David R. Kohler
RADIATION- AND CHEMOTHERAPY-ASSOCIATED EMETIC SYMPTOMS
Radiation- and chemotherapy-associated emetic symptoms are labeled as “acute” or “delayed” by their temporal relationship with the start of emetogenic treatments (Fig. 38.1). Although the terms are useful for describing clinical events and approaches to symptom management, the assignment of symptom onset and duration to fixed periods predated identification of the principal neural mechanisms that elicit acute- and delayed-phase symptoms, and remain an oversimplification of physiologic events that occur when emetogenic treatments are repeated within the span of a single day or on 2 or more consecutive days.
Acute-Phase Symptoms
Emetic symptoms that occur within 24 hours after treatment are identified as acute-phase symptoms (Table 38.1). Acute-phase symptoms correlate with serotonin (5-hydroxytryptamine, 5-HT) release from enterochromaffin cells. Emetic signals are propagated at local serotonin (5-HT3 subtype) receptors and transmitted along afferent vagus nerve fibers. They activate a diffuse series of effector nuclei in the medulla oblongata (the so-called vomiting center), which integrates afferent emetic signals and subsequently activates and coordinates motor nuclei that produce the physiologic changes associated with vomiting.
■In general, the greatest incidence of acute-phase symptoms occurs within 2 to 6 hours after treatment.
■Onset is generally within 1 to 3 hours after commencing chemotherapy. Notable exceptions include
•Mechlorethamine (nitrogen mustard), which generally induces rapid symptom onset (≤1 hour).
•Cyclophosphamide, after intravenous administration, and carboplatin have long latency periods before acute-phase onset, and symptoms may persist or intermittently recur for ≥12 hours after treatment.
Delayed-Phase Symptoms
Delayed-phase symptoms are defined as those that occur >24 hours after treatment (Table 38.1) and are associated with central activation of neurokinin type 1 (NK1) receptors, for which substance P is the natural ligand. Drugs with high emetogenic potential and, in some cases, drugs with moderate emetic risk may cause delayed-phase symptoms (Table 38.2). Symptoms may occur as early as 16 to 18 hours after emetogenic treatment, with a period of greatest incidence between 24 and 96 hours after treatment. Delayed emesis may occur in patients who do not experience symptoms acutely, but incidence characteristically decreases in patients who achieve complete control during the acute phase. Although emesis is typically less severe during the delayed phase than during the acute phase, the reported severity of nausea is similar during both phases.
FIGURE 38.1 Comparison of emetic symptom phases and antiemetic activity. Top: Temporal relation between the start of emetogenic treatment (hour 0) and emetic symptom phases. For each phase, shaded bars indicate generally when nausea and emesis occur before and after emetogenic treatment; greater intensity of shading approximates the incidence of symptoms. Bottom: The most highly active antiemetic categories ranked by relative effectiveness against acute-phase (0 to 24 hours) and delayed-phase (>24 hours) emetic symptoms.
Anticipatory Events
Anticipatory emetic symptoms occur before repeated exposure to an emetogenic treatment as an aversive conditioned response as a consequence of poor emetic control during prior therapy. Although anxiolytic amnestic drugs are helpful in preventing and delaying anticipatory symptoms, complete control throughout all antineoplastic treatments is the best preventive strategy against developing symptoms. Behavioral therapies such as relaxation techniques and systematic desensitization are recommended if symptoms occur. After symptoms develop, medical intervention during subsequent emetogenic treatment is limited to preventing the reinforcement of conditioned stimuli, which may exacerbate anticipatory symptoms.
EMETOGENIC (EMETIC) POTENTIAL
Emetic potential or risk and symptom patterns vary among medications used in antineoplastic chemotherapy and radiation therapy techniques.
Chemotherapy
Intrinsic emetogenicity (Table 38.3) is an antineoplastic drug’s propensity for causing emetic symptoms. Drug dose or dosage is often the second most significant factor affecting emetogenic potential and the duration for which symptoms persist.
The number of emetogenic drugs used in combination, administration schedule, treatment duration, and route of administration are also mitigating factors. Emetic potential may be lessened or eliminated by protracted drug delivery over hours or days, and increased by rapid drug administration, repeated emetogenic treatments, and brief intervals between repeated doses (Table 38.3). When emetogenic treatment is given on more than 1 day, physiologic processes associated with acute- and delayed-phase symptoms may overlap and both should be considered in designing effective antiemetic prophylaxis. The potential and duration for delayed symptoms depend upon the sequence in which emetogenic drugs are administered and the emetogenic risk each drug presents.
Radiation
The emetic potential of ionizing radiation correlates directly with the amount given per dose or fraction, the total dose administered, and the rate of administration. Large treatment volumes (>400 cm2); fields including the upper abdomen, upper hemithorax, and whole body; and a history of poor emetic control with chemotherapy are risk factors for severe emesis. Emetic potential increases when radiation and chemotherapy are administered concomitantly (“radiochemotherapy”).
PATIENT RISK FACTORS
Patients at greatest risk for emetic symptoms include
■Female sex, particularly women with a history of persistent and/or severe emetic symptoms during pregnancy.
■Children and young adults.
■Patients with a history of acute- and/or delayed-phase emetic symptoms during prior treatments are at great risk for poor emetic control during subsequent treatments.
■Patients with low performance status and a predisposition to motion sickness.
■Nondrinkers are at greater risk than patients with a history of chronic alcohol consumption (>100 g ethanol daily for several years).
■Patients with intercurrent pathologies, such as gastrointestinal (GI) inflammation, compromised GI motility or obstruction, constipation, brain metastases, metabolic abnormalities (hypovolemia, hypercalcemia, hypoadrenalism, uremia), visceral organs invaded by tumor, and concurrent medical treatment (opioids, bronchodilators, aspirin, NSAIDS), may predispose to and exacerbate emetic symptoms during treatment and complicate good emetic control.
PRIMARY ANTIEMETIC PROPHYLAXIS
Primary prophylaxis is indicated for all patients whose antineoplastic treatment presents at least a low risk of producing emetic symptoms, that is, when >10% of persons receiving similar chemotherapy or radiation therapy without antiemetic prophylaxis are predicted to experience emetic symptoms (Table 38.3).
■Planning effective antiemetic primary prophylaxis
•Evaluate the emetic potential for each drug included in treatment, which includes the severity, onset, and duration of symptoms associated with individual drugs (Table 38.1), and how drug dose or dosage, schedule, and route of administration may affect those factors.
