Radiation-Induced Nausea and Vomiting

Radiation-Induced Nausea and Vomiting

6. E.G. is a 54-year-old man with newly diagnosed head and neck cancer who will receive radiation therapy concurrently with chemotherapy containing cisplatin and fluorouracil. His daily (Monday through Friday) radiation treatments will last for 6 weeks. He has a heavy smoking history (35 pack-years) and “quit” last week, although it is not going well. After E.G.'s nausea and vomiting from the chemotherapy subsides, is he at risk for developing radiation-induced nausea and vomiting?

Radiation therapy can cause nausea and vomiting through the same basic pathways that chemotherapy does. Radiation induced nausea and vomiting (RINV) affects 40% to 80% of patients receiving radiation therapy. The risk of RINV depends on several factors, namely the size and area to be irradiated. Patients whose radiation areas >400 cm² are more likely to have significant RINV symptoms. Total body irradiation (associated with hematopoietic stem cell transplantation) causes RINV in >90% of patients. Patients receiving radiation to the upper abdominal area experience nausea and vomiting about 50% to 80% of the time. Radiation to other areas of the body is less likely to cause nausea and vomiting. E.G is not at high risk for developing RINV, because his radiation site will be in the head and neck region.

Just as with CINV, symptoms caused by radiation can be prevented with serotonin antagonists, corticosteroids, or both. Evidence- and consensus-based recommendations have been published by several multidisciplinary groups and are shown in Table 7-5. High-risk RINV is best treated with a combination of a serotonin antagonist and a corticosteroid.^65,66.67 Patients receiving radiotherapy in the moderate risk group can receive either prophylaxis or rescue therapy with a serotonin antagonist. Because E.G. is unlikely to develop radiation-induced symptoms, he does not need prophylaxis with a serotonin antagonist. If he develops symptoms later, rescue therapy with a dopamine antagonist or a serotonin antagonist should be offered.

Postoperative Nausea and Vomiting

7. E.W. is a 48-year-old woman who is scheduled for a laparoscopic cholecystectomy. The scheduled duration of her surgery is less than an hour. Her medical history includes hypertension. She does not have a history of motion sickness and she is a nonsmoker. E.W. has never had surgery before. Her sister-in-law had severe nausea and vomiting after an outpatient surgical procedure last year and E.W. is worried that it might happen to her. What is E.W.'s risk of having postoperative nausea and vomiting? What can be done to reduce her risk and how can symptoms be treated if they occur?

Table 7-5 Prophylaxis for Radiation-Induced Nausea and Vomiting

Emetic Risk Radiation Area Recommendation High (>90%) Total body irradiation Prophylaxis with a serotonin antagonist + dexamethasone Moderate (60%–90%) Upper abdomen Prophylaxis with a serotonin antagonist Low (30%–60%) Lower thorax, pelvis, cranium (radiosurgery), craniospinal region Prophylaxis or rescue with a serotonin antagonist Minimal (<30%) Head or neck, extremities, cranium, breast Rescue with a dopamine antagonist or a serotonin antagonist Adapted from references 11, 14, 16, 65, with permission.

Postoperative nausea and vomiting (PONV) is a common complication of surgery, affecting 25% to 30% of all patients, but up to 80% of patients in high risk groups. In surgical patients, PONV can lead to hospitalizations, stress on the surgical closure, hematomas, and aspiration pneumonitis. Patient-related, surgical and anesthetic factors can increase the risk of PONV.^68,69 Some of the patient risk factors include female gender, history of motion sickness, nonsmoking status, obesity, and a history of PONV. Some surgical risk factors for PONV include long duration of surgery and type of surgical procedure (e.g., laparoscopy, ear-nose-throat procedures, gynecologic surgeries, and strabismus repair). Anesthetic risk factors include the use of volatile anesthetics or nitrous oxide (as opposed to IV propofol) and the use of intraoperative or postoperative opioids. Children are twice as likely to develop PONV as adults.^68,70 The risk increases with the child's age but declines after puberty.^68,70

Certain anesthesia practices may reduce the risk of PONV. These include use of regional anesthesia (instead of general anesthesia), use of intraoperative oxygen, hydration and avoidance of nitrous oxide, and volatile anesthesia therapy.^68,69,70,72

Several risk factor models have been studied to correlate these factors into recommendations for prevention and therapy. One model is both simple and practical.^69,71 This model uses the following risk factors: female gender, history of PONV or motion sickness, nonsmoking status, surgery >60 minutes in duration, and the use of intraoperative opioids. If the patient has none or one risk factor, the risk of PONV is about 10% to 20%; no prophylaxis is necessary unless there is a medical risk for emesis. If the patient has two or more risk factors, the incidence increases to 40% to 80%; prophylaxis with one or two medications is warranted. E.W. has at least two risk factors (female, nonsmoker) and may have more if her surgery lasts longer than expected or if she receives intraoperative or postoperative opioids. She has a moderate to high risk of PONV.

Table 7-6 Medications for Prevention and Treatment of Postoperative Nausea and Vomiting (PONV)

Medication Prophylactic Dose Treatment or Rescue Dose Aprepitant Adults: 40 mg PO within 3 hrs before induction of anesthesia   Dexamethasone Adults: 4–10 mg at the start of induction of anesthesia Pediatrics: 0.15 mg/kg/dose Adults: 2–4 mg IV Dolasetron Adults: 12.5 mg IV at end of surgery Pediatrics: 0.35 mg/kg/dose Adults: 12.5 mg IV Droperidol Adults: 0.625–1.25 mg IV at end of surgery Pediatrics: 50–75 mcg/kg/dose Adults: 0.625–1.25 mg IV or IM Q 4–6 h Pediatrics: 10–30 mcg/kg/dose (max 100 mcg/kg/dose) Metoclopramide Adults: 10 mg IV at end of surgery Adults: 10–20 mg IV or IM Q 6 h Granisetron Adults: 0.35–1 mg IV at end of surgery Adults: 0.1 mg Ondansetron Adults: 4–8 mg IV at end of surgery Pediatrics: 0.05–0.1 mg/kg/dose Adults: 1 mg IV Q 8 h Pediatrics: 0.05–0.1 mg/kg/dose Prochlorperazine Adults: 5–10 mg IV at end of surgery Adults: 5–10 mg IV or IM Q 4–6 h Pediatrics: 0.13 mg/kg/dose Promethazine Adults: 12.5–25 mg IV at end of surgery Adults: 12.5–25 mg IV or IM Q 4–6 h Pediatrics (>2 yrs): 0.25–0.5 mg/kg/dose Scopolamine Adults: 1.5 mg TOP evening before or at least 4 hrs before end of surgery   IM, intramuscular; IV intravenous; PO, oral; Q, every; TOP, topical. Adapted from references 68, 69, 70, 72, with permission.

