Cancer and nausea

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A painting from 1681 depicting a person affected by nausea and vomiting 3205 - Milano, Duomo - Giorgio Bonola - Miracolo di Marco Spagnolo (1681) - Foto Giovanni Dall'Orto, 6-Dec-2007-cropped.jpg
A painting from 1681 depicting a person affected by nausea and vomiting

Cancer and nausea are associated in about fifty percent of people affected by cancer. [1] 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. About 70 to 80% of people undergoing chemotherapy experience nausea or vomiting. Nausea and vomiting may also occur in people not receiving treatment, often as a result of the disease involving the gastrointestinal tract, [2] electrolyte imbalance, or as a result of anxiety. [3] Nausea and vomiting may be experienced as the most unpleasant side effects of cytotoxic drugs [4] and may result in patients delaying or refusing further radiotherapy [5] or chemotherapy. [6]

Contents

The strategies of management or therapy of nausea and vomiting depend on the underlying causes. [7] Medical treatments or conditions associated with a high risk of nausea and/or vomiting include chemotherapy, radiotherapy, and malignant bowel obstruction. [8] Anticipatory nausea and vomiting may also occur. [9] Nausea and vomiting may lead to further medical conditions and complications including: dehydration, electrolyte imbalance, malnutrition, and a decrease in quality of life. [3]

Nausea may be defined as an unpleasant sensation of the need to vomit. [7] It may be accompanied by symptoms such as salivation, feeling faint, and a fast heart rate. [7] Vomiting is the forceful ejection of stomach contents through the mouth. [7] Although nausea and vomiting are closely related, some patients experience one symptom without the other and it may be easier to eliminate vomiting than nausea. [1] 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. [10] The detection of emetic stimuli, the central processing by the brain and the resulting response by organs and tissues that lead to nausea and vomiting are referred to as the emetic pathway or emetic arch.

Causes

Some medical conditions that 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), anticipatory nausea and vomiting (ANV), and radiotherapy-induced nausea and vomiting (RINV).[ citation needed ]

Malignant bowel obstruction

Malignant bowel obstruction (MBO) of the gastrointestinal tract is a common complication of advanced cancer, especially in patients with bowel or gynaecological cancer. These include colorectal cancer, ovarian cancer, breast cancer, and melanoma. [8] 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. [11] The mechanisms of action that may lead to nausea in MBO include mechanical compression of the gut, motility disorders, gastrointestinal secretion accumulation, decreased gastrointestinal absorption, and inflammation. [12] Bowel obstruction and the resulting nausea may also occur as a result of anti-cancer therapy such as radiation, [13] or adhesion after surgery. [14] Impaired gastric emptying as a result of bowel obstruction may not respond to drugs alone, and surgical intervention is sometimes the only means of symptom relief. [15] 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. [12]

Chemotherapy

Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared side effects of chemotherapy [16] and is associated with a significant deterioration in quality of life. [17] CINV is classified into three categories: [16]

Risk factors that predict the occurrence and severity of CINV include 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. [10] Other person-related variables, such as chemotherapy dose, rate and route of administration, hydration status, prior history of CINV, emesis during pregnancy or motion sickness, tumour burden, concomitant medication and medical conditions also play a role in the degree of CINV experienced by a person. [9] [18] 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. [9]

Chemotherapeutic agents associated with vomiting
Association with vomitingExamples
Highly emetogenic (>90%) Intravenous agents [19] Cisplatin, Mechlorethamine, Streptozotocin, Cyclophosphamide > 1500 mg/m2, Carmustine, Dacarbazine, Anthracycline
Highly emetogenic (>90%) oral agents [9] Hexamethylmelamine, Procarbazine
Moderately emetogenic (30-90%) intravenous agents [9] Oxaliplatin, Cytarabine > 1g/m2, Carboplatin, Ifosfamide, Cyclophosphamide < 1500 mg/m2, Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Irinotecan, Azacitidine, Bendamustine, Clofarabine, Alemtuzumab
Moderately emetogenic (30-90%) oral agents [9] Cyclophosphamide, Temozolomide, Vinorelbine, Imatinib

The European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC) in 2010 [9] as well as the American Society of Clinical Oncology (ASCO) (2011) [19] 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.

