Bethesda Handbook of Clinical Oncology, 2nd Edition
Management of Emesis in Oncology
David R. Kohler
Pharmacy Department, National Institutes of Health, Clinical Center, Bethesda, Maryland
TYPES OF TREATMENT-RELATED EMETIC SYMPTOMS
Radiation- and chemotherapy-associated emetic symptoms are categorized as acute, delayed, or anticipatory (see Fig. 40.1) (1).
FIG. 40.1. Emetic symptom phases and antiemetic activity comparison. Top: The temporal relation between the start of emetogenic treatment [hour zero (0)] and emetic symptom phases. For each phase, shaded bars indicate generally the periods during which nausea and emesis occur; depth of shading correlates directly with the incidence of symptoms. Bottom: The most highly active drug categories are ranked by their relative effectiveness during the acute (0–24 hours) and delayed (after 24 hours) emetic phases.
Acute-phase symptoms correlate with serotonin (5-HT) release from enterochromaffin cells. Emetic signals are propagated at local 5-HT3receptors and transmitted along afferent vagus nerve fibers, and a diffuse series of effector nuclei are activated in the medulla oblongata (the so-called “vomiting center”). This in turn integrates afferent emetic signals and subsequently activates and coordinates motor nuclei that produce the physiologic changes associated with vomiting.
Although an etiology for delayed symptoms remains elusive, such symptoms may be related to activation of neurokinin type 1 receptors (NK1) for which substance P is the natural ligand. Delayed-phase symptoms have been associated with numerous chemotherapeutic regimens (see Table 40.1). Symptoms may occur as early as 16 to 18 hours after emetogenic treatment, with the period of most frequent incidence between 24 and 96 hours after treatment (2,3).
TABLE 40.1. Antineoplastic Drugs Implicated in Causing Delayed Emesis
Delayed emesis may occur in patients who do not experience symptoms acutely, but its incidence characteristically decreases in patients who achieve complete control during the acute phase. Although the severity of emesis during the delayed phase is typically less than that which occurs during the acute phase, the severity of nausea is reportedly similar during both phases.
Repeated antineoplastic treatments that are characterized by poor emetic control give rise to anticipatory emetic symptoms, which are an aversive conditioned response. Consequently, complete control throughout antineoplastic treatment remains the best preventive strategy against developing symptoms. Although anxiolytic amnestic drugs are helpful in preventing the development of anticipatory symptoms, behavior-modification and cognitive-distraction techniques become the primary modalities of intervention after symptoms occur. After symptoms develop, the role of medical intervention during subsequent emetogenic treatment is limited to preventing reinforcement of conditioned stimulus, which may exacerbate anticipatory symptoms.
EMETIC (EMETOGENIC) POTENTIAL
The potential for producing emesis and the patterns in which symptoms manifest vary among antineoplastic medications and radiation therapy techniques.
Acute Emetic Symptoms:
- Generally, onset of emesis is within 1 to 3 hours after commencing chemotherapy administration (see Table 40.2).
TABLE 40.2. Time to Onset after Commencement of Chemotherapy Administration and Duration of Emesis
- Exceptions include mechlorethamine (nitrogen mustard), cyclophosphamide, and carboplatin.
- Most frequent incidence of emesis occurs during a 2- to 6-hour period after treatment.
- Emesis may persist or recur intermittently for 12 hours or longer after treatment.
Among antineoplastic drugs, the dose administered most often affects emetogenic potential and the duration for which symptoms occur. The number of emetogenic drugs administered in combination, administration schedule, treatment duration, and route of drug administration are also mitigating factors. Emetic potential is often a function of treatment duration; it may be decreased or eliminated by attenuating drug delivery over hours or days and is often increased by rapid administration, by repetitious emetogenic treatment, and by brief intervals between repeated doses.
For ionizing radiation, emetic potential correlates directly with the amount of radiation administered per dose and the dose rate. Large treatment volumes and fields including the upper abdomen, the upper hemithorax, and the whole body are prominent risk factors for
severe emesis. Generally, emetic risk is increased when radiation and chemotherapy are administered concomitantly.
PATIENT RISK FACTORS THAT AFFECT EMETIC CONTROL
It is generally more difficult to prevent and control emesis in
- women than in men, particularly among women with a history of persistent or severe emetic symptoms during pregnancy
- children and young adults than in older patients
- patients with a history of incomplete antiemetic control during earlier treatments, whether (a) acutely, (b) during the delayed phase, or (c) during both periods.