An optimal prophylactic regimen for PONV matches medication choice with the patient's risk level.^68,69,70,72 Appropriate choices for monotherapy include droperidol, a serotonin antagonist, or dexamethasone. Patients at the highest risk for PONV should be given prophylaxis with a combination of two to three antiemetics. Dual therapy choices include a serotonin antagonist plus either droperidol or dexamethasone. Triple therapy would combine a serotonin antagonist plus dexamethasone plus droperidol. Because E.W. has a moderate to high risk for PONV, a combination of a serotonin antagonist and dexamethasone would be a good choice for prophylactic therapy.

The most effective and commonly used medications for the prevention of PONV include serotonin antagonists, dexamethasone, droperidol, and combinations of these agents. No appreciable difference is found in efficacy or adverse effects between the serotonin antagonists; therefore, the costs of the different agents should be taken into consideration when selecting therapy. Droperidol has long been used for PONV, but concerns have been raised about the rare occurrence of QT prolongation and torsades de pointes.^72,73 Most clinicians believe droperidol to be a safe, especially when doses are not excessive (up to 1.25 to 2.5 mg/dose for adults and up to 75 mcg/kg/dose for children).^68,73,74 The mechanism by which dexamethasone protects against PONV is unclear, but its efficacy has been shown in many trials.^68,70,72 Combinations of medications with different mechanisms of action are more effective than monotherapy. Aprepitant, has been studied in the prevention of PONV. Two studies recently compared oral aprepitant

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40 mg or 125 mg with IV ondansetron 4 mg.^45,74 These trials showed equivalency between the two doses of aprepitant and slight superiority over ondansetron in the proportion of patients without nausea, vomiting, or the use of rescue medications. Aprepitant, however, is significantly more expensive than generic ondansetron or dexamethasone, which is a consideration. Aprepitant's role in PONV has yet to be determined. Dexamethasone and serotonin antagonist combinations have been well studied and are highly effective.^68,70,72,74 Dosages for the prophylaxis and treatment of PONV are shown in Table 7-6. 5-HT3 antagonists and droperidol seem to be more effective when given at the end of surgery. Corticosteroids are best given before the induction of anesthesia.^68,72

Several methods for nonpharmacologic techniques for the prevention of PONV have been studied and have been shown to be effective, at least in some patient populations. These include acupuncture, transcutaneous nerve stimulation, acupressure at the P6 wrist point, hypnosis, and aroma therapy with isopropyl alcohol. Ginger remedies were not found to be more effective than placebo for PONV.⁶⁸

Even with appropriate prophylaxis for PONV, some patients will experience breakthrough symptoms and require rescue therapy. Patients who have not received prophylaxis with a serotonin antagonist can be offered a low dose of a serotonin antagonist for rescue. For rescue, only about one-quarter of the prophylaxis dose is needed.⁶⁸ Serotonin antagonists have a fairly flat dose response and larger doses (ondansetron 4 to 8 mg) have not been found to be more effective for treatment of PONV than lower doses (ondansetron 1 mg).^68,74 For all patients who have breakthrough symptoms, it is important to choose an antiemetic from a different pharmacologic class than the agents used for prophylaxis.^69,72 Droperidol, promethazine, metoclopramide, and prochlorperazine are commonly used as rescue medications. If E.W. had breakthrough nausea, droperidol would be a good choice for rescue therapy

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Other Antiemetics

Other Antiemetics

Medications from other drug classes have also been used as antiemetics for CINV. These include dopamine antagonists (prochlorperazine, promethazine), benzodiazepines (lorazepam), butyrophenones (droperidol, haloperidol), benzamides (metoclopramide), and cannabinoids. Many of these agents were used widely until more effective antiemetic agents became available. These agents remain useful for breakthrough symptoms or for patients who are refractory to standard therapy. The appropriate dosages and indications for these agents are shown in Table 7-3. Many of these agents have more side effects than standard agents, especially sedation and extrapyramidal side effects, such as dystonia and akathesia. Lorazepam is commonly used as a rescue antiemetic. Its mechanism of action as an antiemetic is not completely understood, but it may involve disruption of the cortical impulses to the VC, as well as anxiolytic activity. Because each patient has an individualized response to medicines, additional options for rescue antiemetics are needed.

Olanzapine is an atypical antipsychotic agent that antagonizes several serotonin and dopamine receptors as well as other neurotransmitter receptors. Its antiemetic action was first described in patients with refractory nausea or vomiting and advanced cancer.^51,52,53 Preliminary studies have shown that olanzapine prevents acute and delayed CINV associated with moderately and highly emetogenic chemotherapy.^54,55,56,57 In these trials, the complete response rate to antiemetic regimens containing olanzapine with dexamethasone plus either granisetron or palonosetron was 100% in the acute phase and 75% to 80% in the delayed phase. The usual dose of olanzapine ranges from 2.5 to 10 mg daily for control of refractory symptoms. The dose used in the CINV studies was 5 to 10 mg daily starting up to 2 days before the chemotherapy cycle. The common side effects of olanzapine include sleepiness, dry mouth, and dizziness, although these were not significant in the preliminary reports. Olanzapine is a good choice for control of refractory CINV symptoms, but further study is warranted before it should be routinely recommended for prophylaxis of CINV.

Cannabinoids have long been used for refractory nausea and vomiting. This is based on the effect of the CNS cannabinoid receptors on the CTZ, the NTS, and the VC.⁵⁸ Small trials have shown conflicting effectiveness in the prevention of CINV.^59,60 A new oral cannabinoid, nabilone, has recently been approved for the treatment of CINV in patients who do not respond adequately to other antiemetics.⁵⁸ Cannabinoids are associated with side effects, such as drowsiness, dry mouth, dysphoria, vertigo, and euphoria. Although some patients have a clear preference for, and good response to, cannabinoids, side effects and a lack of pronounced efficacy limit their use in the general population of chemotherapy patients. These agents are usually reserved for patients who do not have adequate relief from other rescue medications, such as phenothiazines, benzodiazepines, or olanzapine.

