Chemotherapy-induced nausea and vomiting

Last updated

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. [1] 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.

Contents

Types

There are several subtypes of CINV. The classifications of nausea and vomiting are: [2]

Cause

Emesis is a defense mechanism controlled by the area postrema of the medulla oblongata. There are various sources of input to the vomiting center. Receptors on the floor of the fourth ventricle of the brain represent the chemoreceptor trigger zone. The chemoreceptor trigger zone contains dopamine D2 receptors, serotonin 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P. Stimulation of different receptors are involved in different pathways leading to emesis. In the final common pathway, substance P, which activates the neurokinin-1 receptor, appears to be involved. [3] Additionally, the vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system.

Chemotherapy interferes with cell division, which particularly affects rapidly dividing cells like those of the gastrointestinal mucosa and immune cells. Irritation of the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these inputs. [4] It is now widely known that cytotoxic chemotherapeutic agents cause enterochromaffin cells to produce more serotonin in response to free radical damage, leading to a detectable increase in blood levels of serotonin (5-HT) and its major metabolite, 5-Hydroxyindoleacetic acid (5-HIAA). [5] The presence of these chemicals in the blood activate 5-HT3 receptors in the chemoreceptor trigger zone, in turn releasing substance P, which activates NK1 receptors to cause an emetic response (vomiting).

Risk factors

The risk of chemotherapy-induced nausea and vomiting varies based on the type of treatment received as well as several outside factors. Some types of chemotherapy are more prone to causing nausea and vomiting than others. Some chemotherapeutic agents may not cause nausea and vomiting on their own, but may when used in combination with other agents. [6] Regimens that are linked to a high incidence (90% or higher) of nausea and vomiting are referred to as "highly emetogenic chemotherapy", and those causing a moderate incidence (30–90%) of nausea and vomiting are referred to as "moderately emetogenic chemotherapy". [7]

Some highly emetogenic agents and chemotherapy regimens include: [6] [8]

Some moderately emetogenic agents and regimens include: [8]

Besides the type of treatment, personal factors may put a patient at greater risk for CINV. Other risk factors include: [2] [6] [9]

Treatments

Several treatment methods are available to help prevent CINV. Pharmaceutical treatment is generally separated into two types: prophylactic (preventative) treatment, given before the dose of chemotherapy agents, and rescue treatment, given to treat breakthrough nausea and vomiting.

5-HT3 inhibitors

5-HT3 receptor antagonists are very effective antiemetics and constitute a great advance in the management of CINV. These drugs block one or more of the nerve signals that cause nausea and vomiting. During the first 24 hours after chemotherapy, the most effective approach appears to be blocking the 5-HT3 nerve signal. [10] Approved 5-HT3 inhibitors include dolasetron (Anzemet), granisetron (Kytril, Sancuso), and ondansetron (Zofran). Their antiemetic effect due to blockade of 5HT3 receptor on vagal afferent in the gut. in addition they also block 5-HT3 receptors in CTZ and STN. The newest 5-HT3 inhibitor, palonosetron (Aloxi), also prevents delayed nausea and vomiting, which can occur during the 2–5 days after treatment. Since some patients have trouble swallowing pills, these drugs are often available by injection, as orally disintegrating tablets, or as transdermal patches.

NK1 inhibitors

A newer class of drugs known as the NK1 antagonists are a recently developed class of very efficacious drugs for controlling CINV. These drugs are often used alongside 5HT3 inhibitors and corticosteroids to form a very potent cocktail of antiemetics that verge on achieving a nearly complete patient response (that is, completely stopping CINV). [11] The substance P inhibitor aprepitant (Emend), which became available in 2005, is highly effective in controlling nausea and vomiting associated with cancer chemotherapy. [11] Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brains neurons. Indeed, positron emission tomography (PET) studies have shown that aprepitant can penetrate the brain and NK1 receptors in the brain. [12] Aprepitant has also been shown to increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy. [11] Netupitant has recently been approved by USFDA. It has also been marketed in combination with palonosetron. Rolapitant is the newest addition in the approved NK1 antagonist list. It has advantage of a very long half life, duration of action is around 150 hours. Rolapitant got its approval by USFDA in 2015.