Anticipatory

A common consequence of cancer treatment is the development of anticipatory nausea and vomiting (ANV). [20] 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. [6] Approximately 20% of people undergoing chemotherapy are reported to develop anticipatory nausea and vomiting. Once developed, ANV is difficult to control by pharmacological means. Benzodiazepines are the only drugs that have been found to reduce the occurrence of ANV but their efficacy decreases with time. [9] Recently, clinical trials suggests that cannabidiolic acid suppresses conditioned gaping (ANV) in shrews. [21] Because ANV is widely believed to be a learned response, the best approach is to avoid the development of ANV by adequate prophylaxis and treatment of acute vomiting and nausea from the first exposure to therapy. [9] [20] Behavioral treatment techniques, such as systematic desensitization, progressive muscle relaxation, and hypnosis have been shown to be effective against ANV. [9] [20]

Radiation therapy

The incidence and severity of radiation therapy-induced nausea and vomiting (RINV) 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: [5]

Pathophysiology

Nausea and vomiting may have a number of causes in people with cancer. [7] 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 may be categorized as disease-related and treatment-related. [22]

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. [10] 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 solitarii. [23] 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. [10] [23]

Efferent outputs which transmit the information from the brain leading to the motoric response of retching and vomiting include vagal efferents to the esophagus, 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. [23]

Nausea and vomiting may be initiated by various stimuli, through different neuronal pathways. A stimulus may act on more than one pathway. [23] Stimuli and pathways include:

Patient Reported Outcomes

Patient reported outcomes (PROs) allow patients to voice their perspective on health and behavioral status through self administered questionnaires. [24] Cancer and nausea have been measured with the Patient Reported Outcomes Measurement System (PROMIS) using surveys with questions such as “in the last 7 days, how severe was your nausea?” [24] PROs can aid clinicians in tailoring nausea treatment specific to variations in high or low emetogenic chemotherapy from patient to patient. [25] One notable benefit of PROs is that surveys can be administered electronically, meaning patients who are too sick to go to the doctor can do it from home. [26]

Limitations: While helpful, PROs are subject to bias since they are reported after the symptoms are experienced. [25] Errors in patients’ memories can influence their PROs compared to if they had been asked while experiencing nausea rather than afterwards. [25] This can lead to ratings which may not accurately reflect how patients perceive their nausea at the moment. [25]

Management

The strategies of management or prevention 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 previous effectiveness and side effects. [7]

Medication

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

Side Effects

Side effects of antiemetic drugs are relatively mild. Depending on the type of drug and dosage prescribed, common side effects may include: headache, constipation, diarrhea, insomnia, agitation, acne, weight loss/weight gain, dizziness, or drowsiness. [16] In addition, although cannabis has proven extremely beneficial for emetic relief, a small percentage of patients opting to use medical cannabis have shown to become dependent on it after treatment concludes. [28]

Nonmedical Interventions

Other non-drug measures may include:

Palliative surgery

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. [33]

Sometimes it is possible or necessary to provide relief for cancer-caused nausea and vomiting through palliative surgical intervention. 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. [8] The surgical approach proves beneficial in affected people with operable lesions, a life expectancy greater than 2 months and good performance status. [12] 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 several procedures including:

Epidemiology

In 2008, 12.7 million new cancer cases and 7.6 million cancer deaths were estimated worldwide. [35]

Financial Implications

Individual: CINV has shown to bring a heavy financial burden on cancer patients. These costs may discourage patients from seeking treatment or purchasing medication despite nausea being one of the most debilitating side effects of chemotherapy. [37] In addition to hospital fees, studies have found that costs incurred for prescription antiemetics averaged between $100–1400 per chemotherapy cycle depending on the drugs prescribed. [37]

Healthcare system: In addition to patient costs, CINV also takes a heavy financial toll on the healthcare system at large. General cancer symptom management has shown to make up 5% of annual hospital expenses, with the cost of CINV changing with antiemetic treatment. [38] It was found that people receiving prophylactic treatment posed a significantly lower burden on the healthcare system. In contrast, patients who received no prophylactic treatment were shown to pose a substantial cost to the healthcare system. [38] These additional costs have shown to be associated with repeated hospital visits and emergency medication for uncontrolled CINV. [38]  

See also

Related Research Articles

An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be used for severe cases of gastroenteritis, especially if the patient is dehydrated.

