gastrointestinal tract

Diseases and pathological conditions of the GIT may also lead to nausea and vomiting through direct or indirect stimulation of the above named pathways. Such conditions may include malignant bowel obstruction, hypertrophic pyloric stenosis and gastritis. Pathological conditions in other organs which are linked to the above named emetic pathways may also lead to nausea and vomiting, such as the myocardial infarct (through stimulation of cardiac vagal afferents) and renal failure.

Stimulation of the central nervous system

Certain stimuli of the central nervous system may induce the emetic reflex. These include fear, anticipation, brain trauma and increased intra-cranial pressure. Of particular relevance to cancer patients in this regard are the stimuli of fear and anticipation. Evidence suggests that cancer patients may develop the side effects of nausea and vomiting in anticipation of chemotherapy. In some patients, contextual cues such as smell, sounds or even the sight of the clinic may evoke anticipatory nausea and vomiting prior to treatment.

Pathological conditions of the vestibular system

A disturbance of the vestibular system such as in motion sickness or Meniere's disease can also induce the emetic reflex. Such disturbances of the vestibular system could also be cancer related, such as cerebral or vestibular secondaries (metastasis). They could also be cancer treatment related such as the use of opioids or radiation therapy of the head and neck which may affect the system.

Output pathways

Efferent outputs which transmit the information from the brain leading to the motoric response of retching and vomiting include vagal efferents to the oesophagus, stomach and intestine as well as spinal somatomotor neurones to the abdominal muscles and phrenic motor neurones (C3–C5) to the diaphragm. Autonomic efferents also supply the heart and airways (vagus), salivary glands (chorda tympani) and skin and are responsible for many of the prodromal signs such as salivation and skin pallor.

Management

The strategies of management, therapy or prophylaxis of nausea and vomiting depend on the underlying causes, whether they are reversible or treatable, stage of the illness, the person's prognosis and other person specific factors. Anti emetic drugs are chosen according to the to the cause of nausea and vomiting and the underlying cause is corrected where reversible and appropriate.

Medication

Drugs that are used in the prophylaxis and therapy of nausea and vomiting in cancer include:

5-HT3 antagonists

5-HT3 antagonists produce their anti emetic effect by blocking of the amplifying effect of serotonin on peripheral and central 5-HT3 receptors located on the various vagal afferent nerve endings and the chemoreceptor trigger zone. They are effective in the treatment and prophylaxis of CINV as well as in malignant bowel obstruction and renal failure which are associated with elevated serotonin levels. These substances include Dolasetron, Granisetron, Ondansetron, Palonosetron and Tropisetron. They are often used in combination with other anti emetic drugs in people with high risk of emesis or nausea and are recommended as the most effective anti emetics in the prophylaxis of acute CINV.

Corticosteroids

Corticosteroids such as Dexamethasone are used in the treatment of emesis as a result of chemotherapy, malignant bowel obstruction, raised intracranial pressure and in the chronic nausea of advanced cancer, though their exact mode of action remain unclear. Dexamethason is recommended for use in the acute prevention of highly, moderately, and low emetogenic chemotherapy and in combination with aprepitant for the prevention of delayed emesis in highly emetogenic chemotherapy.

NK1 receptor antagonists

NK1 receptor antagonists such as Aprepitant block the NK1 receptor in the brainstem and gastrointestinal tract. Their antiemetic activity when added to a 5-HT3 receptor antagonist plus dexametasone has been shown in several phase II double-blind studies.

Cannabinoids

Cannabinoids are a useful adjunct to modern anti emetic therapy in selected patients. They show a combination of weak anti emetic efficacy with potentially beneficial side effects such as sedation and euphoria. However, their usefulness is generally limited by the high incidence of toxic effects, such as dizziness, dysphoria, and hallucinations. Some studies have shown that cannabinoids are slightly better than conventional anti emetics such as metoclopramide, phenothiazines and haloperidol in the prevention of nausea and vomiting. Cannabinoids are an option in affected people who are intolerant or refractory to 5-HT3 antagonists or steroids and aprepitant as well as in refractory nausea and vomiting and rescue anti emetic therapy.

Conventional anti emetics

Other anti emetics which may also be used in cancer include:

• Prokinetic agents such as Metoclopramide
• Dopamine receptor antagonists such as Phenothiazines (Prochlorperazine and chlorpromazine), haloperidol, olanzapine and Levomepromazine, block D2 receptors found in the chemoreceptor trigger zone
• Antihistaminic agents like Promethazine block H1 receptors in the vomiting center of the medulla, the vestibular nucleus, and the chemoreceptor trigger zone
• Anticholinergic agents such as Scopolamine (Hyoscine) are used as anti emetics as they relax smooth muscle and reduce gastrointestinal secretions by blockade of muscarinic receptors. They may be useful in the management of terminal bowel obstruction
• Somatostatin analoga such as Octreotide are used for the palliation of malignant bowel obstruction, especially when there is high output vomiting not responding to other measures

Diet

Small palatable meals are normally tolerated better than big meals in people affected by nausea and vomiting in cancer. Carbohydrate meals are better tolerated than spicy, fatty and sweet foods. Cool, fizzy drinks are found to be more palatable than still or hot drinks.

Non drug measures

Non drug measures may include the avoidance of environmental stimuli, such as sights, sounds, or smells that may initiate nausea. Behavioral approaches, such as relaxation and distraction as well as relaxation training may also be useful. Cognitive behavioural therapy is an option considered useful for anticipatory nausea or vomiting.

Alternative medicine

Acupuncture and ginger have been shown to have some anti emetic effects on chemotherapy-induced emesis and anticipatory nausea, but have not been evaluated in the nausea of far advanced disease.

Palliative care

Palliative care is the active care of people with advanced, progressive illness such as cancer. The World Health Organization (WHO) defines it as an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems (such as nausea or vomiting), physical, psychosocial, and spiritual.

Surgery

Sometimes it is possible or necessary to provide relief for cancer caused nausea and vomiting through palliative surgical intervention. Often a malignant bowel obstruction is the cause of the symptoms in which case the purpose of palliative surgery is to relieve the symptoms of bowel obstruction by means of four procedures: stoma formation, bypassing the obstruction, resection of bowel and placement of colorectal stents. Surgery is however not routinely carried out when there are poor prognostic criteria for surgical intervention such as intra-abdominal carcinomatosis, poor performance status and massive ascites. The surgical approach proves beneficial in affected people with operable lesions, a life expectancy greater than 2 months and good performance status. In people affected with abdominal malignancies percutaneous endoscopic gastrostomy (PEG) tube placement to enable gastric venting is an option for palliation of nausea and vomiting due to gastrointestinal obstruction. The endoscopic placement of a self-expanding metal or plastic stent (SEMS) is a minimally invasive option in gastro-duodenal and malignant colorectal obstruction.

Non surgical palliative measures

Gastric venting through a nasogastric tube is a possibility for palliation of nausea and vomiting due to gastrointestinal obstruction in patients with abdominal malignancies who decline surgery or where surgery may not be indicated. However nasogastric tubes are not recommended to be used over a long period of time because of the high risk of displacement, poor tolerance, restrictions in daily routine activities, coughing, clearing pulmonary secretions and can be cosmetically unacceptable and confining. Complications of nasogastric tubes include aspiration, hemorrhage, gastric erosion, necrosis, sinusitis and otitis.

Epidemiology

12.7 million new cancer cases and 7.6 million cancer deaths were estimated worldwide in 2008. Nausea and/or vomiting occur in 50–70% of people with advanced cancer.

See also

• Antiemetic
• Management of cancer