Other drugs

Olanzapine, as well as several other neuroleptic drugs, have also has been investigated for the control of CINV. [13] A 2007 study demonstrated Olanzapine's successful potential for this use, achieving a complete response in the acute prevention of nausea and vomiting in 100% of patients treated with moderately and highly emetogenic chemotherapy, when used in combination with palonosetron and dexamethasone. [14] Neuroleptic agents are now indicated for rescue treatment and the control of breakthrough nausea and vomiting. [13]

Some studies [15] and patient groups say that the use of cannabinoids derived from cannabis during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Synthesized tetrahydrocannabinol (also one of the main active substances in marijuana) is marketed as Marinol and may be practical for this application. Natural medical cannabis is also used and recommended by some oncologists, though its use is regulated and it is not legal in all jurisdictions. [16] However, Marinol was less effective than megestrol acetate in helping cancer patients regain lost appetites. [17] A phase III study found no difference in effects of an oral cannabis extract or THC on appetite and quality of life (QOL) in patients with cancer-related anorexia-cachexia syndrome (CACS) to placebo. [18] [ third-party source needed ]

Dexamethasone, a corticosteroid, is often used alongside other antiemetic drugs, as it has synergistic action with many of them, although its specific antiemetic mechanism of action is not fully understood. Metoclopramide, a dopamine D2 receptor antagonist with possible other mechanisms, is an older drug that is sometimes used, either on its own or in combination with others. Histamine blockers such as diphenhydramine or meclozine may be used in rescue treatment. Lorazepam and diazepam may sometimes be used to relieve anxiety associated with CINV before administration of chemotherapy, and are also often used in the case of rescue treatment. [13]

Alternative treatments

Ginger (Zingiber officinale)

There are several compounds that have been identified within ginger that have been shown to possess properties that are likely to be beneficial in the treatment of CINV. This includes 5-HT3 and substance P antagonism, modulation of gastrointestinal motility, and antioxidant properties. [19] [20] There have been multiple clinical trials that have investigated the use of ginger supplementation as a treatment for CINV. However, due to conflicting results and methodological issues, a 2013 systematic review of seven clinical trials summarized the current evidence as stating that "Despite the widespread use of ginger in the treatment of nausea in other contexts such as gestational nausea, the current literature provides mixed support for the use of ginger as a standard part of anti-CINV control for patients undergoing chemotherapy." [21]

Other

Non-pharmacological approaches to remedy CINV typically involve small lifestyle alterations, such as using unscented deodorants and soaps, avoiding strong scents altogether, and dietary modifications such as eating several small meals throughout the day, eating high-protein, high-calorie food, drinking many clear liquids, and removing spicy, fatty, fried, or acidic foods from the diet. [22] Patients may also participate in alternative practices such as self-hypnosis, relaxation and imagery therapy, distraction, music therapy, biofeedback, desensitization, or acupressure. [2]

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">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 postanesthesia 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.

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">Aprepitant</span> Chemical compound

Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and dexamethasone. It is taken by mouth or administered by intravenous injection.

<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.

<span class="mw-page-title-main">Dacarbazine</span> A chemotherapy medication used for several cancer types

Dacarbazine (DTIC), also known as imidazole carboxamide, is a chemotherapy medication used in the treatment of melanoma and Hodgkin's lymphoma. For Hodgkin's it is often used together with vinblastine, bleomycin, and doxorubicin. It is given by injection into a vein.

<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.

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

Palonosetron, sold under the brand name Aloxi, is used for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is a 5-HT3 antagonist.

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.

A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action of serotonin and serotonergic drugs at serotonin (5-HT) receptors.

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

Lerisetron (code name F-0930-RS) is a drug which acts as an antagonist at the 5-HT3 receptor. It is a potent antiemetic and was in clinical trials for the treatment of nausea associated with cancer chemotherapy.

<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">Vestipitant</span> Chemical compound

Vestipitant (INN) is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus and insomnia.