Another agent being investigated for the control of CINV is gabapentin in doses of 300 to 900 mg daily for 5 days or more, combined with standard antiemetic regimens.^61,62 In preliminary studies, gabapentin improved control of CINV symptoms and was well tolerated. Further studies are needed to define the role of gabapentin in CINV.

5. M.C. is at high risk for acute nausea and vomiting and for delayed symptoms as well. What would be the most appropriate antiemetic regimen for M.C.?

The optimal prophylactic antiemetic regimens depend on the emetic risk of the chemotherapy regimen. Treatment guidelines have been developed by several groups, including the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and the Multinational Association of Supportive Care in Cancer (MASCC). These evidence- and consensus-based guidelines, which are largely in agreement with their recommendations, are summarized in Table 7-4.

For multiday chemotherapy regimens, prophylaxis with a serotonin antagonist and dexamethasone should be offered for each day that moderately or highly emetogenic chemotherapy is administered.^11,14,16 Aprepitant might be useful in these situations, although it has not been studied in this context. Preliminary studies indicated that aprepitant was safe to administer for a total of 5 days. If multiday chemotherapy regimens have a high risk of delayed symptoms, then therapy for the delayed symptoms should be continued for at least 2 to 3 days after the last chemotherapy administration.

For M.C., the best regimen would include a single dose of a serotonin antagonist plus dexamethasone 12 mg oral or IV plus oral aprepitant 125 mg on day 1, then oral dexamethasone 8 mg on days 2 through 4 and oral aprepitant 80 mg on days 2 and 3. She should be offered medications for breakthrough CINV symptoms, such as prochlorperazine and lorazepam. She should be warned of the potential adverse effects of dexamethasone, especially hyperglycemia, and counseled to check her blood sugars more frequently and contact her physician if they remain elevated. M.C. should be advised to maintain a record of her symptoms and contact her physician if the breakthrough medications are not working or if she cannot keep fluids down.

Modern antiemetic regimens can achieve complete emetic control in about 70% to 90% of patients, but the response rate is lower for delayed CINV symptoms. If CINV symptoms are not adequately controlled, alterations in the antiemetic regimen should be made for the next cycle. Suggestions include

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upgrading to the next higher emetogenicity level recommendation, adding aprepitant if not already given, and scheduling agents from other pharmacologic classes.

Table 7-4 Recommended Antiemetic Regimens by Emetogenicity of Chemotherapy Regimen

Emetogenicity Potential Acute Phase (doses should be given 30–60 min before chemotherapy) Delayed Phase Breakthrough High (>90% of patients) Day 1: single dose 5-HT3 antagonist + dexamethasone + aprepitant Dexamethasone days 2–4 + aprepitant days 2–3 One to two agents for PRN use Moderate (30%–90% of patients) with high risk of delayed CINV (i.e., cyclophosphamide plus doxorubicin) Day 1: single dose 5-HT3 antagonist + dexamethasone + aprepitant Dexamethasone days 2–4 + aprepitant days 2–3 One to two agents for PRN use Other moderate regimens (30%–90% of patients) Day 1: single dose 5-HT3 antagonist + dexamethasone None One agent for PRN use Low (10%–30% of patients) Single dose dexamethasone or metoclopramide or prochlorperazine None Either none or one agent for PRN use Minimal (<10%) None None Usually none 5-HT3, 5 hydroxytryptamine type 3; CINV, chemotherapy-induced nausea and vomiting; PRN, as needed. Adapted from references 11, 14, 16, with permission.

Many patients may benefit from nondrug therapy for CINV symptoms, especially for anticipatory nausea and vomiting and anxiety. Techniques include guided imagery, hypnosis, relaxation techniques, systematic desensitization, and music therapy.⁶³ Acupuncture and acupressure techniques have been investigated for use in CINV and some patients benefit from their use. The use of acupressure devices that stimulate the P6 point on the wrist have been proposed; however, in a controlled trial in patients with breast cancer, it was not found to be helpful.⁶⁴ If patients are troubled by CINV symptoms, it is recommended that they refrain from heavy meals for 8 to 12 hours before the chemotherapy. They should also avoid heavy, greasy foods and food with strong aromas. Chewing gum can mask the metallic taste, which some patients perceive. Dry, salty foods can also help settle the stomach.

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Neurokinin-1 Receptor Antagonists

Neurokinin-1 Receptor Antagonists

The potential use of NK-1 receptor antagonists as antiemetics became apparent when the role of substance P in the peripheral and CNS was recognized in the emetic stimulus pathway. Aprepitant, the first NK-1 receptor antagonist available, has been studied for the prevention of CINV caused by moderately and highly emetogenic chemotherapy. Aprepitant is usually given as a 3-day oral regimen 125 mg on day 1 and 80 mg on days 2 and 3. Early trials determined that aprepitant could not replace a serotonin antagonist, but that it would be used best in conjunction with corticosteroids and a serotonin antagonist.

Aprepitant was studied in two phase III trials for the prevention of CINV with highly emetogenic cisplatin-based chemotherapy.^35,36 In both of these trials, aprepitant (or placebo) was added to a standard antiemetic regimen of ondansetron on day 1 and dexamethasone on days 1 through 4. The patients treated with aprepitant showed improved complete response rates (no emesis, and no use of rescue medications) by about 20%, in both the acute and delayed phases. In a recent reanalysis,³⁷ investigators found that the aprepitant-containing regimens were more effective in women than in men, which is fortunate because women have more acute and delayed symptoms than men.

Aprepitant was also studied in the prevention of CINV caused by moderately emetogenic chemotherapy.³⁸ Patients in the treatment arm were given aprepitant, ondansetron, and dexamethasone on day 1 plus aprepitant on days 2 and 3. The patients in the control arm were given ondansetron and dexamethasone on day 1, plus ondansetron on days 2 and 3. The rate of complete response (no emesis and no use of rescue medications) was higher in the aprepitant arm in both the acute and delayed phases. Dexamethasone, however, is one of the most effective agents for delayed CINV symptoms and it was not used in either arm for the delayed phase. In essence, aprepitant was not compared with the standard of care for the delayed phase. The results may not have been significant if a proper comparator had been used.

