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.

CASE 6-2, QUESTION 3: M.C. is at moderate risk for acute

nausea and vomiting and at high risk for delayed CINV

symptoms, as a result of her chemotherapy regimen of

docetaxel, carboplatin, and trastuzumab. 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

107Nausea and Vomiting Chapter 6

TABLE 6-4

Recommended Antiemetic Regimens for Chemotherapy-Induced Nausea and Vomiting (CINV) by Emetogenicity of

Chemotherapy Regimen

Emetogenicity Potential

Acute-Phase CINV (Doses Should

be Given 30–60 Minutes Before

Chemotherapy) Delayed-Phase CINV Breakthrough CINV

High-risk IV chemotherapy regimens Day 1: single dose 5-HT3 antagonist +

dexamethasone + aprepitant/

fosaprepitant

Dexamethasone days 2–4 +

aprepitant days 2 and 3 (not

needed if fosaprepitant

150-mg dose used)

Two agents for PRN use

Moderate-risk IV chemotherapy regimens

with high risk of delayed CINV

Day 1: single dose 5-HT3 antagonist +

dexamethasone + aprepitant/

fosaprepitant

Dexamethasone days 2 and 3 +

aprepitant days 2 and 3a

Two agents for PRN use

Other moderate-risk IV chemotherapy

regimens

Day 1: single dose 5-HT3 antagonist +

dexamethasone

None One agent for PRN use

Low-risk IV chemotherapy regimens Single dose dexamethasone or

metoclopramide or prochlorperazine

None Either none or one agent

for PRN use

Minimal-risk IV chemotherapy regimens None None Usually none

High-moderate risk PO chemotherapy

regimens

5-HT3 antagonist None One agent for PRN use

Low-risk PO chemotherapy regimens None None One agent for PRN use

aNCCN guidelines also include as options dexamethasone alone days 2 and 3 or ondansetron/granisetron/dolasetron days 2 and 3 of chemotherapy.

5-HT3, serotonin; CINV, chemotherapy-induced nausea and vomiting; PRN, as needed.

Source: Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology. V2.2010. http://www.nccn.org/professionals/physician gls/pdf/antiemesis.pdf.

Accessed September 30, 2010; American Society of Clinical Oncology et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006

[published correction appears in J Clin Oncol. 2006;24:5341]. J Clin Oncol. 2006;24:2932; Roila F 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.

Society of Clinical Oncology (ASCO; http://jco.ascopubs.org/

content/24/18/2932.full.pdf+html)

12; the National Comprehensive Cancer Network (NCCN; http://www.nccn.org/

professionals/physician gls/PDF/antiemesis.pdf; guidelines

can be accessed by creating a free login)1; and the Multinational

Association of Supportive Care in Cancer (MASCC; http://

annonc.oxfordjournals.org.floyd.lib.umn.edu/content/21/

suppl 5/v232.full.pdf+html).13 These evidence- and consensus-based guidelines, which are similar in regard to the roles

of the various antiemetics, are summarized in Table 6-4 and

Figure 6-2.

For M.C., the best regimen would include a single dose of

a 5-HT3 antagonist plus dexamethasone 8 to 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.

If M.C. had been prescribed a multiday chemotherapy regimen, prophylaxis with a 5-HT3 antagonist and dexamethasone

should be offered for each day that moderately or highly emetogenic chemotherapy is administered.1,12,13,44 Aprepitant might

be useful with multiday chemotherapy regimens, although it

has not been studied in this context. Preliminary studies indicated that aprepitant was safe to administer for a total of 5 days,

but it is not clear whether the additional doses would increase

the antiemetic effects. If multiday chemotherapy regimens have

a high risk of delayed symptoms, then some therapy (e.g., dexamethasone plus prochlorperazine or metoclopramide, if aprepitant was already administered) for the delayed symptoms should

be continued for at least 2 to 3 days after the last chemotherapy

administration.

Modern antiemetic regimens 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 prophylactic antiemetic

regimen should be made for the next cycle (Fig. 6-3). Suggestions include upgrading to the next higher emetogenicity level

recommendation, adding aprepitant if not already given, and

scheduling antiemetic agents from other pharmacologic classes.

For additional patient cases covering more

CINV situations, go to http://thepoint.

lww.com/AT10e.

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.45

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.46 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 that some

patients perceive. Dry, salty foods can also help settle the stomach.

