Chemotherapy-Induced Nausea and Vomiting (CINV)
Background
Nausea and vomiting may occur for various reasons in patients with cancer. Different conditions may cause nausea or vomiting, including bowel obstruction, brain tumors, or treatment with radiation therapy.1 However, CINV is common and can occur with most chemotherapeutic agents. Although there have been great strides in the management of CINV, patients still rank this side effect as one of the most significant adverse events associated with chemotherapy.2 The classifications of nausea and vomiting are as follows3:
- Acute: occurring within 24 hours of chemotherapy
- Delayed: occurring 24 hours to several days after initial treatment with chemotherapy
- Breakthrough: occurring despite preventive therapy
- Anticipatory: triggered by taste, odor, memories, visions related to the administration of chemotherapy
- Refractory: occurring during subsequent cycles when antiemetics have failed in earlier cycles
The incidence of CINV varies according to chemotherapy protocol and individual patient risk factors for the symptom. Patients at higher risk for CINV may include the following2:
- Younger age (< 50)
- Female gender
- Little or no history of alcohol intake
- Emesis with past pregnancy
- History of motion sickness
Despite the discovery of the serotonin antagonist agents (5-HT3) (introduced in the early 1990s), nausea and vomiting still occurred in many patients receiving chemotherapy treatments.1,2 The discovery of substance P as a mediator of nausea and vomiting, and a new class of agents that target substance P (neurokinin 1 [NK1] receptor antagonist), led to significant improvements in the control of nausea and vomiting and confirmed the role of substance P and serotonin as the most important mediators of CINV.
Response to chemotherapy is activated through two mechanisms4,5:
- Chemoreceptor trigger zone (CTZ)—nucleus of vagus nerve at vomiting center in the medulla
- Cell damage in gastrointestinal tract leads to release of neuroactive agents that activate vagal receptors
The central pathway is
- Activated by substance P
- Mediated by neurokinin (NK1) receptors in the brain
The peripheral pathway is
- Activated by serotonin
- Mediated by 5-HT3 located in the gastrointestinal tract
Emetogenic (emetic) risk of agents commonly used in the treatment of CRC is as follows:
- Lower (10%-30%): fluorouracil, capecitabine, and biologic agents. The monoclonal antibodies, cetuximab and panitumumab, are considered agents with low emetogenicity. Bevacizumab, approved for treating metastatic CRC, has a minimal (< 10%) emetic risk
- Moderate (30%-90%): oxaliplatin and irinotecan
- High (> 90%): may be individualized with other agents. Combination therapies emetogenicity can be increased.
Targeted therapies are generally well tolerated. Guidelines published by the American Society of Clinical Oncology (ASCO) (2006), Multinational Association of Supportive Care in Cancer (MASCC) (2008), Oncology Nursing Society (ONS) (2009), and National Comprehensive Cancer Network (NCCN) (2010) all agree that highly emetogenic chemotherapy regimens require triple antiemetic therapy, which includes the administration of
- An NK1 receptor antagonist (aprepitant)
- A 5-HT3 serotonin receptor antagonist (dolasetron, granisetron, ondansetron, tropisetron, palonosetron)
- Corticosteroids (dexamethasone)
Other categories of agents useful in the management of CINV include
- Cannabinoids (nabilone, dronabinol)
Aprepitant is currently approved for oral (125 mg) or intravenous (115 mg) administration on day 1, with oral aprepitant given on days 2 and 3 (80 mg each day). With highly emetogenic agents, the serotonin antagonist is given on day 1, followed by aprepitant and a corticosteroid.