The effects of aprepitant seem to be maintained over four cycles of chemotherapy in patients receiving moderately emetogenic chemotherapy.³⁹ The addition of aprepitant to the antiemetic regimen on cycle 2 (even when it was omitted from cycle 1) also seems to improve control of CINV symptoms.^40,41 For patients who have had inadequate response to an antiemetic regimen that did not include aprepitant, it may be useful to add it in later cycles.

The efficacy of aprepitant for the control of delayed CINV symptoms was confirmed in a trial that included 489 patients comparing a standard aprepitant regimen (aprepitant, ondansetron, and dexamethasone on day 1, followed by aprepitant and dexamethasone on days 2 and 3, and dexamethasone on day 4) to a nonaprepitant regimen (ondansetron and dexamethasone on days 1 through 4) in patients receiving highly emetogenic chemotherapy.⁴² The aprepitant-containing regimen offered superior control of CINV in the acute, delayed, and overall time periods. The study confirmed that aprepitant is a better choice than a serotonin antagonist during the delayed phase of CINV.

Aprepitant is generally well tolerated with mild side effects, including fatigue, hiccups, headache, and diarrhea.^35,36,38,42 The overall adverse effects in standard aprepitant-containing regimens are not appreciably different from regimens without aprepitant.^{35,36,37,38,42} A potential disadvantage of aprepitant is the unavailability of an IV formulation.

Aprepitant is metabolized by the CYP3A4 enzyme system. It is a moderate inhibitor and inducer of CYP3A4, and an inducer of CYP2C9.^11,43,44,45 Consequently, several drugs potentially interact with aprepitant. The most commonly encountered interaction is with the corticosteroids. Aprepitant increases the area under the curve of dexamethasone such that the dexamethasone dose (when used as an antiemetic) should be reduced by about one-half of the usual dose when these drugs are used together.⁴⁶ The effect is greatest when the corticosteroid is administered orally.^{11,43,44,45,46,47} When the corticosteroid is also given as part of the antitumor regimen, however, the dose should not be reduced because of concern that the antineoplastic activity might be compromised.¹⁴ Aprepitant may also enhance warfarin metabolism by inducing CYP2C9. International normalized ratio (INR) values in patients treated

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with warfarin and the standard aprepitant regimen are significantly reduced, especially on day 8 of the chemotherapy cycle.⁴⁸ The patient's coagulation status after aprepitant administration should be monitored, especially during the 7- to 10-day time period. The dosage of warfarin should be adjusted if the INR is high or low. Several chemotherapy agents (paclitaxel, etoposide, paclitaxel, ifosfamide, irinotecan, imatinib, vinca alkaloids, and others) are metabolized by the CYP3A4 enzyme system and the metabolism of these agents may be altered by aprepitant. Aprepitant was used in clinical trials with some of these agents. Caution is warranted, however, because the clinical relevance of this effect is not known.¹⁸ Other drugs that may interact with aprepitant include oral contraceptives, itraconazole, terfenadine, and phenytoin.^43,44,47

A new investigational NK-1 receptor antagonist, casopitant, has been studied for the prevention of CINV symptoms in patients receiving moderately and highly emetogenic chemotherapy in preliminary phase II/III trials using doses of 50 to 150 mg daily.^49,50 The initial results suggest that further trials with this agent are warranted

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Corticosteroids

Corticosteroids

The mechanism of action of corticosteroids as antiemetics has not been fully determined. Some suggest that corticosteroids may decrease serotonin release, antagonize serotonin receptors, or activate corticosteroid receptors in the NTS of the medulla in the CNS.²⁰ Many studies validate the effectiveness of corticosteroids in the prophylaxis of CINV symptoms. Efficacy with both dexamethasone and methylprednisolone has been described, but dexamethasone is much more widely studied and utilized. Dexamethasone improves the antiemetic control of serotonin antagonists by about 15% to 20%.^20,21 In addition, dexamethasone is one of the cornerstone agents used to prevent delayed CINV. It is inexpensive and available in both IV and oral formulations.

The optimal dose of dexamethasone with different emetic stimuli has been studied in two controlled trials. For moderately emetogenic chemotherapy in the acute phase, a single 8-mg dose was as effective as larger doses or prolonged administration.³³ In the setting of highly emetogenic cisplatin-based chemotherapy, higher doses of 12 or 20 mg were superior to doses of 4 and 8 mg.³⁴ If used with aprepitant, the lower 12-mg prechemotherapy dose is recommended because of inhibition of steroid metabolism by aprepitant (see the neurokinin-1 receptor antagonist section).¹⁴ For prevention of delayed CINV symptoms, the most commonly used dose of dexamethasone is 8 mg twice daily on days 2 and 3 after chemotherapy without aprepitant. The dose should be reduced to 8 mg daily when used with aprepitant.

Corticosteroids are sometimes underutilized because of the potential risk of side effects. The adverse effects of corticosteroids include insomnia, jitteriness, increased appetite, GI distress, and perineal irritation if the IV dose is infused too quickly.²⁰ For most patients, however, dexamethasone is well tolerated, especially because the therapy is typically short term at lower doses. Hyperglycemia can occur, especially in patients with pre-existing diabetes. These patients should be advised to monitor their glucose levels more frequently and contact their practitioner if the levels remain elevated. In the nondiabetic patient, hyperglycemia is rare. Tapering the corticosteroid dose after the end of treatment for CINV is usually unnecessary because the duration of therapy is short. Rare patients who have withdrawal-like symptoms may, however, benefit from a short taper.