- Patients in the category (c) are at greatest risk for poor antiemetic control during subsequent treatments (6).
Decreased performance status and a predisposition to motion sickness have also been associated with poor emetic control. In contrast, patients who have chronically consumed alcoholic beverages (generally, >100 g ethanol per day for several years) are more likely to have complete emetic control than “nondrinkers,” even if the former are not using alcohol now.
For a minority of patients who receive treatment-appropriate antiemetic prophylaxis, effective emetic control is beyond the scope of evidence-based guidelines and requires a rational empiric approach. Unfortunately, empiric interventions predispose patients to a risk of overtreatment that may adversely affect their safety and unjustifiably increase treatment costs. In comparison, undertreatment is equally unsatisfactory because it places patients at risk for emesis and debilitating morbidity that may adversely affect their safety, comfort, and quality of life, and it complicates their care.
PRIMARY ANTIEMETIC PROPHYLAXIS
To prevent emetic symptoms during each emetogenic treatment, treatment-appropriate antiemetic prophylaxis should precede treatment and proceed on a fixed schedule. Unscheduled medications require patients to recognize prodromes or develop symptoms before an antiemetic is administered. It is essential that patients who receive emetogenic treatments are not left to rely on unscheduled antiemetics; however, it is also rational to provide a supply of antiemetic medications that patients can self-administer for symptoms that surmount (i.e., “breakthrough”) primary prophylaxis.
TREATMENT FOR BREAKTHROUGH SYMPTOMS
Up to 50% of patients receiving highly emetogenic therapy may experience breakthrough symptoms. Consequently, patients who receive moderately or more highly emetogenic treatment should receive a supply of medication to treat breakthrough symptoms and clear instructions about how to modify their prophylactic regimen.
Cyclic emetogenic treatments present an opportunity to evaluate a patient's suboptimal response to antiemetic prophylaxis:
- Does an unsuccessful prophylaxis strategy constitute an adequate trial?
- Can emetic control be improved with the same drugs by escalating doses or by shortening administration intervals?
Alternatively, it may be preferable to “rescue” a patient from a suboptimal response by
- adding one or more agents from a pharmacologic class that complements or potentiates drugs already in use
- replacing a drug with a more potent agent from the same pharmacologic class.
Either one or both strategies may be utilized with cyclic treatment or to intervene when response to prophylaxis is unsatisfactory. Mitigating factors to be considered in developing a treatment strategy for breakthrough symptoms include the following:
- Diminished gastrointestinal motility and impaired drug absorption from the gut around times when emetic symptoms occur
- Some patients may be too ill to swallow and retain oral medications
- Rectal suppositories are a practical alternative, but clinicians should ascertain whether a patient finds that route of administration acceptable before anticipating compliance.
- Avoid sustained-release drug products for treating acute symptoms
- Breakthrough symptoms require a rapidly acting intervention for which sustained-release drug products are ill suited.
Antiemetics in combination can be more effective than single agents. The rationale for combining antiemetic agents is to
- improve neurotransmitter blockade by targeting multiple receptor types
- decrease the adverse effects associated with (a) a patient's malignant disease (e.g., anxiety), (b) antineoplastic treatment (e.g., diarrhea), and (c) other antiemetic agents (e.g., sedation, extrapyramidal effects), which may improve their overall comfort and ability to tolerate treatment
- develop simple antiemetic strategies suitable for outpatients that decrease the duration of hospitalization and the amount of time spent in an ambulatory care setting.
Numerous studies have demonstrated that acute-phase emetic control is considerably improved when 5-HT3 receptor antagonists and glucocorticoids are combined. An NK1 receptor antagonist, aprepitant, also contributes to antiemetic activity and augments symptom control during the acute phase when it is used in combination with a 5-HT3 receptor antagonist and glucocorticoid. Delayed-phase control is improved by glucocorticoids or aprepitant or both drugs combined; however, medication use can be complicated by aprepitant, which may alter the metabolism and elimination of other drugs. In cases in which prophylaxis against delayed-phase symptoms is indicated but aprepitant may adversely interact with other medications, glucocorticoids alone or in combination with either metoclopramide or a 5-HT3antagonist and perhaps with dopamine (D2) receptor antagonists may provide adequate control.