<span class="mw-page-title-main">Cancer and nausea</span>

Cancer and nausea are associated in about fifty percent of people affected by 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. 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, electrolyte imbalance, or as a result of anxiety. Nausea and vomiting may be experienced as the most unpleasant side effects of cytotoxic drugs and may result in patients delaying or refusing further radiotherapy or chemotherapy.

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

Netupitant is an antiemetic medication. In the United States, the combinations of netupitant/palonosetron and the prodrug fosnetupitant/palonosetron are approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy-induced nausea and vomiting, including highly emetogenic chemotherapy such as with cisplatin. In the European Union, the combinations are approved by the European Medicines Agency (EMA) for the same indication.

<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.

References

  1. ↑ Gill, Paula; Grothey, Axel; Loprinzi, Charles (2006). "Nausea and Vomiting in the Cancer Patient". Oncology. pp. 1482–96. doi:10.1007/0-387-31056-8_83. ISBN   978-0-387-24291-0.
  2. 1 2 3 "Chemotherapy-Induced Nausea and Vomiting (CINV) > OncUView > OncUView.tv - Symptom Management - Oncology News and Information for Healthcare Professionals". Archived from the original on 2011-08-24. Retrieved 2011-09-02. "Chemotherapy-Induced Nausea and Vomiting"
  3. ↑ Hornby, P (2001). "Central neurocircuitry associated with emesis". The American Journal of Medicine. 111 (8): 106S–112S. doi:10.1016/S0002-9343(01)00849-X. PMID   11749934.
  4. ↑ Minami, Masaru; Endo, Toru; Hirafuji, Masahiko (1996). "Role of serotonin in emesis". Folia Pharmacologica Japonica. 108 (5): 233–42. doi: 10.1254/fpj.108.233 . PMID   8974084.
  5. ↑ Minami, Masaru; Endo, Toru; Hamaue, Naoya; Hirafuji, Masahiko (2004). "Serotonin and Anticancer Drug-induced Emesis". Yakugaku Zasshi. 124 (8): 491–507. doi: 10.1248/yakushi.124.491 . PMID   15297719.
  6. 1 2 3 "CINV Risk Factors". Cesamet Patient Education. Meda Pharmaceuticals. 2011. Retrieved 2011-09-02.
  7. ↑ "Chemotherapy Induced Nausea and Vomiting (CINV)". Patient Education. AP Pharma. 2011. Archived from the original on 2002-04-06. Retrieved 2011-09-02.
  8. 1 2 "PROTOCOL FOR THE USE OF ANTIEMETICS TO PREVENT CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING" (PDF). VHA Pharmacy Benefits Management Strategic Healthcare Group and Medical Advisory Panel. Archived from the original (PDF) on February 10, 2012. Retrieved September 2, 2011.
  9. ↑ "Chemotherapy-Induced Nausea and Vomiting: Addressing the Problem of Delayed Nausea: Risk Factors for CINV". Medscape.com. Retrieved September 2, 2011.
  10. ↑ Rojas, Camilo; Li, Ying; Zhang, Jie; Stathis, Marigo; Alt, Jesse; Thomas, Ajit G.; Cantoreggi, Sergio; Sebastiani, Silvia; Pietra, Claudio; Slusher, Barbara S. (November 2010). "The Antiemetic 5-HT 3 Receptor Antagonist Palonosetron Inhibits Substance P-Mediated Responses In Vitro and In Vivo". Journal of Pharmacology and Experimental Therapeutics. 335 (2): 362–368. doi:10.1124/jpet.110.166181. PMC   3202469 . PMID   20724484.
  11. 1 2 3 Gralla, Richard J.; De Wit, Ronald; Herrstedt, Jorn; Carides, Alexandra D.; Ianus, Juliana; Guoguang-Ma, Julie; Evans, Judith K.; Horgan, Kevin J. (2005). "Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin". Cancer. 104 (4): 864–8. doi: 10.1002/cncr.21222 . PMID   15973669. S2CID   24860776.