Corticosteroids also have antitumor properties and are a part of the antineoplastic regimen for some malignancies, such as lymphoma, lymphoid leukemia, and myeloma. In these cases, no need is seen to administer additional dexamethasone for the antiemetic protection; however, the corticosteroid should be administered before the rest of the chemotherapy to provide antiemetic activity. If aprepitant is part of an antiemetic regimen in a situation where the corticosteroid is given for antitumor reasons, the dose of the corticosteroid should not be reduced.¹⁴

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5-HT3 Antagonists

5-HT3 Antagonists

The 5-HT3 antagonists inhibit the action of serotonin in the GI tract and the CNS and thereby block the transmission of emetic signals to the VC. Serotonin antagonists are both highly effective and have minimal side effects. Several agents in this class are now available: ondansetron, granisetron, dolasetron, and palonosetron. Dosages of these agents are shown in Table 7-3. These agents have been widely studied and some 

commonalities have emerged. All of these agents have a threshold effect and so a sufficiently large dose must be given to block the relevant receptors. The dose-response curve is relatively flat, such that escalating doses do not enhance efficacy. When given in appropriate doses, all of these agents have similar efficacy for acute CINV, with response rates ranging from about 60% to 80%, depending on study design.^{11,14,17,18,19} The effectiveness of each of these agents is enhanced by the addition of dexamethasone. The response rate increases by about 15% to 20% in regimens that include dexamethasone and a 5-HT3 antagonist.^20,21 Oral and IV 5-HT3 administration are equally effective assuming the patient can take oral medications. The side effects of the 5-HT3 antagonists are similar and fairly mild and include headache, constipation, diarrhea, and transient elevations of liver function tests. These agents are one component of optimal antiemetic prophylaxis for acute CINV, but are not more effective than agents from other classes (notably dexamethasone, aprepitant, or prochlorperazine) for delayed CINV.^22,23,24,25 Serotonin antagonists, therefore, are not recommended for delayed CINV.

Palonosetron, the newest member of the serotonin antagonist family, is distinguished by its longer elimination half-life than others in its class. Palonosetron was compared with single doses of ondansetron or dolasetron in two trials of moderately emetogenic chemotherapy and in one trial of highly emetogenic chemotherapy.^26,27,28 In each of these trials, palonosetron resulted in the same or higher complete response rate (no emesis and no use of rescue medication in the acute or delayed phase) than that of the comparator agents, but methodologic concerns limit the conclusions. In two of these trials, corticosteroid administration was allowed, but not required, although dexamethasone is recommended for prophylaxis for moderately and highly emetogenic chemotherapy. Prophylaxis with dexamethasone for delayed symptoms was not included. These trials essentially compared palonosetron with placebo for the delayed phase, because the comparator was not continued for the 3 days. Palonosetron has not been compared with other serotonin antagonists where dexamethasone dosing was included for both the acute and delayed phase.¹⁴ In addition, it has not been compared with regimens containing other 5-HT3 antagonists (in the delayed setting), dexamethasone, and aprepitant. One group of researchers described a three-drug combination of palonosetron, dexamethasone, and aprepitant in a noncomparative, phase II study, and found that the three-drug combination was safe and effective.²⁹ Whether palonosetron is equivalent or superior to other 5-HT3 antagonists will be determined by trials that compare palonosetron with a 5-HT3 antagonist, with both treatment arms consisting of dexamethasone and aprepitant in the acute and delayed phases.

Table 7-3 Antiemetic Agents for Chemotherapy-Induced Nausea and Vomiting (CINV)

Medication (Trade name) Class Indication/Phase Dose in Adults (doses should be given 30–60 minutes before chemotherapy) Dose in Pediatrics Aprepitant (Emend) NK-1 antagonist Acute/Delayed 125 mg PO on day 1, 80 mg PO on days 2,3 Dexamethasone (Decadron) Corticosteroid Acute (high emetogenicity) 12 mg (if with aprepitant) or 20 mg IV or PO Acute (moderate emetogenicity) 8 mg IV or PO Acute (low emetogenicity) 4–8 mg IV or PO Delayed 8 mg PO daily days 2–4 (when with aprepitant) Dolasetron Serotonin antagonist Acute IV: 100 mg or 1.8 mg/kg PO: 100–200 mg 1.8 mg/kg IV or PO Dronabinol (Marinol) Cannabinoid Breakthrough 2.5–10 mg PO TID to QID Droperidol (Inapsine) Butyrophenone Breakthrough 0.625–1.25 mg IV Q 4–6 h PRN 50–60 mcg/kg/dose Granisetron (Kytril) Serotonin antagonist Acute IV:1 mg or 0.01 mg/kg PO: 2 mg 0.01 mg/kg/dose Haloperidol (Haldol) Butyrophenone Breakthrough 0.5–1 mg PO, IV, or IM Q 6 h PRN Metoclopramide (Reglan) Dopamine antagonist Breakthrough 10–20 mg PO or IV Q 6 h PRN 0.1 mg/kg/dose Lorazepam (Ativan) Benzodiazepine Breakthrough 0.5–2 mg PO, IV, IM, or SL Q 6 h PRN 0.05 mg/kg/dose Nabilone (Cesamet) Cannabinoid Refractory CINV 1–2 mg PO BID (max 2 mg PO TID) Olanzapine (Zyprexa) Serotonin/dopamine antagonist Acute/delayed/breakthrough 2.5–10 mg PO QHS Ondansetron (Zofran) Serotonin antagonist Acute (moderate or high emetogenicity) IV: 8–12 mg or 0.15 mg/kg PO: 16–24 mg PO 0.15 mg/kg Q 4 h ×3 doses or 0.45 mg/kg single dose Palonosetron (Aloxi) Serotonin antagonist Acute/delayed IV: 0.25 mg Prochlorperazine (Compazine) Dopamine antagonist Breakthrough 5–10 mg (up to 20 mg) PO, IV, IM Q 4–6 h PRN >2 yo: 0.1–0.15 mg/kg/dose Promethazine Dopamine antagonist Breakthrough 12.5–25 mg PO, IV, IM, PR Q 4–6 h PRN >2 yo: 0.25–1 mg/kg/dose BID, twice daily; IM, intramuscular; IV, intravenous; PO, oral; PR, rectal; PRN, as needed; QHS, every night; QID, four times daily; TID, three times daily. Adapted from references 11, 14, 16, with permission.

Palonosetron is normally administered as a single 0.25 mg IV dose before chemotherapy. Repeated dosing within 1 week is not approved by the U.S. Food and Drug Administration (FDA). With its long elimination half-life, palonosetron should be effective for at least a few days, but little data are published regarding repeated doses. Palonosetron has been studied in a three-dose regimen (administration on days 1, 3, 5) for multiday chemotherapy in a noncontrolled trial published only in abstract form.³⁰ This regimen appeared to be safe and effective, but was not compared with any other regimen.

Other serotonin antagonists, including tropisetron, ramosetron, lerisetron, and others,^31,32 are under development and study.

It is difficult to identify the serotonin antagonist with the highest overall cost-effectiveness because drug acquisition costs vary between the inpatient and outpatient clinics and from institution to institution. Costs of the different agents should be compared at each practice site to determine the preferred agent.