PLANNING ANTIEMETIC PROPHYLAXIS
Planning effective antiemetic prophylaxis for chemotherapy entails evaluating each agent's emetic potential; the severity, onset, and duration of symptoms; and how drug dosage, schedule, and route of administration may affect those factors. An expert panel has developed a method for categorizing the emetic potential of drugs (see Table 40.3) and an algorithm with which one may predict the cumulative emetic potential of drug combinations (see Table 40.4) (7,8,9,10,11).
TABLE 40.3. Emetic Potential as a Function of Drug, Dosage, and Route of Administration
TABLE 40.4. Algorithm for Estimating the Emetogenic Potential of Combination Chemotherapy Regimens
The guidelines for selecting treatment-appropriate antiemetic prophylaxis described in Fig. 40.2 integrate evidence-based guidelines recommended by the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) and the consensus of experts in oncology practice (11,12,13,14).
FIG. 40.2. Algorithms for antiemetic prophylaxis and treatment. i.v., intravenous administration; PO, oral administration; PR, rectal insertion.
*Medications are not listed in order of preference. Pharmacologically similar alternatives are bounded by broken lines.
†Oral prophylaxis should begin 1 hour before commencing cytotoxic treatment. Intravenous prophylaxis may be given within minutes before emetogenic treatment.
‡Generally, regimens containing D2 receptor antagonists and metoclopramide doses ≥20 mg should include primary prophylaxis with anticholinergic agents against acute dystonic extrapyramidal reactions; e.g., diphenhydramine 25–50 mg PO or i.v. every 6 hours is often used; benztropine and trihexyphenidyl are alternatives. Parenteral administration is preferred for rapidly treating extrapyramidal symptoms.
§When administered i.v., phenothiazines should be given over 30 minutes to prevent hypotension.
||When administered i.v., dexamethasone should be given as a short infusion over 10–15 minutes to prevent uncomfortable sensations of warmth.
¶Medications identified for “breakthrough” symptoms are not alternatives to primary prophylaxis, but should be added to a patient's antiemetic regimen.
**When indicated, prophylaxis for delayed phase symptoms may begin 12–24 h after emetogenic treatment began.
In Fig. 40.2, primary prophylaxis is indicated for all patients whose treatment has a cumulative emetogenicity score equal to 2, where more than 10% of patients receiving similar chemotherapy are expected to experience emetic symptoms. The guidelines in Fig. 40.2 base prophylaxis and treatment on an assessment of emetic risk; they are generally limited in application to adult patients and may not be appropriate in all clinical situations. Decisions to follow the recommendations and to utilize particular drugs must be based on professional judgment, circumstances of the individual patient, and available resources.
Serotonin Receptor Antagonists
- All 5-HT3antagonists provide equal benefit at maximally effective dosages.
- Maximal antiemetic benefit is achieved by meeting or exceeding an “effective threshold” dose.
- Doses greater than a maximally effective dose do not substantively improve antiemetic control.
- Single-dose prophylaxis is adequate against 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.
- Repeated doses of palonosetron have not yet been studied and cannot be recommended.
- 5-HT3antagonists are more effective against acute-phase symptoms and are safer to use than other types of antiemetics.
- Dolasetron, granisetron, and ondansetron have excellent oral bioavailability and provide equivalent antiemetic protection after either oral or parenteral administration. Palonosetron is equally effective, but an oral formulation is not available.
- Among dolasetron, granisetron, and ondansetron, activity during the delayed phase is similar to less expensive alternatives such as metoclopramide. Palonosetron has the longest half-life among 5-HT3antagonists, which may be advantageous against delayed-phase symptoms.
- Profiles of adverse effects are qualitatively similar among agents and include
- transiently increased hepatic transaminase concentrations
- transient electrocardiogram (ECG) changes ± decreased cardiac rate.
- Glucocorticoids are effective as single agents against acute-phase symptoms that are of mild-to-moderate emetogenic nature (emetic potential levels ≤2)
- Active against delayed-phase symptoms.
- Parenteral and oral dexamethasone and methylprednisolone provide equivalent benefit.
- Prophylaxis and treatment are empirically based; safety and efficacy comparisons are lacking.
- Single doses are as effective as multiple-dose schedules.
- Optimal dosages and schedules are yet to be determined.