RADIATION-INDUCED NAUSEA

AND VOMITING

Clinical Presentation and Risk Factors

CASE 6-3

QUESTION 1: 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

108 Section 1 General Care

Monitor patient for efficacy and toxicity

Minimal or no breakthrough

symptoms; no toxicity

No change in therapy

More than minimal breakthrough

symptoms

Schedule PRN medications, add

other PRN medications, consider

need for IV hydration or electrolyte

supplementation

Adverse effects from antiemetics

 Reduce dose for

drowsiness/confusion, offer pain

medication for headaches, offer

hypnotic agents for insomnia,

monitor glucose and give insulin

for hyperglycemia

Minimal emetogenicity

chemotherapy

Low emetogenicity

chemotherapy

Moderately emetogenic

chemotherapy without a

high risk of delayed

CINV

Moderately emetogenic

chemotherapy with risk

of delayed CINV

Highly emetogenic

chemotherapy

Acute phase:

none

Acute phase:

prochlorperazine or

metoclopramide or

dexamethasone or

Acute phase: singledose 5-HT3-RA +

dexamethasone

Acute phase:

single-dose 5-HT3-RA +

dexamethasone +

fosaprepitant/aprepitant

Acute phase:

single-dose 5-HT3-RA +

dexamethasone +

fosaprepitant/aprepitant

Delayed phase:

none

Delayed phase:

none

Delayed phase:

none

Delayed phase:

dexamethasone D2-3 +

aprepitant D2-3

Delayed phase:

dexamethasone D2-4 +

aprepitant D2-3 (not

if fosaprepitant 150 mg

used )

Possibly one PRN

medication

Provide one PRN

medication

Provide one PRN

medication

Provide two PRN

medications

Provide two PRN

medications

Determine the highest emetogenicity

of the chemotherapy given on each day

Consider patient risk factors

Patient receiving first cycle of chemotherapy

FIGURE 6-2 Algorithm for antiemetic selection for an initial chemotherapy cycle. CINV, chemotherapy-induced nausea and vomiting; D,

days; 5-HT3-RA, serotonin type 3 receptor antagonist; PRN, as needed.

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 experiencing

radiation-induced nausea and vomiting? What antiemetic

prophylaxis is appropriate?

Radiation therapy can cause nausea and vomiting through

the same basic pathways that chemotherapy does. Radiationinduced 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,

larger fractional doses of radiation, and whether the patient has

had previous chemotherapy.1,47,48 Patients with radiation areas

larger than 400 cm2 are more likely to have significant RINV

symptoms. The radiation therapy oncologist will determine the

size of the radiation field and fractional doses of radiation to

maximize the efficacy of the radiation therapy. The high dose

used in total body irradiation (associated with hematopoietic

stem cell transplantation) causes RINV in greater than 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 at low risk for experiencing RINV because

his radiation site will be in the head and neck region, his radiation site is not likely to be larger than 400 cm2, and he will likely

receive a smaller fractional dose, although he will be receiving

concurrent chemotherapy.

Overview of Treatment

Just as with CINV, symptoms caused by radiation can be

prevented with 5-HT3 antagonists, corticosteroids, or both.

109Nausea and Vomiting Chapter 6

Assess for adverse effects from antiemetics

Adverse effects from antiemetics:

reduce dose, offer pain medication

for headaches, offer hypnotic

agents for insomnia, monitor

glucose, and give insulin for

hyperglycemia

Consider efficacy of last cycle

Anticipatory nausea and vomiting

Offer therapy with a

benzodiazepine; offer behavioral

therapies such as hypnosis or

relaxation techniques

Therapeutic success

Repeat last regimen

Not a therapeutic success

Did patient get an appropriate

prophylaxis regimen?

Schedule around-theclock agents that were

previously given PRN,

add olanzapine

or cannabinoids;

upgrade to next

emetogenicity level

Use appropriate

regimen for next cycle

No Yes

FIGURE 6-3 Algorithm for selection of antiemetic regimens for subsequent chemotherapy cycles. PRN, as needed.

Evidence- and consensus-based recommendations have been

published by several multidisciplinary groups and are shown

in Table 6-5. High-risk RINV is best treated with a combination of a 5-HT3 antagonist and a corticosteroid.1,47–51

Patients receiving concomitant chemotherapy and radiation

should receive antiemetics appropriate for the chemotherapy

regimen.1 Patients receiving radiotherapy in the moderate RINV

risk group can receive either prophylaxis or rescue therapy with

a 5-HT3 antagonist. Because E.G. is at low risk for having RINV

symptoms, he does not need prophylaxis with a 5-HT3 antagonist. If he experiences symptoms, rescue therapy with a dopamine antagonist or a serotonin antagonist should be

offered.