For patients receiving moderately emetogenic chemotherapy other than an anthracycline-cyclophosphamide combination, the recommendation is generally a 5-HT3 agent with dexamethasone, although ONS and NCCN recommend the addition of aprepitant for selected patients in this setting as well. In the delayed setting, current guidelines are not entirely congruent in their recommendations. ASCO calls for steroid only in the delayed setting, while ONS recommends either steroid or serotonin antagonist. If aprepitant is used acutely for moderately emetogenic chemotherapy, the drug is continued for the entire 3 days. MASCC generally calls for steroid alone in the delayed setting, but allows for a 5-HT3 if a steroid cannot be used:
- Dopamine antagonists (prochlorperazine, promethazine)
- Benzodiazepines (alprazolam, lorazepam)3
Selected agents with phase 2 data or currently under study:
- Atypical antipsychotic (benzodiazepine), which blocks dopamine and serotonin receptors—olanzapine8
- Anticonvulsant agent blocking serotonin receptors gamma-aminobutyric acid (GABA)—gabapentin9
New Data
New data have emerged regarding specific drugs used in the treatment of patients with CRC and their emetogenicity, including several abstracts specific for patients with CRC presented at the 2008 ASCO meeting.
Abstracts
Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer who receiving oxaliplatin-based chemotherapy, by Hesketh et al.10
Although oxaliplatin is considered a moderately emetogenic agent in most chemotherapy classification systems, some patients experience more significant CINV with this agent. Generally, platinum agents are characterized by their ability to produce delayed nausea and vomiting; cisplatin is particularly known for this, and it can occur with carboplatin as well. However, oxaliplatin had not been studied for this effect, and the researchers wanted to determine the frequency of delayed CINV with oxaliplatin after antiemetic treatment (5-HT3 antagonist with dexamethasone). Although patients received excellent control of emesis (CR = 91%), the CR rate dropped to 51% without further antiemetic therapy in the delayed period. Delayed nausea and vomiting was noted in 57% of patients, with moderate to severe nausea in 26%. The researchers conclude that delayed nausea and vomiting is a significant problem in the population receiving oxaliplatin-based chemotherapy and that routine antiemetic prophylaxis is necessary.
A multi-center, open label trial to evaluate the efficacy and tolerability of aprepitant (A) and palonosetron (P) for the prevention of chemotherapy-induced nausea and vomiting in colorectal cancer (CRC) patients receiving FOLFOX chemotherapy, by Bubalo and colleagues.11
The researchers proposed that the CINV risk with modern combination chemotherapy for treatment of CRC had not been well characterized and wanted to test the ability of modern combination antiemetic therapy to control both CINV and quality of life during and after FOLFOX chemotherapy.
The patients received an NK1 receptor antagonist (aprepitant) combined with palonosetron (a long-acting 5-HT3 antagonist) on day 1 prior to FOLFOX, followed by aprepitant 80 mg orally on days 2 and 3, with dexamethasone 8 mg daily, days 2 to 4. In an interim analysis, the responses for the 32 patients showed CRs in 14 of the 32 patients (44%), with major responses (no emesis with nausea and/or rescue medication use) in 15 of 32 patients (47%). Of the 32 patients, 3 (9%) had an emetic event within 5 days of starting cycle 1 and were considered antiemetic failures. Improvements were seen in the quality of life end points for appetite, oral intake, and decreased or stable nausea measured from baseline.
The researchers concluded that the aprepitant, palonosetron, and dexamethasone combination produced an emesis-free treatment experience with FOLFOX chemotherapy for 91% of the patients while adding no toxicity, and demonstrated an improvement over the historical emetogenicity seen with FOLFOX of 30% to 70%.
Adapting of ASCO and NCCN guidelines in institutional antiemetic guidelines benefits patients receiving chemotherapy, by Moreno and colleagues.12
The goal of the study was to determine the overall impact of using established guidelines in specific institutions, using the Hesketh classification for emetogenicity. The study compared 2 patient groups: those who received the newly adopted institutional antiemetic guidelines and those who received no established antiemetic therapy. Patients recorded CINV episodes in a diary on the day of treatment and for the following 4 days. Of the 225 consecutive patients enrolled on the study, patients who received the new antiemetic guidelines trended toward a higher CR, with the cisplatin patients achieving a statistically significant benefit.12 The researchers concluded that the use of revised antiemetic guidelines produced better control of CINV with a higher CR rate, particularly when they received cisplatin. This abstract points to the need to use antiemetic guidelines within your own institution, following updated, evidence-based national guidelines.