•Patients who receive combination chemotherapy should receive antiemetic prophylaxis based on the most emetogenic component of treatment.
•Include primary prophylaxis against acute-phase symptoms for all treatments with low, moderate, or high emetic potential, and delayed-phase prophylaxis for treatments with moderate or high emetic potential.
•For patients who receive antineoplastic chemotherapy and radiation concomitantly, antiemetic prophylaxis is selected based on the chemotherapy component that presents the greatest emetogenic potential, unless the emetic risk from radiation is greater.
•Patients who receive moderately or highly emetogenic treatment for more than 1 day should receive antiemetic prophylaxis appropriate for the drug with greatest emetogenic potential on each day of treatment.
•If antineoplastic treatment is associated with delayed emetic symptoms, continue antiemetic prophylaxis:
•For at least 3 days after highly emetogenic treatment is completed.
•For at least 2 days after moderately emetogenic treatment is completed.
•Treatment-appropriate antiemetic prophylaxis should precede each emetogenic treatment and proceed on a fixed schedule. Patients should not be expected to recognize symptom prodromes and to rely on unscheduled (i.e., as needed) antiemetics.
•Antiemetics should be given at the lowest effective doses.
•Patients’ responses to antiemetic prophylaxis and treatment should be monitored and documented with standardized validated tools.
•Healthcare providers historically underestimate the incidence and severity of emetic symptoms, particularly nausea.
•Patient input is essential to capture information about
οEvents that healthcare providers cannot observe due to patient location and the subjective nature of nausea.
οConditions and interventions that modulate a patient’s emetic symptoms.
•The MASCC has developed and makes available online a standardized eight-item questionnaire that can be used to document the number of vomiting episodes and the number and severity of episodes of nausea both acutely and within the 4 days (24 to 120 hours) after emetogenic treatment.
οThe MASCC Antiemesis Tool (MAT), a guide for using the tool, and an outcomes score sheet are available in 12 languages in digital formats for downloading, and in an application for handheld devices.
οInformation about gaining approval for using the MAT is available online at www.mascc.org
Figure 38.2 integrates evidence-based guidelines for treatment-appropriate antiemetic prophylaxis recommended by the National Comprehensive Cancer Network, the Multinational Association of Supportive Care in Cancer and European Society for Medical Oncology, the American Society of Clinical Oncology, and the consensus of experts in oncology. Recommendations are based on assessment of emetic risk and generally apply to adult patients, but may not be appropriate in all clinical situations. Drug selection and utilization should be tempered by professional judgment, including an assessment of patient-specific risk factors and circumstances, and recognition of available resources.
Clinicians may expect to encounter a minority of patients who do not respond to treatment-appropriate antiemetic prophylaxis recommended by oncology specialty organizations’ guidelines. Suboptimal antiemetic prophylaxis places patients at risk for breakthrough and refractory emetic symptoms and debilitating morbidity, which may adversely affect their safety, comfort, and quality of life, and complicate their care.
For patients who respond suboptimally to initial antiemetic prophylaxis, reevaluate factors that may cause or contribute to emetic symptoms, and those that may compromise the effectiveness of pharmacologic prophylaxis, including
■The emetogenic risk associated with treatment.
•The appropriateness of initial antiemetic prophylaxis for the emetogenic challenge presented by treatment
•Selection of drugs, doses/dosages, and administration routes and schedules for use
■Healthcare provider adherence in prescribing and patient compliance in using planned antiemetic prophylaxis.
■Disease status.
■Comorbid conditions (electrolyte abnormalities, renal failure, sepsis, constipation, tumor infiltrating or obstructing the GI tract, intracranial disease).
■Whether concomitantly administered medications may potentially compromise the effectiveness of the antiemetics utilized by including additional emetogenic medications or through pharmacokinetic interactions.
Empiric secondary prophylaxis and treatment for patients who demonstrate suboptimal antiemetic control should follow a rational approach. Pharmacologic interventions typically include drugs presumed to mediate antiemetic effects through an interaction with one or more neurotransmitter receptors implicated in either provoking or mitigating emesis, and through mechanisms not addressed by medications already in use. Unfortunately, drugs used empirically often are less safe at effective or clinically useful doses and schedules (e.g., dopaminergic and cannabinoid receptor antagonists) than agents recommended for primary prophylaxis. Whether used adjunctively or as replacement for initial prophylaxis, second-line alternatives may increase treatment costs and the risks of overtreatment and adverse effects.
BREAKTHROUGH SYMPTOMS
Primary antiemetic prophylaxis recommended by oncology specialty organizations’ guidelines are associated with complete control (no emesis) during the acute phase in ≥80% of patients who receive highly emetogenic treatments and even greater complete control rates in the setting of moderately emetogenic treatment; however, more than 50% of patients who receive moderately or highly emetogenic therapy still may experience delayed or breakthrough nausea or emesis in spite of good control achieved acutely. In general, it is more difficult to arrest emetic symptoms after they develop than it is to prevent them from occurring. Breakthrough symptoms require rapid intervention. All patients who receive moderately or highly emetogenic treatment should from the outset of treatment have access to antiemetic medications for treating breakthrough symptoms, whether through orders for treatment during a visit or admission to a healthcare facility or, for outpatients, a supply of antiemetic medication and clear instructions about how to use it in supplementing or modifying their initial antiemetic regimen. If needed and once begun, breakthrough treatment should be administered at scheduled intervals and continued at least until after emetogenic treatment is completed and symptoms abate.
In general, nausea may still occur and often is more prevalent than vomiting even in patients who achieve overall good or better emetic control.
Suboptimal Control
Suboptimal control of emetic symptoms with antiemetic prophylaxis raises the following questions:
■Was the prophylactic strategy given an adequate trial (time of initiation relative to the start of emetogenic treatment and duration of use)?
■Were the antiemetics selected and the doses and administration schedules prescribed appropriate for the emetogenic challenge?
■Did the patient understand and comply with instructions for antiemetic use?
■Would increased doses or shorter administration intervals improve antiemetic effectiveness without causing or exacerbating adverse effects associated with the antiemetics utilized?
Rescue Interventions
If it becomes necessary to “rescue” a patient from a suboptimal response:
■Assess a symptomatic patient’s state of hydration and serum/plasma electrolytes for abnormal results.
•Replace fluids and electrolytes as needed.
■Add antiemetic agents that act through mechanisms different from antiemetics already in use.
•It may be necessary to use more than one additional drug to establish antiemetic control.