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Chemotherapy-Induced Nausea and Vomiting

Chemotherapy-Induced Nausea and Vomiting

3. M.C., a 54-year-old woman with breast cancer, is in the clinic today to receive her first cycle of “AC” (doxorubicin and cyclophosphamide) chemotherapy. She will receive paclitaxel and trastuzumab after the completion of the AC. Her chemotherapy doses will be intravenous (IV) doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² IV for one dose on day 1 of each cycle. This will be repeated every 21 days for four cycles. M.C. does not drink alcohol or smoke. Her only other medical condition is adult onset diabetes, which is controlled with metformin and diet. She has had four children, now all grown, and had substantial morning sickness with each of her pregnancies. M.C.'s neighbor has told her that all chemotherapy causes severe nausea and vomiting. How likely is M.C. to experience nausea and vomiting?

Chemotherapy-induced nausea and vomiting (CINV) occurs in many patients receiving chemotherapy for cancer. The mechanisms of the emetic response described at the beginning of this chapter apply to CINV as well. The major neurotransmitter receptors involved in these pathways include serotonin, NK-1 and dopamine receptors. CINV can occur in different patterns. Acute phase CINV symptoms occur within a few hours after the administration of the chemotherapy. These symptoms often peak several hours after administration and can last for

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the first 24 hours. Some antineoplastic agents can also cause nausea and vomiting symptoms for a longer period of time after chemotherapy administration. Delayed CINV symptoms peak in about 2 to 3 days and can last 6 to 7 days. Some patients who have received previous chemotherapy treatments may experience a conditioned response in which they have symptoms even before the chemotherapy starts. This is called anticipatory nausea and vomiting and it is difficult to treat because it is primarily triggered by poor nausea and vomiting control in previous cycles. Breakthrough nausea and vomiting occur if the primary prophylactic antiemetics fail to work completely. Of course, regardless of the time course and cause, these are very distressing, unpleasant, and disruptive symptoms for the patient.

Table 7-1 Medications for Prevention or Treatment of Motion Sickness in Adults

Medication (Trade name) Dosage Recommended Use Adverse Effects Scopolamine (Transderm-Scop) 1.5 mg TOP behind the ear Q 3 days. Apply at least 3 hrs (preferably 6–8 hrs) before exposure Long term exposure (>6 hrs) of moderate-intense stimulus. Alternative treatment for shorter or milder stimulus. Dry mouth, drowsiness, blurred vision, confusion, fatigue, ataxia Dimenhydrinate (Dramamine) 50–100 mg PO Q 4–6 h (max 400 mg/day). May be taken PRN or on scheduled basis if required. Short- or long-term exposure to mild to moderate stimulus. Alternative for other situations. Drowsiness, dry mouth, thickening of secretions, dizziness Promethazine (Phenergan) 25 mg PO Q 4–6 h. May be taken PRN or on scheduled basis if required. 25–50 mg IM Q 4–6 h for established severe symptoms. May be taken PRN or on scheduled basis if required. In combination with dextroamphetamine for short exposure of intense stimulus. Alternative for other situations. Drowsiness, orthostatic hypotension, dry mouth Meclizine (Antivert, Bonine) 12.5–50 mg PO Q 6–24 h. May be taken PRN or on scheduled basis if required. Alternative for mild stimulus or in combination for moderate to severe stimulus Drowsiness, dry mouth, thickening of secretions, dizziness Dextroamphetamine (Dexedrine) 5–10 mg PO Q 4–6 h. May be taken PRN or on scheduled basis if required. In combination with promethazine for short exposure of intense stimulus. Restlessness, abuse potential, insomnia, overstimulation, tachycardia, palpitations, hypertension Cyclizine (Marezine) 50 mg PO Q 4–6 h (max 200 mg/day). May be taken PRN or on scheduled basis if required. Alternative for mild stimulus situations. Drowsiness, dry mouth, IM, intramusculare; PO, oral; PRN, as needed; Q, every; TOP, topically. Adapted from reference 2, with permission.

Table 7-2 Emetogenicity of Selected Antineoplastic Agents

High Emetogenicity (>90% of patients developing nausea or vomiting [N/V]) Antineoplastic Altretamine (PO) Cisplatin (IV) (≥50 mg/m2) Cyclophosphamide (IV) (≥1,500 mg/m2) Dacarbazine (IV) Dactinomycin (IV) Mechorethamine (IV) Procarbazine (PO) Combination of doxorubicin/cyclophosphamide or epirubicin/cyclophosphamide (IV) Moderate Emetogenicity (30% to 90% of patients developing N/V) Aldesleukin (IV) (>12–15 million units) Amifostine (IV) Arsenic Trioxide (IV) Carboplatin (IV) Cisplatin (IV) (<50 mg/m2) Cyclophosphamide (PO) Cyclophosphamide (IV) (<1,500 mg/m2) Cytarabine (IV) (>1g/m2) Daunorubicin (IV) Doxorubicin (IV) Epirubicin (IV) Etoposide (PO) Idarubicin (IV) Ifosfamide (IV) Imantinib (PO) Irinotecan (IV) Methotrexate (IV) (250 mg to >1 g/m2) Oxaliplatin (IV) Temozolamide (PO) Low Emetogenicity (10% to 30% of patients developing N/V) Antineoplastic Bortezomib (IV) Capecitabine (PO) Cetuximab (IV) Cytarabine (IV) (100–200 mg/m2) Docetaxel (IV) Etoposide (IV) Fluorouracil (IV) Gemcitabine (IV) Lapatinib (PO) Mitoxantrone (IV) Methotrexate (IV) (<1g/m2) Paclitaxel (IV) Panitumumab (IV) Pemetrexed (IV) Topotecan (IV) Trastuzumab (IV) Vorinostat (IV) Minimal Emetogenicity (<10% of patients developing N/V) Bevacizumab (IV) Bleomycin (IV) Chlorambucil (PO) Dasatinib (PO) Decitabine (IV) Erlotinib (PO) Fludarabine (IV) Gefitinib (PO) Gemtuzumab ozogamicin (IV) Hydroxyurea (PO) Lenalidomide (PO) Methotrexate (PO) Nelarabine (IV) Rituximab (IV) Sorafenib (PO) Sunitinib (PO) Thalidomide (PO) Thioguanine (PO) Vinblastine (IV) Vincristine (IV) Vinorelbine (IV) Adapted from references 11, 13, 14, with permission.