Because individual risk factors for emesis must be considered along with the emetogenic classification of specific chemotherapy protocols, a comprehensive assessment is necessary to truly assess emesis risk. Adequate control of CINV is essential to help ensure the patient’s quality of life and ability to complete therapy, as well as to prevent the physiologic effects of uncontrolled CINV, such as dehydration or gastrointestinal or pulmonary effects.
A novel preparation, granisetron transdermal 5-HT3 agent (Sancuso), received Food and Drug Administration (FDA) approval for moderately to highly emetogenic CINV.13 A new NK1 antagonist (casopitant), which has filed for FDA approval, may provide more options and possibly different dosing schedules.10,14
The Role of Oncology Nursing
Nurses are key in the assessment and management of CINV.3 This role can be performed through a comprehensive baseline assessment before initiating chemotherapy to determine risk factors for emetogenicity. Noting the risk factors outlined above, oncology nurses can then factor in the emetogenicity of individual agents, while recognizing that combination chemotherapy can increase the overall treatment emetogenicity. For patients with CRC, nurses should recognize that oxaliplatin can produce more significant nausea and vomiting, and that the addition of an NK1 antagonist may improve antiemetic control. The use of national guidelines to standardize the appropriate approach to management of CINV is recommended Table 1. 15
Table 1. Guildeines and Recommendations for CINV Management
Guideline Organization
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Last Updated
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Recommendations for Delayed CINV: Highly Emetogenic Agents
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Recommendations for Acute CINV: Highly Emetogenic Agents
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ASCO
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2006
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5-HT3 RA with dexamethasone plus aprepitant
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Dexamethasone plus aprepitant
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ONS
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2009
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5-HT3 RA with dexamethasone plus aprepitant with consideration of lorazepam
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Dexamethasone plus aprepitant with consideration of lorazepam
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MASCC
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2008
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5-HT3 RA with dexamethasone plus aprepitant or fosaprepitant
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Dexamethasone plus aprepitant
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NCCN
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2010
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5-HT3 RA* with dexamethasone plus aprepitant or fosaprepitant with consideration of lorazepam and an H2 blocker or proton pump inhibitor for highly emetogenic chemotherapy, including AC combination
|
Dexamethasone (d 1-4) plus aprepitant (d 2 and 3) with consideration of lorazepam (d 1-4)
|
Guideline Organization
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Last Updated
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Recommendations for Delayed CINV: Moderately Emetogenic Agents
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Recommendations for Acute CINV: Moderately Emetogenic Agents
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ASCO
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2006
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AC combination use 5-HT3 RA with dexamethasone and aprepitant; non-AC patients use 5-HT3 RA with dexamethasone
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Aprepitant alone for AC combination patients; non-AC patients should get dexamethasone or a 5-HT3
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ONS
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2009
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5-HT3 RA with dexamethasone plus aprepitant with consideration of lorazepam
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Consideration of dexamethasone, 5-HT3 RA (ondansetron, granistetron, or dolasetron), metoclopramide plus or minus diphenhydramine
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MASCC
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2008
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AC combination use 5-HT3 RA with dexamethasone plus aprepitant or fosaprepitant; non-AC patients use 5-HT3 RA with dexamethasone
|
AC combination:aprepitant or dexamethasone
Non-AC: dexamethasone alone is preferred: if not able to use consider use of 5-HT3
|
NCCN
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2010
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Selected patients† use 5-HT3 RA* with dexamethasone plus aprepitant or fosaprepitant with consideration of lorazepam and H2 blocker or proton pump inhibitor; non-AC or selected patients, use 5-HT3 RA with dexamethasone with consideration of lorazepam and H2 blocker or proton pump inhibitor
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Selected patients† aprepitant (d 2 and 3) if used on day one, with consideration of dexamethasone, or dexamethasone, or 5-HT3 RA,‡ lorazepam, H2 blocker or proton pump inhibitor
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*5-HT3 agents may include ondansetron (IV/PO), granisetron (IV/PO/transdermal), dolasetron (IV/PO), or palonosetron (IV/PO).