■Give scheduled doses around the clock at least until emetogenic treatment is completed, and at doses and on a schedule appropriate for the medication.
•Do not rely on as needed administration to achieve or maintain control of emetic symptoms.
■Consider replacing ineffective drugs with a more potent or longer-acting agent from the same pharmacologic class.
■Consider replacing an antiemetic medication that requires ingestion and absorption from the GI tract or percutaneous absorption with the same or a different drug administered by an alternative administration route (disintegrating tablets and soluble films for oral administration, injectable formulations).
•Emetic symptoms may impair GI motility and drug absorption from the gut.
•Some patients may be too ill to swallow and retain oral medications.
•Rectal suppositories are a practical alternative for patients who cannot ingest medications, but the rate and extent of absorption varies among drugs and patients.
•Clinicians should query and ascertain patients’ willingness to comply with rectal administration.
•Sustained- and extended-release formulations (oral and transdermal products) should not be used to initially bring ongoing symptoms under control.
■Replace drugs associated with unacceptable adverse effects with one or more drugs from the same or a different pharmacologic class without potential for the same toxicity, or for which particular adverse effects are less likely to occur.
These strategies may be utilized during cyclical treatment or to intervene when response to prophylaxis is unsatisfactory.
FIGURE 38.2 Algorithms for antiemetic prophylaxis and treatment for parenterally and orally administered emetogenic drugs. 5-HT3, serotonin (5-HT3 subtype); ASCO, American Society of Clinical Oncology; D2, dopamine (D2 subtype); IM, intramuscular; IV, intravenous; MASCC/ESMO, Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network®; PO, oral; PR, rectal; RT, radiation therapy; SL, sublingual. aMedications are not listed in order of preference except where indicated. Pharmacologically similar alternatives are circumscribed by a broken line. bOral prophylaxis should begin 1 hour before commencing cytotoxic treatment. IV prophylaxis may be given minutes before emetogenic treatment. cAntiemetic prophylaxis should be repeated each day emetogenic treatment is administered. dDelayed-phase prophylaxis may begin 12 to 24 hours after the start of emetogenic treatment. eConsider administering a histamine (H2 subtype) receptor antagonist (other than cimetidine) or a proton pump inhibitor concurrently with dexamethasone to prevent GI irritation. f The recommended schedule for dexamethasone is twice daily if used without aprepitant and once daily if used with aprepitant. gIncrease dexamethasone dose to 20 mg if it is given without aprepitant or fosaprepitant. hDexamethasone 12 mg is the only dexamethasone dose tested in combination with aprepitant in large randomized trials. i When administered IV, dexamethasone should be given as a short infusion over 10 to 15 minutes to prevent uncomfortable sensations of warmth. jProduct labeling for ondansetron approved by the FDA recommends single intravenously administered doses should not exceed 16 mg. kMASCC/ESMO guidelines recommend combination antiemetic prophylaxis with dexamethasone and palonosetron for all chemotherapy with moderate emetic risk, including chemotherapy regimens containing an anthracycline and cyclophosphamide (an “AC” regimen) when an NK1 receptor antagonist cannot be used in combination with dexamethasone and a 5-HT3 receptor antagonist. NCCN Guidelines® recommend palonosetron as the preferred 5-HT3 receptor antagonist antiemetic in combination with dexamethasone for antiemetic prophylaxis for patients who receive intravenous chemotherapy with high or moderate emetogenic risk. l NCCN Guidelines recommend adding aprepitant in primary antiemetic prophylaxis for selected antineoplastics when those medications are given at dosages associated with moderate emetogenic risk, including carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate. mGranisetron Transdermal System (Sancuso®; ProStraken Inc., Bedminster, NJ), an adhesive-backed patch, contains 34.3 mg granisetron and delivers an average daily dose of 3.1 mg. nGenerally, regimens containing D2 receptor antagonists and metoclopramide doses ≥20 mg should include primary prophylaxis with anticholinergic agents against acute dystonic extrapyramidal reactions, for example, diphenhydramine 25 to 50 mg PO or IV every 6 hours. Benztropine and trihexyphenidyl are alternatives. Parenteral administration is preferred for prompt treatment of extrapyramidal symptoms, as well as interrupting or discontinuing the drug which provoked the adverse reaction. oWhen administered IV, phenothiazines should be given over 30 minutes to prevent hypotension. pMedications identified for breakthrough symptoms should be added to a patient’s primary antiemetic prophylaxis regimen without replacing drugs used in primary prophylaxis unless drugs used to treat breakthrough symptoms duplicate mechanistically those used in primary prophylaxis or a patient has experienced unacceptable adverse effects attributable to a component of primary prophylaxis. qContinue for at least 24 hours after completion of radiation treatment. rASCO guideline update (2011) identifies granisetron and ondansetron as the 5-HT3 receptor antagonists preferred in prophylaxis against radiation-induced emetic symptoms.
Secondary Antiemetic Prophylaxis and Treatment
When antiemetic treatment is needed for breakthrough symptoms, reevaluate the prophylactic regimen that failed to provide adequate antiemetic control before repeating cycles of emetogenic treatment. Consider alternative antiemetic prophylaxis strategies during subsequent emetogenic treatments, including:
■Consider escalating antiemetic prophylaxis to a regimen appropriate for the next greater level of emetic risk.
■Add additional scheduled antiemetics at appropriate doses and administration intervals.
•Consider drugs that proved of value in controlling breakthrough symptoms or another drug that acts through the same pharmacologic mechanism.
■For regimens that included a 5-HT3 antagonist, consider switching to a different 5-HT3 antagonist.
•There is evidence, albeit meager, that suggests all patients may not achieve the same measure of antiemetic control with all 5-HT3 antagonists.
■Consider adding an anxiolytic drug to the patient’s regimen.
■Consider adding aprepitant to antiemetic prophylaxis if its potential for pharmacokinetic interactions will not adversely affect concomitantly administered medications.
■If alternative treatment for a patient’s neoplastic disease exists, consider a different regimen with which similar therapeutic benefit may be achieved without greater adverse outcomes.
•Perhaps worth considering only if the goal of treatment is not curative.
NONPHARMACOLOGIC INTERVENTIONS
■Guidance for patients that may preserve nutritional status and alleviate emetic symptoms includes:
•Eat small frequent meals low in fat content, especially for patients with anorexia or early satiety.
•Choose healthful foods.
•Avoid foods and beverages known or found to produce nausea.
