Chemotherapy-induced nausea and vomiting
Encyclopedia
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. 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.
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 receptor
s, acetylcholine receptor
s, 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. 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. 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). 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).
Some highly emetogenic agents and chemotherapy regimens
include:
Some moderately emetogenic agents and regimens include:
Besides the type of treatment, personal factors may put a patient at greater risk for CINV. Other risk factors include:
are very effective antiemetic
s 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. 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 tablet
s, or as transdermal patch
s.
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). The substance P
inhibitor aprepitant
(Emend), which became available in 2005, is highly effective in controlling nausea and vomiting associated with cancer chemotherapy. 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. 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.
, as well as several other neuroleptic drugs, have also has been investigated for the control of CINV. 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
. Neuroleptic agents are now indicated for rescue treatment and the control of breakthrough nausea and vomiting.
Some studies 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.
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.
patients taking fish oil daily help maintain their weight during chemotherapy.
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
treatments. Nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
are two of the most feared cancer treatment-related side effects
Side Effects
Side Effects is an anthology of 17 comical short stories written by Woody Allen between 1975 and 1980, all but one of which were previously published in, variously, The New Republic, The New York Times, The New Yorker, and The Kenyon Review. It includes Allen's 1978 O...
for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
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. 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:- 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 postremaArea postrema
The area postrema is a medullary structure in the brain that controls vomiting. Its privileged location in the brain also allows the area postrema to play a vital role in the control of autonomic functions by the central nervous system.-Anatomy:...
of the medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...
. 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
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
, opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
s, acetylcholine receptor
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
s, and receptors for substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
. 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. 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. 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-Hydroxyindoleacetic acid
5-Hydroxyindoleacetic acid is the main metabolite of serotonin in the human body. In chemical analysis of urine samples, 5-HIAA is used to determine the body's levels of serotonin.- Clinical significance :...
(5-HIAA). 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. 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."Some highly emetogenic agents and chemotherapy regimens
Chemotherapy regimens
A fundamental philosophy of combination cancer therapy is that different drugs work through different cytotoxic mechanisms. Because they have different dose-limiting adverse effects, they can be given together at full doses in chemotherapy regimens....
include:
- CisplatinCisplatinCisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
- DacarbazineDacarbazineDacarbazine is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas.Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl...
- CyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
(>1500mg/m2) - CarmustineCarmustineCarmustine or BCNU is a mustard gas-related β-chloro-nitrosourea compound used as an alkylating agent in chemotherapy...
(>250mg/m2) - Mechlorethamine
- Streptozocin
- ABVDABVDABVD is a chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma, supplanting the older MOPP protocol. It consists of concurrent treatment with the chemotherapy drugs:*Adriamycin *bleomycin...
- MOPPMOPPMOPP is a military term used to describe protective gear to be used in a toxic environment, i.e., during a chemical, biological, radiological, or nuclear strike:* Protective mask — Commonly referred to as a gas mask or pro mask...
/COPPCOPPCOPP is a chemotherapy regimen for treatment of Non-Hodgkin's lymphoma, consisting of treatment with cyclophosphamide, oncovin, procarbazine and prednisone. All drugs are administered intravenously....
/BEACOPP - CBVCBV (chemotherapy)CBV refers to Cytoxan , BCNU , and VP-16 , three drugs in a chemotherapy regimen commonly given to lymphoma patients in conjunction with stem cell therapy CBV is usually given in high doses to patients who have relapsed or who have refractory disease and cannot benefit from standard chemotherapy...
- VIP
- PEB
- AC
Some moderately emetogenic agents and regimens include:
- CarboplatinCarboplatinCarboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
- MethotrexateMethotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
- DoxorubicinDoxorubicinDoxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
/Adriamycin - Docetaxel
- PaclitaxelPaclitaxelPaclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
- EtoposideEtoposideEtoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
- IfosfamideIfosfamideIfosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
- CyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
(≤1500mg/m2) - CHOPCHOPCHOP is the acronym for a chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. CHOP consists of:* Cyclophosphamide, an alkylating agent which damages DNA by binding to it and causing cross-links...
/CHOP-R
Besides the type of treatment, personal factors may put a patient at greater risk for CINV. Other risk factors include:
- 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 antagonists5-HT3 antagonist
The 5-HT3 antagonists are a class of medications 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....
are very effective antiemetic
Antiemetic
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....
s 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. Approved 5-HT3 inhibitors include dolasetron
Dolasetron
Dolasetron 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...
(Anzemet), granisetron
Granisetron
Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic 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 effect...
(Kytril, Sancuso), and ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
(Zofran). The newest 5-HT3 inhibitor, palonosetron
Palonosetron
Palonosetron is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting...
(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
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
, as orally disintegrating tablet
Orally disintegrating tablet
An orally disintegrating tablet or orodispersible tablet is a drug dosage form available for a limited amount of over-the-counter and prescription medications. ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole...
s, or as transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
s.
NK1 Inhibitors
A newer class of drugs known as the NK1 antagonistsNK1 receptor antagonist
Neurokinin 1 antagonists are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. The discovery of neurokinin 1 receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.An example of...
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). The substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
inhibitor aprepitant
Aprepitant
Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
(Emend), which became available in 2005, is highly effective in controlling nausea and vomiting associated with cancer chemotherapy. 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
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET) studies, which have demonstrated that aprepitant can penetrate the brain and NK1 receptors in the brain. It has also been shown to increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
, which are also used to prevent nausea and vomiting caused by chemotherapy.
Other Drugs
OlanzapineOlanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, as well as several other neuroleptic drugs, have also has been investigated for the control of CINV. 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
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. Neuroleptic agents are now indicated for rescue treatment and the control of breakthrough nausea and vomiting.
Some studies and patient groups say that the use of cannabinoids derived from marijuana
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
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
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
or THC) such as Marinol may be practical for this application. Natural marijuana, known as medical cannabis
Medical cannabis
Medical cannabis refers to the use of parts of the herb cannabis as a physician-recommended form of medicine or herbal therapy, or to synthetic forms of specific cannabinoids such as THC as a physician-recommended form of medicine...
is also used and recommended by some oncologists, though its use is regulated and it is not legal in all jurisdictions.
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
Metoclopramide
Metoclopramide is an antiemetic and gastroprokinetic agent. It is commonly used to treat nausea and vomiting, to facilitate gastric emptying in people with gastroparesis, and as a treatment for the gastric stasis often associated with migraine headaches.-Medical uses:Metoclopramide is commonly...
, a 5HT4 receptor agonist, is an older drug that is sometimes used, either on its own or in combination with others. Histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
blockers such as diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
or meclozine
Meclozine
Meclozine is an antihistamine considered to be an antiemetic. It is sold under the brand names Bonine, Bonamine, Antivert, Postafen, Sea Legs, and Dramamine . Emesafene is a combination of meclozine and pyridoxine...
may be used in rescue treatment. Lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
and Diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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.
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. Patients may also participate in alternative practices such as self-hypnosis, relaxation and imagery therapy, distraction, music therapy, biofeedback, desensitization, or accupressure. Also, recent trial studies have shown that lung cancerLung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
patients taking fish oil daily help maintain their weight during chemotherapy.
External links
- http://www.sancuso.com/patient/cinv/whatToDo.php "How to Prevent CINV, Minimize CINV"
- http://www.cesamet.com/patient-helpful-tips-for-cinv.asp "CINV Tips"