†Selected chemotherapy combinations for consideration of aprepitant or fosaprepitant may include carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irintotecan, or methotrexate.
‡Ondansetron, granisetron, or dolasetron
AC = anthracycline and cyclophosphamide chemotherapy combination; ASCO = American Society of Clinical Oncology; MASCC = Multinational Association of Supportive Care in Cancer; NCCN = National Comprehensive Cancer Network; 5-HT3 RA = 5-HT3 receptor antagonist; ONS = Oncology Nursing Society.
Adapted from Hawkins and Grunberg.15 Data from Naeim et al16 and Hesketh.10
Nurses provide frontline care for these patients and are able to intervene by communicating ineffectiveness of antiemetics to prescribing clinicians and advocating for changes in therapy when appropriate. The ONS Putting Evidence Into Practice (PEP) cards (see Assessment Tools, below) also suggest that some experts recommend smaller, more frequent meals, reduced food aromas, and milder foods to minimize symptoms of nausea, although evidence for those strategies is limited. Oncology nurses can also implement nonpharmacologic interventions in many settings without orders. Nonpharmacologic approaches to the management of CINV may include the following3:
- Self-hypnosis
- Relaxation and imagery
- Distraction
- Desensitization
- Acupressure
- Music therapy
- Biofeedback
Dibble and colleagues17 presented interesting data on breast cancer patients receiving anthracycline-based chemotherapy who were randomized to receive acupressure or placebo. The researchers studied 160 women on their second or third cycle of therapy and randomized to receive acupressure to P6 point (active), acupressure to S13 point (placebo), or the usual care only. The subjects kept a daily log for 3 weeks. Although no significant differences were found in acute CINV or emesis in any of the treatment groups, the acupressure intervention in the delayed CINV group had a statistically significant reduction in the amount of vomiting and the intensity of nausea, compared with the placebo and usual-care groups. The researchers concluded that acupressure is safe and has efficacy in women with breast cancer who are on chemotherapy.17 Although this method should be studied further in other cancer types, it would be an inexpensive and easily implemented treatment strategy for CINV.
Substantial improvements have been made in the treatment of CINV; however, more progress is needed, including identification of optimal drug scheduling. Institutions should be rigorous in their adoption of national guidelines to improve efficacy, control of CINV, and patient quality of life.
Assessment Tools
Multinational Association of Supportive Care in Cancer (MASCC)
MASCC, an international multidisciplinary organization, is dedicated to research and education in all areas of supportive care, regardless of a patient’s stage of cancer. On the home page at http://www.mascc.org. Accessed February 22, 2010.
National Cancer Institute (NCI) (US National Institutes of Health)
Classification and criteria for grading the severity of nausea and vomiting are useful assessment tools. Go to: http://www.cancer.gov/cancertopics/pdq/supportivecare/nausea. Updated October 2, 2009. Accessed February 22, 2010.
Oncology Nursing Society (ONS)
The ONS has released new “Putting Evidence Into Practice” cards (PEP) for management of nausea and vomiting. These can be accessed here. Accessed February 22, 2010.
Clinical Practice Guidelines
American Society of Clinical Oncology (ASCO)
Nine oncology organizations participated in producing the ASCO Guideline for Antiemetics in Oncology: Update 2006. They anticipate that this collaborative effort will result in more consistency in implementation of the guidelines. Available here. Accessed February 22, 2010.
Multinational Association of Supportive Care in Cancer (MASCC)
MASCC publishes guidelines, consensus papers, and the monthly journal Supportive Care in Cancer. Antiemetic Guidelines are found here: Accessed February 22, 2010.
National Comprehensive Cancer Network (NCCN)
The NCCN promotes awareness of the importance of continuous improvement in quality of care and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision makers. The home page at http://www.nccn.org offers links to guidelines for patients and professionals; click on Clinical Practice Guidelines in Oncology. Antiemesis is also reached directly through http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Accessed February 22, 2010.