•Advise patients to avoid favorite foods particularly at times when symptoms may be expected to prevent developing conditioned aversions to those foods.
•Eat foods served at room temperature.
•Avoid sweet, fatty, highly salted and spicy foods, dairy products, and foods with strong odors.
•For patients who are nauseated by the smell of food:
•Let someone else do the cooking. Leave areas when and where cooking smells are present.
•Avoid foods and beverages that provoke nausea.
οOdors, appearance, taste, and texture (“mouth feel”).
οGreasy and fried foods and brewing coffee may provoke symptoms.
•Use prepared foods that can be warmed at a low temperature or a meal that does not need to be cooked.
■Acupressure or acupuncture.
•Stimulation of the ventral side of the wrist where the median nerve is closest to the surface of the skin, an acupuncture point referred to as pericardium-6 (P-6) or Neiguan point may be of benefit in some patients.
ANTIEMETIC DRUGS
Serotonin (5-HT3 Subtype) Receptor Antagonists
Acute Phase
■5-HT3 antagonists are safer and more effective against acute-phase symptoms than other medications with clinically useful antiemetic activity.
■All 5-HT3 antagonists provide equal benefit at maximally effective dosages. Administering more than a maximally effective dose does not substantially improve emetic control.
■Single-dose prophylaxis is preferred for acute-phase symptoms. Additional doses of dolasetron, granisetron, or ondansetron within the first 24 hours after emetogenic treatment have not been shown to improve emetic control.
■Dolasetron, granisetron, ondansetron, and palonosetron have excellent oral bioavailability and provide equivalent antiemetic protection after either oral or parenteral administration.
Delayed Phase
■Metoclopramide and prochlorperazine are less expensive, and as effective as dolasetron, granisetron, and ondansetron at controlling emetic symptoms.
■Palonosetron has the longest half-life among commercially available 5-HT3 antagonists, and is the only drug in the class that has received FDA approval for use in delayed-phase prophylaxis of emetic symptoms associated with moderately emetogenic chemotherapy.
•A single 0.25 mg dose of palonosetron is recommended before starting chemotherapy, but other doses and schedules have proven safe (see below).
Potential Side Effects
■Side effects common to all 5-HT3 antagonists include
•Headache
•Constipation
•Diarrhea
•Transiently increased hepatic transaminase concentrations
•Transient ECG changes, decreased cardiac rate, and cardiovascular adverse effects (see drug-specific comments below)
Dolasetron
■The oral tablet formulation is approved for use in antiemetic prophylaxis in initial and repeat courses of moderately emetogenic chemotherapy in patients aged ≥2 years.
■The frequency and magnitude of adverse effects associated with dolasetron use are related to serum concentrations of hydrodolasetron, its active metabolite.
■On December 17, 2010, the U.S. Food and Drug Administration (FDA) announced the removal of the indication for dolasetron mesylate injection for preventing nausea and vomiting associated with initial and repeated courses of emetogenic chemotherapy, and the addition to product labeling of a contraindication against this use in pediatric and adult patients. The FDA Communication explained dolasetron mesylate causes a dose-dependent prolongation in cardiac QT, PR, and QRS intervals, which can increase the risk of developing torsade de pointes, which may be fatal [FDA Drug Safety Communication: Abnormal heart rhythms associated with use of Anzemet (dolasetron mesylate). URL: http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm. Last accessed December 6, 2012.].
•Risk factors for serious abnormal arrhythmias include:
•Underlying structural heart disease and preexisting conduction system abnormalities, for example, patients with congenital long-QT syndrome, with complete heart block, or at risk for complete heart block
•Elderly individuals
•Sick sinus syndrome, atrial fibrillation with slow ventricular response, myocardial ischemia, persons receiving drugs known to prolong the PR interval (e.g., verapamil) and QRS interval (e.g., flecainide and quinidine)
•Hypokalemia or hypomagnesemia
οSerum potassium and magnesium concentrations should be evaluated, and, if abnormal, corrected before initiating treatment with dolasetron.
οPotassium and magnesium concentrations should be monitored after dolasetron administration as clinically indicated.
οPatients at risk for developing hypokalemia or hypomagnesemia while receiving dolasetron should be monitored with ECG.
•The FDA also recommended ECG monitoring in patients with congestive heart failure, bradycardia, underlying heart disease, and in the elderly and patients with renal impairment who receive dolasetron.
•Dolasetron mesylate tablets may still be used in antiemetic prophylaxis for emetogenic chemotherapy, because the risk of developing aberrant cardiac conduction with the oral formulation is considered less than what has been observed with dolasetron injection.
•Dolasetron mesylate injection also retained FDA approval for the prevention and treatment of postoperative nausea and vomiting, because dosages for that indication (0.35 mg/kg per dose) are less than those used in antiemetic prophylaxis for chemotherapy (1.8 mg/kg per dose), and therefore, are less likely to adversely affect cardiac electrophysiology.
Granisetron
■Used in antiemetic prophylaxis in initial and repeat courses of emetogenic cancer therapies.
•Granisetron injection has received FDA approval for use in patients aged ≥2 years.
•Injectable products may contain benzyl alcohol, which has been associated with serious adverse reactions including death in neonates.
•Oral formulations (tablets and solution) have not received FDA approval for use in pediatric patients.
■Granisetron transdermal patch (Sancuso®; ProStrakan, Inc., Bedminster, NJ), an adhesive backed patch, contains 34.3 mg of granisetron and delivers an average daily dose of 3.1 mg granisetron for up to 7 days.
•The patch is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.
•Safety and effectiveness in patients aged <18 years have not been established.
•A patch is applied to clean, dry, intact skin on the outer upper arm 24 to 48 hours before administration of emetogenic chemotherapy and remains in place ≥24 hours after chemotherapy is completed.
•The duration of application should not exceed 7 days.
•During clinical development, patients who received granisetron 3.1 mg per day transdermally experienced a slightly greater incidence of constipation than patients who received 2 mg per day granisetron orally (5.4% vs. 3%, respectively) and a lesser incidence of headache than patients who received 2 mg per day granisetron orally (0.7% vs. 3%, respectively).
•Continuous administration of transdermal granisetron may increase the potential for 5-HT3 receptor antagonists to mask progressive ileus and gastric distention attributable to malignancy or another pathology.
•Granisetron may degrade with exposure to natural or artificial sunlight, and an in vitro study has suggested a potential for photogenotoxicity. Patients must be instructed to keep the transdermal patch covered with clothing at all times, and to keep the application site covered for 10 days after a patch is removed.