The likelihood of CINV depends on several factors.¹¹ Patient-related factors that increase the risk of acute-phase CINV include age <50 years, female gender, poor control of symptoms in prior cycles, history of motion sickness or nausea with pregnancy, anxiety, or depression. A significant history of alcoholism actually protects against CINV. Delayed symptoms are more common in women and in those who have had poor emetic control in the acute phase.

Recently, a new predictive model has been developed to identify patients at highest risk for serious CINV symptoms.¹² The predictive factors most associated with acute CINV symptoms included age, disease site and stage, comorbid conditions, chemotherapy agent (Table 7-2), absence of alcohol abuse, increasing number of chemotherapy cycles, and nonprescription

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drug use. The factors associated with increased delayed CINV included age, type of antiemetics used, prior nausea and vomiting, including that with pregnancy, increasing number of chemotherapy cycles, previous acute CINV, and nonprescription drug use.

Chemotherapy-related factors also predict the likelihood of symptoms. Factors, such as shorter infusion time, higher dose, and more chemotherapy cycles, increase the risk of CINV. With multiday chemotherapy regimens, the symptoms usually peak on about the third to fourth day of chemotherapy, when the acute symptoms caused by the later days' doses are overlapping with the delayed symptoms from the first days' doses. The most predictive factor, however, is the chemotherapy agent's inherent ability to cause CINV, or its emetogenicity.^11,12,13,14 Antineoplastics that are most likely (>90% of patients) to cause symptoms are classified as highly emetogenic chemotherapy. Agents that cause nausea and vomiting in 30% to 90% of patients are classified as moderate-risk agents. Low emetogenicity agents cause symptoms in 10% to 30% of patients. Other chemotherapy agents have a minimal risk, causing CINV in <10% of patients. Table 7-2 lists selected chemotherapy agents in the various emetogenicity classes. References differ in the estimation of emetic risk for some antineoplastic agents. Note, for some agents, that the emetogenicity depends on the dosage used.

Certain antineoplastic agents are more likely to cause delayed CINV symptoms. These include cisplatin, carboplatin, cyclophosphamide, doxorubicin, epirubicin, and ifosfamide. Patients receiving more than one of these agents are at high risk for delayed symptoms.

Most chemotherapy agents are given in combinations, rather than as single agents. Estimating the emetogeniticity of chemotherapy combinations has always been difficult. One method¹⁵ using a mathematical formula for estimating the total effect, is based on a five-level classification of emetogenicity. No method has been prospectively evaluated or unanimously accepted, however. Chemotherapy regimens that contain cyclophosphamide and an anthracycline, such as doxorubicin, are highly emetogenic (symptoms in >90% of patients.) The primary literature should be examined for the incidence of nausea and vomiting for established chemotherapy combination regimens. In the absence of specific information regarding the risk of CINV in certain combinations, the antiemetic regimen should be geared toward the chemotherapy agent with the highest emetogenicity level given on that day.^11,14,16 For example, for a chemotherapy combination with one agent with a high risk and one with a moderate risk, the antiemetic regimen should be appropriate for the high-risk chemotherapy agent.

Antiemetic efficacy, or complete emetic response, is usually defined as no emesis and no nausea or only mild nausea in the first 24 hours after chemotherapy administration. With currently recommended antiemetic regimens, most but not all patients will be protected from emesis in the acute phase (first 24 hours). Nausea, however, is more difficult to control. In addition, delayed CINV symptoms are more difficult to prevent.

4. Our patient, M.C., is at high risk for acute CINV. Her personal risk factors include female gender, history of morning sickness with pregnancy, and being a nondrinker. The chemotherapy regimen she will receive (cyclophosphamide and doxorubicin) is highly emetogenic in the acute phase and also has a high risk of delayed symptoms. What antiemetics are available for M.C.?

Appropriate antiemetic therapy is based on the emetogenicity of the chemotherapy regimen and patient risk factors. Because the pathophysiologic response of nausea and vomiting involves many neurotransmitters, combinations of antiemetics from different therapeutic classes will be more effective in most situations than a single agent. The predominant classes of antiemetics used for CINV include serotonin (5HT3) antagonists, the neurokinin-1 antagonist and corticosteroids.

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Pharmacotherapy of Emesis

Pharmacotherapy of Emesis

The initial evaluation of the patient with nausea and vomiting should include the onset of symptoms; the severity and duration of symptoms; hydration status; precipitating factors; current medical conditions and medications; and food and infectious contacts. The etiology of the nausea and vomiting should be determined, if possible, so that underlying conditions can be treated specifically. Supportive treatment should be initiated, if needed, including fluid and electrolyte replacement. If the nausea and vomiting is mild and self-limited, antiemetic therapy may not be required. For others, however, the appropriate antiemetic therapy will depend on the patient and the etiology of the nausea and vomiting.

Motion Sickness

1. P.C. is a 27-year-old woman who has no significant medical history, with the exception of moderate dysmenorrhea and motion sickness associated with travel by air. Previously, she has taken dimenhydrinate before airplane trips with moderate success. She is engaged to be married, and she and her fiancé have decided on a week-long Caribbean cruise for their honeymoon. P.C. is concerned that she may also develop sea sickness and that dimenhydrinate may not control her symptoms, particularly in the event of rough weather at sea. Will P.C. be at higher risk for motion sickness?

The symptoms of motion sickness occur in response to an unusual perception of real or apparent motion. In these situations, there is sensory conflict about body position or motion through the visual, vestibular, or body proprioceptors. Acetylcholine is thought to be the primary neurotransmitter involved in signaling the VC, as is histamine, to a lesser extent. Adrenergic stimulation can block this transmission. Symptoms begin with stomach discomfort and progress to salivation changes, sweating, dizziness, lethargy, retching, and emesis. The risk of motion sickness is low in children <2 years of age. The risk is highest in children and adolescents, and higher in females than males. In some individuals, sensitivity to motion sickness diminishes over time. Travel by boat is most likely to cause symptoms; air, car, and train travel is less likely.^1,2 Because of P.C.'s history and her travel plans, she is at high risk for recurrence of her motion sickness symptoms.