<span class="mw-page-title-main">Metoclopramide</span> Medication

Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.

<span class="mw-page-title-main">Granisetron</span> Serotonin 5-HT3 antiemetic

Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy and radiotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the post-anesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.

<span class="mw-page-title-main">Ondansetron</span> Medication to prevent nausea and vomiting

Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, migraines or surgery. It is also effective for treating gastroenteritis. It can be given orally, intramuscularly, or intravenously.

The chemoreceptor trigger zone (CTZ) is an area of the medulla oblongata that receives inputs from blood-borne drugs or hormones, and communicates with other structures in the vomiting center to initiate vomiting. The CTZ is located within the area postrema, which is on the floor of the fourth ventricle and is outside of the blood–brain barrier. It is also part of the vomiting center itself. The neurotransmitters implicated in the control of nausea and vomiting include acetylcholine, dopamine, histamine, substance P, and serotonin. There are also opioid receptors present, which may be involved in the mechanism by which opiates cause nausea and vomiting. The blood–brain barrier is not as developed here; therefore, drugs such as dopamine which cannot normally enter the CNS may still stimulate the CTZ.

<span class="mw-page-title-main">Nabilone</span> Synthetic cannabinoid

Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.

<span class="mw-page-title-main">Dolasetron</span> Pharmaceutical drug

Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

ABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma, replacing the older MOPP protocol. It consists of concurrent treatment with the chemotherapy drugs:

<span class="mw-page-title-main">Vomiting</span> Involuntary, forceful expulsion of stomach contents, typically via the mouth

Vomiting is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.

Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.

Radiation enteropathy is a syndrome that may develop following abdominal or pelvic radiation therapy for cancer. Many affected people are cancer survivors who had treatment for cervical cancer or prostate cancer; it has also been termed pelvic radiation disease with radiation proctitis being one of the principal features.

5-HT<sub>3</sub> antagonist Anti-nausea group of medications

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

<span class="mw-page-title-main">Metopimazine</span> Chemical compound

Metopimazine, sold under the brand names Vogalen and Vogalene, is an antiemetic of the phenothiazine group which is used to treat nausea and vomiting. It is marketed in Europe, Canada, and South America. As of August 2020, metopimazine has been repurposed and is additionally under development for use in the United States for the treatment of gastroparesis.

<span class="mw-page-title-main">Azasetron</span> Chemical compound

Azasetron is an antiemetic which acts as a 5-HT3 receptor antagonist, pKi = 9.27 It is used in the management of nausea and vomiting induced by cancer chemotherapy (such as cisplatin chemotherapy). Azasetron hydrochloride is given in a usual dose of 10 mg once daily by mouth or intravenously. It is approved for marketing in Japan, and marketed exclusively by Torii Pharmaceutical Co., Ltd. under the trade names "Serotone I.V. Injection 10 mg" and "Serotone Tablets 10 mg". Pharmacokinetics data from S. Tsukagoshi.

<span class="mw-page-title-main">Nausea</span> Medical symptom or condition

Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat.

<span class="mw-page-title-main">Dazopride</span> Chemical compound

Dazopride (AHR-5531) is an antiemetic and gastroprokinetic agent of the benzamide class which was never marketed. It acts as a 5-HT3 receptor antagonist and 5-HT4 receptor agonist. In addition to its gastrointestinal effects, dazopride facilitates learning and memory in mice.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.

<span class="mw-page-title-main">Rolapitant</span> Pharmaceutical drug

Rolapitant (INN, trade name Varubivə-ROO-bee in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor). It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.

Paul L. R. Andrews is a British physiologist whose basic research on the mechanisms of action and efficacy of antiemetic substances contributed to development of treatments for anti-cancer chemotherapy-induced nausea and vomiting.

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