■ECG abnormalities are rare at FDA-approved dosages and schedules.
Ondansetron
■Used in antiemetic prophylaxis in initial and repeat courses of emetogenic cancer therapies:
•Ondansetron injection has received FDA approval for use in patients ≥6 months of age.
•Oral formulations (tablets, orally disintegrating tablets, and solution) have received FDA approval for use in patients aged ≥4 years receiving emetogenic chemotherapy.
■The risk of adverse effects at dosages and schedules currently approved by the FDA is low.
•The risk of ECG abnormalities associated with use has been shown to vary directly with the dose administered.
■On June 29, 2012, the FDA announced preliminary results from a clinical study conducted by GlaxoSmithKline showed that ondansetron prolongs the cardiac QT interval in a dose-dependent manner, which could predispose patients to develop an abnormal and potentially fatal ventricular tachyarrhythmia known as torsades de pointes (FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron [Zofran] URL: http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Last accessed December 6, 2012).
•Risk factors for developing QT prolongation with ondansetron include:
•Underlying heart conditions, such as congenital long QT syndrome, congestive heart failure, or bradyarrhythmias
•Hypokalemia and hypomagnesemia
•Concomitant use of medications that also are associated with QT prolongation
•A comparison between single intravenous doses of ondansetron 32 and 8 mg revealed the maximum mean difference in QTcF (the QT interval measurement corrected by the Fridericia formula) from placebo after baseline correction was 20 and 6 milliseconds, respectively.
•Consequently, product labeling was amended to state ondansetron 0.15 mg/kg administered intravenously over 15 minutes every 4 hours for three doses may continue to be used in adults and children with chemotherapy-induced nausea and vomiting, but no single intravenous dose should exceed 16 mg.
•Ondansetron product labeling includes warnings against using the drug in patients with congenital long QT syndrome and recommends ECG monitoring in patients with uncorrected electrolyte abnormalities such as hypokalemia or hypomagnesemia, congestive heart failure, bradyarrhythmias, and in patients concomitantly using other medications that can prolong the QT interval.
•Patients should be advised to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm while they are taking ondansetron.
•Recommendations for a single, orally-administered, 24-mg ondansetron dose in prophylaxis against chemotherapy induced nausea and vomiting were not affected.
Palonosetron
■FDA approved for use in patients aged ≥18 years in antiemetic prophylaxis for:
•Acute and delayed nausea and vomiting in initial and repeat courses of moderately emetogenic chemotherapy.
•Acute nausea and vomiting in initial and repeat courses of highly emetogenic chemotherapy.
■Palonosetron is the 5-HT3 receptor antagonist for antiemetic prophylaxis recommended preferentially by:
•American Society of Clinical Oncology guidelines for patients who receive intravenous chemotherapy with moderate emetic risk
•National Comprehensive Cancer Network® guidelines for patients who receive intravenous chemotherapy with high or moderate emetogenic risk
•Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology guidelines for patients treated with chemotherapy regimens containing an anthracycline and cyclophosphamide (an “AC” regimen) when an NK1 receptor antagonist cannot be used in combination with dexamethasone and a 5-HT3 receptor antagonist, and for all chemotherapy with moderate emetic risk in combination with dexamethasone
■There is a low risk of adverse effects at dosages and schedules currently approved by the FDA.
■The risk of ECG abnormalities including QTc prolongation has been shown less than that associated with dolasetron and ondansetron.
•FDA-approved product labeling indicates single doses of palonosetron 0.25, 0.75, or 2.25 mg in 221 healthy adult men and women in a double-blind, randomized, parallel, placebo, and positive (moxifloxacin) controlled trial demonstrated no significant effect on any ECG interval including QTc interval duration.
■Product labeling for palonosetron injection indicates a single dose before starting chemotherapy, but safety has been demonstrated with other doses and schedules:
•10 mcg/kg single dose (healthy subjects).
•0.75 mg single dose before chemotherapy.
•0.25 mg per dose every second day for three doses with dexamethasone before chemotherapy.
•0.25 mg per day for 3 consecutive days (healthy subjects).
•0.25 mg per day for 1, or 2 or 3 consecutive days (prior to high-dose chemotherapy).
•No differences were observed in control of vomiting over a 7-day evaluation period among patients who received 1, 2, or 3 doses.
•Only about 8% of patients who received one dose and about 20% of patients who received two or three doses were without emesis and did not receive rescue medications.
•Palonosetron 0.25 mg IV followed at least 72 hours after the initial dose by a second 0.25-mg dose for breakthrough symptoms was effective in 67% of patients who experienced nausea or vomiting.
■Oral palonosetron in August 2008 received FDA approval for prevention of acute-phase symptoms associated with initial and repeated courses of moderately emetogenic chemotherapy; however, an oral formulation has not yet become commercially available in the United States.
Pharmacogenomics
■Pharmacogenomic evaluation may help to identify patients at risk for suboptimal and adverse responses to 5-HT3 receptor antagonists, which are substrates for catabolism by cytochrome P450 (CYP) enzymes (Table 38.4).
■CYP2D6 is polymorphically expressed among human populations.
•Persons with more than two functionally competent (wild-type) CYP2D6 alleles may have increased metabolic capacity (characterized as ultra-rapid metabolizers), which has been associated with diminished emetic control in patients who received 5-HT3 receptor antagonists for which CYP2D6 metabolism predominates.
•Patients who lack one or both CYP2D6 alleles or express one or more variant alleles with reduced function generally have altered functional capacity for CYP2D6 substrates (poor and intermediate metabolizers) and may have high concentrations and attenuated elimination of 5-HT3 receptor antagonists for which CYP2D6 metabolism predominates.
■Patients who express genetic polymorphism for the 5-HT3 receptor or ABCB1 (MDR1, P-glycoprotein) transporter may experience suboptimal antiemetic responses with 5-HT3 receptor antagonists.
Glucocorticoids
■High-potency glucocorticoids such as dexamethasone and methylprednisolone are effective as single agents against mild to moderate acute-phase symptoms.
■Dexamethasone and methylprednisolone are active against both acute- and delayed-phase symptoms.
•At clinically useful doses, dexamethasone and methylprednisolone are equally effective after either intravenous or oral administration.
•Both dexamethasone and methylprednisolone enhance the antiemetic effectiveness of 5-HT3 and NK1 receptor antagonists when used concomitantly.