- There is no evidence that dexamethasone doses >20 mg improve antiemetic response.
- Incidence of adverse effects after single doses is
- usually very low
- limited to “activating” psychogenic effects such as insomnia and sleep disturbances, which can be minimized by administering steroids early during a patient's routine waking cycle.
- Adrenocortical suppression is generally not a problem when steroids are used for brief periods.
- Glycemic control may be problematic in patients with incipient or frank diabetes.
- Aprepitant is the first NK1receptor antagonist antiemetic that is approved for use in adult patients (aged 18 years or older).
- The approval was based on studies with emetogenic chemotherapy given on a single day.
- Product labeling indicates aprepitant use in combination with a 5-HT3receptor antagonist, and a glucocorticoid.
- Initial dose: Aprepitant 125 mg orally, 60 minutes before emetogenic chemotherapy.
- Subsequent dose: Aprepitant 80 mg per day orally for 2 days, the second and third day after chemotherapy.
- Aprepitant has been given safely for 5 days: an initial dose of 125 mg (day 1), followed by daily doses of 80 mg for 4 consecutive days (days 2–5).
- The use of aprepitant with multiple-day chemotherapy regimens and for durations exceeding five consecutive days have not yet been adequately studied.
- Utilization is complicated by aprepitant's potential for pharmacokinetic interactions with other medications.
- Aprepitant is a substrate, moderate inhibitor, and inducer of the cytochrome P-450 enzyme, CYP3A4. It is also an inducer of CYP2C9 and perhaps the CYP2D6 isoform.
- Its potential for interaction with many CYP3A4 substrate drugs is largely unknown.
- Experience with aprepitant during chemotherapy administration for a single day may not accurately represent the significance of potential interactions with chemotherapy administered for 2 or more days.
- When given concomitantly with aprepitant, dexamethasone and methylprednisolone doses should be decreased by 50% and 25% when they are administered by the oral and intravenous routes, respectively.
- Aprepitant metabolism may be perturbed by drugs that inhibit or induce CYP3A4.
- Adverse events that commonly occur in patients who receive aprepitant plus a 5-HT3receptor antagonist and a glucocorticoid:
- Abdominal pain
- Epigastric discomfort
- Metoclopramide is a D2receptor antagonist, and is a weak competitive 5-HT3 receptor antagonist at high doses.
- Its activity against delayed-phase symptoms is equivalent to that of ondansetron.
- The profile of adverse effects is similar to that of other potent D2receptor antagonists.
- Dose-related sedation
- Extrapyramidal reactions (EPRs).
- Gastrointestinal prokinetic effects may be useful for patients who have concomitant motility disorders or gastroesophageal reflux disease.
Dopamine-2 Receptor Antagonists
- Optimal dosages and schedules for dopamine-2 (D2) receptor antagonists have not been established.
- Overall, antiemetic activity varies directly with D2receptor antagonism.
- Incidence of adverse effects also correlates directly with the magnitude of the dose and the frequency of administration:
- Anticholinergic effects.
- Anecdotes and meager data support D2receptor antagonist combinations with 5-HT3 antagonists, with or without steroids, for acute-phase symptoms and with steroids, metoclopramide, or lorazepam for delayed-phase symptoms.
- Benzodiazepines are important adjuncts to antiemetics for their anxiolytic and anterograde amnestic effects.
- They are clinically useful for mitigating EPRs associated with D2receptor antagonists.
- Many clinically useful agents are available in oral formulations, injectable formulations, or both.
- Lorazepam and alprazolam tablets are rapidly absorbed after sublingual administration.
- Primary liability is dose-related sedation.
- Pharmacodynamic effects are exaggerated in elderly patients.
- Dronabinol is an oral formulation of Δ9-tetrahydrocannabinol, with activity similar to low doses of prochlorperazine.
- Regulated as controlled substances in the United States.
- Antiemetic benefit may be achieved without producing psychotropic effects.
- Utilization is empiric; optimal doses and administration schedules have not been determined.
- Dronabinol produces a greater incidence of adverse effects than phenothiazines at doses and schedules that produce comparable antiemetic effects.
- Dose-related side effects occur throughout the range of clinically useful doses.
- Profile of adverse effects includes
- recent memory impairment
- euphoria or dysphoria
- dry mouth
- orthostatic hypotension with or without an increased heart rate.
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