References
- Warr D. Chemotherapy-and cancer-related nausea and vomiting. Curr Oncol. 2008;15(suppl 1):S4-S9.
- Viale PH. Integrating aprepitant and palonosetron into clinical practice: a role for the new antiemetics. Clin J Oncol Nurs. 2005;9:77-84.
- Bender CM, McDaniel RW, Murphy-Ende K, et al. Chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs. 2002;6:94-102.
- Hesketh PJ. Chemotherapy-induced nusea and vomiting. N Engl J Med. 2008;358:2482-2494.
- Jordan K, Sipple C, Schmoll. HJ. Guidelines for anti-emetic treatment of chemotherapy-induced nausea and vomiting: past, present and future recommendations. Oncologist. 2007;12:1143-1150.
- Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24:2932-2947.
- National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: Antiemesis. http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Accessed February 22, 2010..
- Navari RM, Einhorn LH, Loehrer PJ, et al. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer. 2007;15:285-1291.
- Pacheco A, Verschragaegen CF, Mangalik A, et al. A randomized open-label comparison of aprepitant (A) versus gabapentin (G) in the prevention of the refractory nausea and vomiting associated with moderately and severely emetogenic chemotherapy. J Clin Oncol. 2008:26(suppl);725s. Abstract 20509.
- Hesketh J, Sanz-Altamira P, Bushey J, et al. Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. J Clin Oncol. 2008;26(suppl):538s. Abstract 9645.
- Bubalo JS, Takemoto MH, Herrington J, et al. A multi-center, open label trial to evaluate the efficacy and tolerability of aprepitant (A) and palonosetron (P) for the prevention of chemotherapy-induced nausea and vomiting in colorectal cancer (CRC) patients receiving FOLFOX chemotherapy. J Clin Oncol. 2008;26(suppl):739s. Abstract 20684.
- Moreno E, Majem M, Gonzalez X, et al. Adapting ASCO and NCCN guidelines in institutional antiemetic guidelines benefits patients receiving chemotherapy. J Clin Oncol. 2008;26(suppl):725s. Abstract 20508.
- Sancuso (granisetron transdermal system) product information. Prostrakan, Inc. http://www.sancuso.com/pdfs/SANCUSO-Full_PI.pdf. Accessed February 22, 2010.
- Grunberg SM, Aziz Z, Shaharyar A, et al. Phase III results of a novel oral neurokinin-1 (NK-1) receptor antagonist, casopitant: Single oral and 3-day oral dosing regimens for chemotherapy-induced nausea and vomiting (CINV) in patients (pts) receiving moderately emetogenic chemotherapy (MEC). J Clin Oncol. 2008;26(suppl):511s. Abstract 9540.
- Hawkins R, Grunberg S. Chemotherapy-induced nausea and vomiting: challenges and opportunities for improved patient outcomes. Clin J Oncol Nurs. 2009;13:54-64.
- Naeim A, Dry SM, Lorenz KA, et al. Evidence-based recommendations for cancer nausea and vomiting. J Clin Oncol. 2008;26:3903-3910.
- Dibble S. Acupressure for chemotherapy-induced nausea and vomiting: a randomized clinical trial. Oncol Nurs Forum. 2008;34:813-820.
Key Definitions
emetogenic—describing a substance that causes vomiting (also called emetic)
NK1 receptor antagonist—antagonist of the endogenous receptor for substance P, or neurokinin 1 receptor (NK1-receptor [NK1R]). NK1R belongs to the tachykinin receptor subfamily of G protein–coupled receptors (GPCRs.) The vomiting center in the brainstem contains high concentrations of substance P and its receptor. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting.
5-HT3 serotonin receptor antagonist—5-hydroxytryptamine 3 (5-HT3) receptor antagonist. An antiemetic drug used to relieve nausea and vomiting (also called type 3 serotonin receptor antagonist)
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