■Prophylaxis and treatment are empirically based; safety and efficacy comparisons are lacking.
■In antiemetic prophylaxis for emetogenic treatment given on a single day, single doses of dexamethasone and methylprednisolone are as effective as multiple-dose schedules.
•Optimal dosages and schedules have not been determined, but there is no evidence that single doses of dexamethasone >20 mg improves antiemetic response.
■Potential for adverse effects after a single dose is generally low and limited to GI upset and activating psychogenic effects such as anxiety, insomnia, and sleep disturbances.
•Coadministration with drugs that decrease gastric acid production (histamine H2 receptor antagonists or proton pump inhibitors) is recommended to prevent GI irritation.
•Administering steroids early in a patient’s waking cycle may minimize adverse effects on sleep.
■Adrenocortical suppression is generally not a problem when high-potency glucocorticoids are used for brief periods.
■Glycemic control may be a problem in patients with incipient or frank diabetes.
Neurokinin (NK1 Subtype) Receptor Antagonists
■Currently, aprepitant and fosaprepitant dimeglumine, a pro-drug for aprepitant, are the only NK1 receptor subtype antagonist antiemetics that have received FDA approval for use in patients aged ≥18 years. Approval was based on studies with emetogenic chemotherapy given on a single day.
■Aprepitant is recommended for use in combination with a glucocorticoid; a 5-HT3 receptor antagonist is added for acute-phase emetic symptoms.
■Utilization in prophylaxis for emetogenic chemotherapy given on a single day (day 1; Table 38.5).
■Potential drug interactions:
•Aprepitant is a substrate and moderate inhibitor of the CYP enzyme CYP3A4, and a moderate inducer of CYP3A4 and CYP2C9. Inhibition may occur after a single dose; induction occurs after repeated doses.
•Aprepitant inhibits CYP3A4 in the gut and liver.
•The potential for interaction with many CYP3A4 substrates is unknown.
•Aprepitant increases the bioavailability of concomitantly administered dexamethasone and methylprednisolone.
•When either dexamethasone or methylprednisolone is used in combination with aprepitant for antiemetic prophylaxis, decrease orally administered glucocorticoid doses by 50% and intravenous doses by 25%.
•Do not modify the doses of steroids used as components of a chemotherapy regimen.
•Aprepitant metabolism and elimination may be adversely affected by drugs that inhibit or induce CYP3A4.
■Common side effects of aprepitant in combination with a 5-HT3 receptor antagonist and high-potency glucocorticoids include:
•Abdominal pain
•Epigastric discomfort
•Hiccups
•Anorexia
•Dizziness
•Asthenia
•Fatigue
Dopamine (D2 Subtype) Receptor Antagonists
■Optimal doses and schedules have not been established.
■Overall, antiemetic activity varies directly with D2 receptor antagonism.
■Adverse effects correlate with dose and frequency of administration, and include:
•Sedation
•Extrapyramidal reactions (dystonias, akathisia, dyskinesia)
•Anticholinergic effects
•ECG changes (haloperidol, droperidol)
•Hypotension with rapid intravenous administration (phenothiazines)
■Anecdotal evidence supports the use of D2 receptor antagonists with 5-HT3 antagonists ± steroids for acute-phase symptoms, and with steroids, metoclopramide, or lorazepam for delayed-phase symptoms.
Metoclopramide
■Metoclopramide has affinity for several neurotransmitter receptors associated with antiemetic activity, but is often categorized among D2 receptor antagonists, and, at high doses, becomes a competitive antagonist at vagal and central 5-HT3 receptors.
■Activity against delayed-phase symptoms is equivalent to that of ondansetron.
■GI prokinetic effects may benefit patients with intercurrent GI motility disorders or gastroesophageal reflux disease.
■Long-term use has been associated with developing tardive dyskinesia which may be irreversible.
Benzodiazepines
■Benzodiazepines are important adjuncts to antiemetics for their anxiolytic and anterograde amnestic effects.
•Irrespective of its cause, anxiety may be a factor in developing or exacerbating emetic symptoms prior, during, and after completing emetogenic treatments.
•Benzodiazepines are clinically useful for mitigating akathisias associated with D2 receptor antagonists.
■Available products:
•Lorazepam, midazolam, and diazepam are available in oral and injectable formulations.
•Alprazolam is available in solid formulations for oral administration.
•Lorazepam and alprazolam tablets are rapidly absorbed after sublingual administration.
■Primary liability is dose-related sedation.
■Pharmacodynamic effects are exaggerated in elderly patients.
Cannabinoids
■Commercially available cannabinoids are agonists at endocannabinoid (CB1 subtype) receptors.
•Dronabinol is an oral formulation of Δ9-tetrahydrocannabinol (Δ9-THC) with antiemetic activity similar to low doses of prochlorperazine.
•Nabilone is a synthetic CB1 receptor agonist formulated for oral administration.
•Cannabinoids are controlled substances (schedule II) in the United States.
■Antiemetic benefit may be achieved without producing psychotropic effects. Cannabinoid use is empiric since optimal doses and administration schedules have not been determined.
■The incidence of adverse effects associated with dronabinol and nabilone is greater than with phenothiazines at doses and schedules that produce comparable antiemetic effects.
■Adverse effects occur within the range of clinically useful doses; incidence and severity vary with dose and correlate inversely with the interval between successive doses. Potential adverse effects include:
•Sedation
•Confusion/decreased cognition
•Dizziness
•Short-term memory loss
•Euphoria/dysphoria
•Ataxia
•Dry mouth
•Orthostatic hypotension ± increased heart rate
Anticholinergic (Antimuscarinic) Agents and Histamine (H1) Receptor Antagonists
■Utility in preventing and treating emetic symptoms is not defined.
■Anticholinergics may be most effective in prophylaxis; less effective after emetic symptoms develop.
■Anticholinergics are useful in prophylaxis and treatment for patients whose emetic symptoms are referable to movement.
■Individual agents have in different proportions affinities for histaminic and cholinergic neuronal receptors, and, in some cases, agonistic and antagonistic activities at adrenergic, dopaminergic, and other neuroreceptors.
■Adverse effects correlate directly with dose and frequency of administration, and include:
•Sedation
•Dry mouth
•Loss of visual accommodation/blurred vision
•Deceased GI motility with constipation or diarrhea
•Urinary retention or frequency
•Mydriasis ± photophobia
•Increased heart rate
Other Neurotransmitter Antagonists
■Olanzapine, an atypical neuroleptic or antipsychotic, is a potent antagonist at multiple neurotransmitter receptors, including muscarinic, serotonergic, dopaminergic, and histaminergic receptors.