  12. ↑ Bergström, Mats; Hargreaves, Richard J; Burns, H Donald; Goldberg, Michael R; Sciberras, David; Reines, Scott A; Petty, Kevin J; Ögren, Mattias; et al. (2004). "Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant". Biological Psychiatry. 55 (10): 1007–12. doi:10.1016/j.biopsych.2004.02.007. PMID   15121485. S2CID   21071199.
  13. 1 2 3 Jordan, K.; Sippel, C.; Schmoll, H.-J. (2007). "Guidelines for Antiemetic Treatment of Chemotherapy-Induced Nausea and Vomiting: Past, Present, and Future Recommendations". The Oncologist. 12 (9): 1143–50. doi: 10.1634/theoncologist.12-9-1143 . PMID   17914084.
  14. ↑ Navari, Rudolph M.; Einhorn, Lawrence H.; Loehrer, Patrick J.; Passik, Steven D.; Vinson, Jake; McClean, John; Chowhan, Naveed; Hanna, Nasser H.; Johnson, Cynthia S. (2007). "A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: A Hoosier oncology group study". Supportive Care in Cancer. 15 (11): 1285–91. doi:10.1007/s00520-007-0248-5. PMID   17375339. S2CID   23266144.
  15. ↑ Tramer, M. R; Carroll, D; Campbell, FA; Reynolds, DJ; Moore, RA; McQuay, HJ (2001). "Cannabinoids for control of chemotherapy induced nausea and vomiting: Quantitative systematic". BMJ. 323 (7303): 16–21. doi:10.1136/bmj.323.7303.16. PMC   34325 . PMID   11440936.
  16. ↑ "Frequently Asked Questions - Medical Marihuana"
  17. ↑ Jatoi A, Windschitl HE, Loprinzi CL, et al. (2002). "Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study". Journal of Clinical Oncology. 20 (2): 567–73. doi:10.1200/JCO.20.2.567. PMID   11786587 . Retrieved 30 January 2002.
  18. ↑ Strasser, F; Luftner, D; Possinger, K; Ernst, G; Ruhstaller, T; Meissner, W; Ko, YD; Schnelle, M; et al. (20 July 2006). "Comparison of Orally Administered Cannabis Extract and Delta-9-Tetrahydrocannabinol in Treating Patients With Cancer-Related Anorexia-Cachexia Syndrome: A Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial From the Cannabis-In-Cachexia-Study-Group". Journal of Clinical Oncology. 24 (21): 3394–3400. doi: 10.1200/JCO.2005.05.1847 . PMID   16849753.
  19. ↑ Marx, Wolfgang; Kiss, Nicole; Isenring, Liz (June 2015). "Is ginger beneficial for nausea and vomiting? An update of the literature". Current Opinion in Supportive and Palliative Care. 9 (2): 189–195. doi:10.1097/SPC.0000000000000135. ISSN   1751-4266. PMID   25872115. S2CID   23359181.
  20. ↑ Marx, Wolfgang; Ried, Karin; McCarthy, Alexandra L.; Vitetta, Luis; Sali, Avni; McKavanagh, Daniel; Isenring, Elisabeth (2015-04-07). "Ginger-Mechanism of Action in Chemotherapy-induced Nausea and Vomiting: A Review". Critical Reviews in Food Science and Nutrition. 57 (1): 141–146. doi:10.1080/10408398.2013.865590. ISSN   1549-7852. PMID   25848702. S2CID   24523559.
  21. ↑ Marx, WM; Teleni L; McCarthy AL; Vitetta L; McKavanagh D; Thomson D; Isenring E. (2013). "Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting: a systematic literature review" (PDF). Nutr Rev. 71 (4): 245–54. doi:10.1111/nure.12016. PMID   23550785. S2CID   19187673. Archived from the original (PDF) on 2020-05-07. Retrieved 2019-12-13.
  22. ↑ "How to Prevent CINV, Minimize CINV: Sancuso". Archived from the original on 2012-01-13. Retrieved 2011-09-02. "How to Prevent CINV, Minimize CINV"
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.