Chemotherapy-induced nausea and vomiting

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 curable 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 crippling 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.

Types

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

• Acute: occurring within 24 hours of chemotherapy
• Delayed: occurring between 24 hours and 5 days after treatment
• Breakthrough: occurring despite prophylactic treatment
• Anticipatory: triggered by taste, odor, memories, visions, or anxiety related to chemotherapy
• Refractory: occurring during subsequent cycles when antiemetics have failed in earlier cycles

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. 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 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 chemotheraputic 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: ^[8][6]

• Cisplatin
• Dacarbazine
• Cyclophosphamide (>1500mg/m²)
• Carmustine (>250mg/m²)
• Mechlorethamine
• Streptozocin
• ABVD
• MOPP/COPP/BEACOPP
• CBV
• VIP
• PEB
• AC

Some moderately emetogenic agents and regimens include: ^[8]

• Carboplatin
• Methotrexate
• Doxorubicin/Adriamycin
• Docetaxel
• Paclitaxel
• Etoposide
• Ifosfamide
• Cyclophosphamide (≤1500mg/m²)
• CHOP/CHOP-R

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

• Female sex
• Patient age (under 55 years old)
• History of light alcohol use
• History of previous CINV
• History of nausea and vomiting during pregnancy
• History of motion sickness
• Anxiety or depression
• Anticipation of CINV

Treatments

There are several methods of treatment 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^{[citation needed]}. Approved 5-HT₃ inhibitors include dolasetron (Anzemet), granisetron (Kytril, Sancuso), and ondansetron (Zofran). 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 patchs.

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).^[10] The substance P inhibitor aprepitant (Emend), which became available in 2005, is highly effective in controlling nausea and vomiting associated with cancer chemotherapy.^[10] 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. This has been proven by Positron Emission Tomography (PET) studies, which have demonstrated that aprepitant can penetrate the brain and NK₁ receptors in the brain.^[11] It 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.^[10]

Other Drugs

Olanzapine, as well as several other neuroleptic drugs, have also has been investigated for the control of CINV.^[12] 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.^[13] Neuroleptic agents are now indicated for rescue treatment and the control of breakthrough nausea and vomiting.^[12]

Some studies^[14] and patient groups say that the use of cannabinoids derived from marijuana during chemotherapy greatly reduces the associated nausea and vomiting, and enables the patient to eat. Some synthetic derivatives of the active substance in marijuana (Tetrahydrocannabinol or THC) such as Marinol may be practical for this application. Natural marijuana, known as medical cannabis is also used and recommended by some oncologists, though its use is regulated and it is not legal in all jurisdictions.^[15]

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 5HT₄ receptor agonist, 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.^[12]

Alternative Treatments

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 lots of clear liquids, and removing spicy, fatty, fried, or acidic foods from the diet.^[16] Patients may also participate in alternative practices such as self-hypnosis, relaxation and imagery therapy, distraction, music therapy, biofeedback, desensitization, or accupressure.^[2] Also, recent trial studies have shown that lung cancer patients taking fish oil daily help maintain their weight during chemotherapy.^[17]

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. ^ ^{a b c} [1] "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. ^ ^{a b c} "CINV Risk Factors". Cesamet Patient Education. Meda Pharmaceuticals. 2011. http://www.cesamet.com/patient-cinv-risk-factors.asp. Retrieved 2011-09-02. 
7. ^ "Chemotherapy Induced Nausea and Vomiting (CINV)". Patient Education. AP Pharma. 2011. http://www.appharma.com/products/development.html. Retrieved 2011-09-02. 
8. ^ ^{a b} "PROTOCOL FOR THE USE OF ANTIEMETICS TO PREVENT CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING". VHA Pharmacy Benefits Management Strategic Healthcare Group and Medical Advisory Panel. http://www.pbm.va.gov/monitoring/antiemeticdosing.pdf. Retrieved September 2, 2011. 
9. ^ "Chemotherapy-Induced Nausea and Vomiting: Addressing the Problem of Delayed Nausea: Risk Factors for CINV". Medscape.com. http://www.medscape.org/viewarticle/527451_4. Retrieved September 2, 2011. 
10. ^ ^{a b c} 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. 
11. ^ 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. 
12. ^ ^{a b c} 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. 
13. ^ Navari, Rudolph M.; Einhorn, Lawrence H.; Loehrer, Patrick J.; Passik, Steven D.; Vinson, Jake; McClean, John; Chowhan, Naveed; Hanna, Nasser H. et al. (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. 
14. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=34325. 
15. ^ "Frequently Asked Questions - Medical Marihuana"
16. ^ [2] "How to Prevent CINV, Minimize CINV"
17. ^ Murphy, Rachel. "Fish oil no snake oil for chemotherapy". New Scientist. http://web.ebscohost.com/ehost/detail?vid=6&hid=12&sid=d8b41f3d-7288-46f9-92a0-ad027f6f5ee3%40sessionmgr4&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=ulh&AN=64078377. 

See Also

• Chemotherapy
• Cancer
• Vomiting
• Nausea

External links

• [3] "How to Prevent CINV, Minimize CINV"
• [4] "CINV Tips"