Nonpharmacologic measures or natural remedies may be useful for reducing motion sickness. These include riding in the middle of the boat or plane where the motion is less dramatic; lying in a semirecumbent position; fixing the vision on the horizon; avoiding reading; and closing the eyes if below deck or in the cabin. Many people recommend keeping active on a ship to “get their sea-legs” faster through habituation. The effectiveness of acupressure at the P6 point of the wrist (about three fingerbreadths above the wrist) is unclear. A controlled-stimulus trial compared two brands of wristbands with placebo; neither band was more effective than placebo in preventing symptoms of motion sickness.³ Studies of ginger preparations also are equivocal. The action of ginger may be of promotion of gastric emptying and not on the vestibular system.^4,5

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2. For P.C., what medications are available to prevent and treat motion sickness symptoms?

Anticholinergic agents and antihistamines that cross the blood–brain barrier effectively prevent and treat motion sickness.^1,2 In general, these medications are more effective in preventing than treating established symptoms. 5-hydoxytryptamine 3 (5-HT3) receptor antagonists and neurokinin-1 (NK-1) receptor antagonists have not been shown to be effective in preventing motion sickness^6,7 and are very costly. Nonsedating antihistamines are not as effective as other antihistamines because they do not sufficiently cross the blood–brain barrier.¹ Scopolamine has been well studied for the prevention of motion sickness and is highly effective.⁸ In a controlled trial, scopolamine was more effective than promethazine and both were more effective than placebo, meclizine, or lorazepam.⁹ Scopolamine is available as a topical patch, which bypasses the problem of GI symptoms associated with motion sickness. Scopolamine is less likely than dimenhydrinate to effect psychomotor performance.¹⁰ Table 7-1 describes medications effective for motion sickness, including the recommended use and the adult doses. The severity of the stimulus is highly dependent on the individual and also varies with the weather and with position in the plane or boat.

Because P.C. is a susceptible individual in a moderate-severe stimulus situation, prevention with a scopolamine patch applied behind the ear every 3 days, starting 6 to 8 hours before departure should be recommended. If she experiences breakthrough symptoms, dimenhydrinate or promethazine can be recommended as well. She should be advised about the potential adverse effects of these agents, which include drowsiness, confusion, and dry mouth.

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Nausea and Vomiting

Nausea and Vomiting

Lisa Lohr

Nausea and vomiting are unpleasant symptoms caused by self-limiting disorders or serious conditions such as cancer. These symptoms can range from mild, short-lived nausea to continuing severe emesis and retching. In addition to the suffering involved, uncontrolled vomiting can lead to dehydration, electrolyte imbalances, malnutrition, aspiration pneumonia, and esophageal tears. Nausea and vomiting often reduce food intake and can impair a person's ability to care for themselves. Significant reductions in quality-of-life scores have been demonstrated in cancer patients with chemotherapy-induced nausea and vomiting compared with patients who did not have those symptoms. Clinicians can improve the care of patients by recommending appropriate preventive medications in situations where nausea and vomiting can be predicted (e.g., postoperative, chemotherapy-induced and radiation-induced symptoms). In addition, by assuring appropriate use of rescue antiemetics, clinicians can help reduce existing symptoms.

Pathophysiology and Neurotransmitters

The neurophysiology of the emetic response is complex, with multiple organs and neurotransmitters involved. The emetic response can be described in three phases: nausea, vomiting, and retching. Nausea is the subjective feeling of the need to vomit. It includes an unpleasant sensation in the mouth and stomach and can be associated with salivation, sweating, dizziness, and tachycardia. Vomiting is the forceful expulsion of the stomach contents through the mouth, but is preceded by the relaxation of the esophageal sphincter, contraction of the abdominal muscles, and temporary suspension of breathing. Retching is the rhythmic contraction of the abdominal muscles without actual emesis. It can accompany nausea, or occur before or after emesis.

Nausea and vomiting are caused by many disorders. Central nervous system (CNS) causes include increased intracranial pressure, migraine, brain metastases, vestibular dysfunction, alcohol intoxication, and anxiety. Infectious disease causes include viral gastroenteritis, food poisoning, peritonitis, meningitis, and urinary tract infections. Metabolic causes include hypercalcemia, uremia, hyperglycemia, and hyponatremia. Gastrointestinal disorders, such as gastroparesis, bowel obstruction, distention, and mechanical irritation, can cause nausea and vomiting. Among the many medications that can cause nausea and vomiting are cancer chemotherapy, antibiotics, antifungals, and opiate analgesics.

The CNS, the peripheral nervous system, and the gastrointestinal (GI) tract are all involved in initiating and coordinating the emetic response. In the CNS, the vomiting center (VC) receives incoming signals from other parts of the brain and the GI tract and then coordinates the emetic response by sending signals to the effector organs. The VC is located in the medulla oblongata of the brain, near the nucleus tractus solitarius (NTS). The VC is stimulated by neurotransmitters released from the chemoreceptor trigger zone (CTZ), the GI tract, the cerebral cortex, the limbic system, and the vestibular system (Fig. 7-1). The major neurotransmitter receptors associated with the emetic response include serotonin (the 5-hydroxytryptamine type 3) receptors, neurokinin-1 receptors, and dopamine receptors. Other receptors involved include corticosteroid, acetylcholine, histamine, cannabinoid, gabaminergic, and opiate receptors. Many of these receptors are targets for antiemetic therapy.

In the CNS, the CTZ is located in the area postrema on the floor of the fourth ventricle in the brainstem; it lies outside the blood–brain barrier. When the CTZ senses toxins and noxious substances in the blood and cerebrospinal fluid, it triggers the emetic response by releasing neurotransmitters that travel to the VC and the NTS. The major neurotransmitter receptors involved in this pathway include serotonin, dopamine, and neurokinin-1.

The GI system also plays a large part in the initiation of the emetic response. The GI tract contains enterochromaffin cells in the GI mucosa. When these cells are damaged by chemotherapy, radiation, or mechanical irritation, serotonin is released, which can stimulate the vagal afferents as well as directly stimulate the VC and NTS. The vomiting center then propagates the emetic response.

The cerebral cortex and limbic system can stimulate the emetic center in response to emotional states such as anxiety, pain, and conditioned responses (anticipatory nausea and vomiting). The neurotransmitters involved in this pathway are less well understood. Disorders of the vestibular system, such as vertigo and motion sickness, stimulate the VC through acetylcholine and histamine release.

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