•Adverse effects include:
•Somnolence and insomnia
•Nervousness, agitation
•Headache
•Dizziness and orthostatic hypotension
•Weight gain, new-onset diabetes, hyperlipidemia, and increased serum alanine aminotransferase with prolonged use
•CAUTION: Product labeling for olanzapine includes a boxed warning about its use in elderly patients. In clinical trials, elderly patients (≥65 years) with dementia-related psychosis experienced an increased incidence of death and adverse cerebrovascular events including stroke.
•Olanzapine is a substrate for oxidation to an inactive metabolite catalyzed by CYP1A2 and direct glucuronidation catalyzed by uridine diphosphate glucuronosyltransferase (UGT) enzymes, UGT1A4 and UGT2B10.
οOlanzapine’s pharmacokinetic behavior is susceptible to drugs and substances that induce and inhibit CYP1A2 (e.g., carbamazepine, fluvoxamine, tobacco).
STRATEGIES FOR COMBINING ANTIEMETICS
Antiemetics in combination can be more effective than single agents by targeting two or more operative neural pathways.
■Numerous studies have demonstrated that control of acute-phase emetic symptoms improves significantly with the combination of 5-HT3 receptor antagonists and high-potency glucocorticoids. Acute-phase symptom control is further augmented when aprepitant is used in combination with a 5-HT3 receptor antagonist and a glucocorticoid.
■Delayed-phase symptom control is improved by the combination of high-potency glucocorticoids and aprepitant. However, aprepitant may compromise the safety of concomitantly administered medications due to its effects on CYP metabolizing enzymes.
•In cases where prophylaxis against delayed-phase symptoms is indicated but concurrent medications make the use of aprepitant problematic, glucocorticoids alone or in combination with either metoclopramide or a 5-HT3 or D2receptor antagonist may improve control of symptoms.
REVIEW QUESTIONS
1.A 57-year-old woman with breast cancer returns to the outpatient clinic to receive her first cycle of adjuvant chemotherapy with docetaxel 75 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 50 mg/m2. All three drugs are administered intravenously on the first day of a 3-week cycle. Which of the following regimens is most consistent with antiemetic primary prophylaxis recommended by MASCC/ESMO, ASCO, and NCCN guidelines?
A.A single dose of dolasetron 100 mg PO + dexamethasone 20 mg PO + fosaprepitant 150 mg IV prior to chemotherapy.
B.Any serotonin (5-HT3) receptor antagonist + dexamethasone 20 mg PO prior to chemotherapy + a 3-day regimen of aprepitant (125 mg PO day 1 before chemotherapy, then 80 mg per day PO days 2 and 3).
C.Palonosetron 0.25 mg IV + fosaprepitant 115 mg IV + dexamethasone 12 mg IV on day 1, followed by dexamethasone 8 mg per day PO on days 2 and 3.
D.Granisetron 2 mg PO + dexamethasone 12 mg PO + fosaprepitant 150 mg IV prior to chemotherapy, followed by dexamethasone 8 mg per day PO for 3 days on days 2 to 4.
E.Ondansetron 24 mg IV + fosaprepitant 150 mg IV prior to chemotherapy.
2.At presentation in clinic, the same patient’s height and weight are measured. Her height is 170.2 cm (67˝); current weight is 110 kg (243 lb). A pretreatment analysis of serum chemistries revealed the following (results outside of normal ranges identified by up and down arrows):
Her medical history includes
■Type 2 diabetes managed with extended-release metformin 2,000 mg daily
■Hypertension controlled with losartan 100 mg + hydrochlorothiazide 12.5 mg per day
■A 2-year history of depression for which she takes controlled-release paroxetine 50 mg daily
What factors should the patient’s healthcare providers take into consideration in selecting antiemetic agents?
A.Dexamethasone should be excluded from her antiemetic regimen to prevent exacerbating hyperglycemia.
B.A potential for pharmacokinetic drug interactions between particular 5-HT3 receptor antagonists (dolasetron, palonosetron) and paroxetine.
C.Recommendations for empiric antiemetic doses (not based on body weight) should be doubled to compensate for obesity.
D.A potential for adverse pharmacodynamic drug interactions between particular 5-HT3 receptor antagonists (dolasetron, ondansetron) and paroxetine.
E.Choices B and D.
3.In addition to the emetogenicity of antineoplastic treatment, what patient-specific factors place the patient at increased risk for suboptimal emetic control?
A.Comorbid pathologies associated with diabetes
B.Female sex
C.Depressive disorder
D.History of motion sickness
E.Difficulty with emesis during pregnancy
F.Chronic constipation
4.A 20-year-old male with a recent diagnosis of nonseminomatous germ cell tumor presents for his first course of BEP chemotherapy (bleomycin 30 units per dose IV for three doses on days 1, 8, and 15 + etoposide 100 mg/m2 per day IV on days 1 to 5 + cisplatin 20 mg/m2 per day IV on days 1 to 5). What antiemetic regimen would you choose for primary prophylaxis?
A.Aprepitant 125 mg PO on day 1 before chemotherapy, then 80 mg per day PO on days 2 to 5 with granisetron 2 mg per day PO + dexamethasone 20 mg per day PO both given before chemotherapy for 5 days on days 1 to 5.
B.Any 5-HT3 receptor antagonist daily before chemotherapy for 5 days + fosaprepitant 150 mg per dose IV for 3 doses on days 1, 3, and 5, prior to chemotherapy.
C.Dexamethasone 12 mg per day IV for 5 days on days 1 to 5 prior to chemotherapy, then 8 mg per day PO for 3 days on days 6 to 8 + palonosetron 0.25 mg per dose IV for 3 doses on days 1, 3, and 5, before chemotherapy.
D.Granisetron 34.3 mg transdermal patch applied 24 hours before starting chemotherapy and left in place for 7 days (1 day after completing emetogenic chemotherapy) + dexamethasone 12 mg per day PO for 5 days on days 1 to 5 prior to chemotherapy, then 8 mg per day PO for 3 days on days 6 to 8 + aprepitant 125 mg PO on day 1 before chemotherapy, then 80 mg per day PO on days 2 to 5.
E.Any 5-HT3 receptor antagonist daily before chemotherapy for 5 days + aprepitant 125 mg PO on day 1, then 80 mg per day PO on days 2 and 3 before chemotherapy + dexamethasone 8 mg PO daily for 8 days.
5.A 41-year-old patient with ovarian cancer presents to the outpatient clinic for a second cycle of carboplatin (dosed to achieve a standardized systemic exposure consistent with an estimated area under the plasma concentration vs. time curve [AUC]) AUC = 4 mg/mL·min and docetaxel 75 mg/m2, both drugs are administered intravenously, sequentially, on the first day of a 21-day cycle. The patient’s previous (first) treatment cycle was complicated by facial flushing, nausea, and shortness of breath during docetaxel administration. Docetaxel administration was transiently interrupted until symptoms abated, and then resumed at a slower administration rate without recurrent symptoms. Although the patient achieved complete protection from vomiting during the first 24 hours after treatment, she reported experiencing three vomiting episodes during the 2 days after she received chemotherapy and nausea that persisted throughout the week after treatment in spite of having received outpatient prescriptions appropriate for prophylaxis against delayed symptoms for a moderately emetogenic risk treatment regimen. However, you learn when she returns to clinic for a second cycle of chemotherapy, she had not had her antiemetic prescriptions filled and did not continue antiemetic prophylaxis as planned during the 3 days that followed her last treatment. The patient’s medical history is significant for a history of severe and persistent nausea and vomiting during the first and second trimesters of pregnancy and episodes of motion sickness as a function of where she is seated when traveling by automobile and when she participated in boating excursions during family vacations. Would you modify the patient’s antiemetic regimen to prevent or manage persistent symptoms after chemotherapy, and, if so, in what way?
A.Do nothing to modify the previous strategy for antiemetic prophylaxis, but discuss with the patient how compliance with plans for antiemetic prophylaxis while she is an outpatient is an essential part of treatment for her neoplastic disease by preventing debilitating and serious complications associated with uncontrolled emetic symptoms, and doing so improves the likelihood she will be able to complete treatment without compromising her ability to tolerate chemotherapy with respect to doses and scheduling.
B.Consider escalating the aggressiveness of antiemetic prophylaxis to a regimen appropriate for highly emetogenic treatment.
C.Consider adding an anxiolytic before starting chemotherapy and as needed during treatment to prevent the patient from developing anticipatory symptoms.
D.Use the antiemetic regimen previously employed, but add an anticholinergic agent to mitigate symptoms related to motion sickness.
E.Add a dopaminergic (D2) receptor antagonist during antineoplastic treatment and for 3 days afterward to “saturate” neuroreceptors unaffected by previously used antiemetics.
Suggested Readings
1.Aapro M. Methodological issues in antiemetic studies. Invest New Drugs. 1993;11(4):243-253.
2.Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17(9):1441-1449.
3.Aapro MS, Molassiotis A, Olver I. Anticipatory nausea and vomiting. Support Care Cancer. 2005;13(2):117-121.
4.Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189-4198.
5.Borison HL, McCarthy LE. Neuropharmacology of chemotherapy-induced emesis. Drugs. 1983;25(Suppl 1):8-17.
6.Botrel TE, Clark OA, Clark L, Paladini L, Faleiros E, Pegoretti B. Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis. Support Care Cancer. 2011;19(6):823-832.
7.Bubalo JS, Cherala G, McCune JS, Munar MY, Tse S, Maziarz R. Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J Clin Pharmacol. 2012;52(4):586-594.
8.Celio L, Frustaci S, Denaro A, et al. Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial. Support Care Cancer. 2011;19(8):1217-1225.
9.D’Acquisito R, Tyson LB, Gralla RJ, et al. The influence of a chronic high alcohol intake on chemotherapy-induced nausea and vomiting [abstract]. Proc Am Soc Clin Oncol. 1986;5:257.
10.de Wit R, Herrstedt J, Rapoport B, et al. Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy [see comments]. J Clin Oncol. 2003;21(22):4105-4111. Comment in: J Clin Oncol. 2003;21:4077-4080.
11.Feyer PC, Maranzano E, Molassiotis A, Roila F, Clark-Snow RA, Jordan K. Radiotherapy-induced nausea and vomiting (RINV): MASCC/ESMO guideline for antiemetics in radiotherapy: update 2009. Support Care Cancer. 2011;19(Suppl 1):S5-S14.
12.Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol.2003;14(10):1570-1577.
13.Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6(10):765-772.
14.Hunt TL, Gallagher SC, Cullen MR Jr, Shah AK. Evaluation of safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron in healthy subjects. J Clin Pharmacol. 2005;45(5):589-596.
15.Italian Group for Antiemetic Research. Cisplatin-induced delayed emesis: pattern and prognostic factors during three subsequent cycles. Ann Oncol. 1994;5(7):585-589.
16.Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes [see comments]. J Clin Oncol. 2002;20(12):2805-2811. Comment in: J Clin Oncol. 2002;20:2765-2767.
17.Kris MG, Gralla RJ, Clark RA, et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol. 1985;3(10):1379-1384.
18.Kris MG, Roila F, De Mulder PH, Marty M. Delayed emesis following anticancer chemotherapy. Support Care Cancer. 1998;6(3):228-232.
19.Molassiotis A, Coventry PA, Stricker CT, et al. Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool. J Pain Symptom Manage. 2007;34(2):148-159.
20.Morrow GR, Hickok JT, Burish TG, Rosenthal SN. Frequency and clinical implications of delayed nausea and delayed emesis. Am J Clin Oncol. 1996;19(2):199-203.
21.Multinational Association of Supportive Care in Cancer. MASCC/ESMO Antiemetic Guideline 2011. Available at: http://www.mascc.org/. Last accessed December 28, 2012.
22.National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Antiemesis. Available at: http://www.nccn.org/index.asp. Last accessed December 28, 2012.
23.Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(Suppl 5):v232-v243.
24.Roscoe JA, Morrow GR, Aapro MS, Molassiotis A, Olver I. Anticipatory nausea and vomiting. Support Care Cancer. 2011;19(10):1533-1538.
25.Ruhlmann C, Herrstedt J. Palonosetron hydrochloride for the prevention of chemotherapy-induced nausea and vomiting. Expert Rev Anticancer Ther. 2010;10(2):137-148.
26.Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10(2):115-124.
27.Sullivan JR, Leyden MJ, Bell R. Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion. N Engl J Med. 1983;309(13):796.
28.Tremblay PB, Kaiser R, Sezer O, et al. Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J Clin Oncol. 2003;21(11):2147-2155.