POSTOPERATIVE NAUSEA AND

VOMITING

Clinical Presentation and Risk Factors

CASE 6-4

QUESTION 1: 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?

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.52 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.52–56

Patient risk factors include female sex, 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 have PONV

as adults.53,57 The risk increases with the child’s age but declines

after puberty.

110 Section 1 General Care

TABLE 6-5

Prophylaxis for Radiation-Induced Nausea and Vomiting

(RINV) for Adults

Emetic Risk Radiation Area Recommendation

High risk Total body irradiation Prophylaxis with a 5-HT3

antagonist (e.g.,

ondansetron 8 mg PO

BID–TID or

granisetron 2 mg PO

daily + dexamethasone

(2 mg PO TID)

Moderate risk Upper abdomen Prophylaxis with a 5-HT3

antagonist (e.g.,

ondansetron 8 mg PO

BID or granisetron

2 mg PO daily) ±

dexamethasone 4 mg

PO daily

Low risk Lower thorax, pelvis,

cranium, craniospinal

region, head/neck

Prophylaxis or rescue with

a 5-HT3 antagonist

Minimal risk Extremities, breast Rescue with a dopamine

antagonist or a 5-HT3

antagonist

Source: Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology.

V2.2010. http://www.nccn.org/professionals/physician gls/pdf/

antiemesis.pdf. Accessed September 30, 2010; Grunberg SM et al. Evaluation of

new antiemetic agents and definition of antineoplastic agent emetogenicity—an

update. Support Care Cancer. 2005;13:80; Roila F et al. Guideline update for

MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: results of the Perugia consensus conference. Ann

Oncol. 2010;21(Suppl 5):v232; Feyer P et al. Radiotherapy-induced nausea and

vomiting (RINV): MASCC/ESMO guideline for antiemetics in radiotherapy:

update 2009. Support Care Cancer. 2010 Aug 10 [Epub ahead of print]; Abdelsayed

GG. Management of radiation-induced nausea and vomiting. Exp Hematol.

2007;35(4 Suppl 1):34; Urba S. Radiation-induced nausea and vomiting. J Natl

Compr Canc Netw. 2007;5:60.

Certain anesthesia practices may reduce the risk of PONV.

These include use of regional anesthesia (instead of general

anesthesia), use of total IV anesthesia with propofol, use of

intraoperative oxygen, adequate hydration, and avoidance of

nitrous oxide, volatile anesthesia therapy, and intraoperative or

postoperative opiates.52–54,56–58

Several risk factor models have been studied to correlate these

factors into recommendations for prevention and therapy.52,54

One model is both simple and practical, and uses the following

risk factors: female sex, history of PONV or motion sickness,

nonsmoking status, surgery longer than 60 minutes in duration,

and the use of intraoperative opioids. If the patient has zero or

one risk factor, the risk of PONV is about 10% to 20%, and 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%, and 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.

Overview of Treatment

An optimal prophylactic regimen for PONV matches medication choice with the patient’s risk level.52–54,56,57,59 Patients

with zero or one risk factor usually will not need any prophylaxis. Patients with moderate risk (two to three risk factors)

should receive one to two antiemetics. Appropriate choices for

monotherapy include droperidol, a 5-HT3 antagonist, or dexamethasone. Patients at the highest risk for PONV (at least four

risk factors) should be given prophylaxis with a combination of

two to three antiemetics. Dual-therapy choices include a 5-HT3

antagonist plus either droperidol or dexamethasone. Triple therapy would combine a 5-HT3 antagonist plus dexamethasone

plus droperidol. Because E.W. has a moderate to high risk for

PONV, a combination of a 5-HT3 antagonist (such as ondansetron

4–8 mg at the end of surgery) and dexamethasone (4–8 mg at the

start of anesthesia induction) would be a good choice for prophylactic therapy.

The most effective and commonly used medications 

 Emetogenicity of Selected Antineoplastic Agents by Dose and Route of Administration

Chemotherapy Agent Injectable Administration Oral Administration

Aldesleukin (Proleukin) >12–15 million units/m2 = Moderate

≤12 million units/m2 = Low

Alemtuzumab (Campath) Minimal

Altretamine (Hexalen) High

Arsenic trioxide (Trisenox) Moderate

Asparaginase (Elspar) Minimal

Azacitdine (Vidaza) Moderate

Bendamustine (Treanda) Moderate

Bevacizumab (Avastin) Minimal

Bexarotene (Targretin) Low

Bleomycin (Blenoxane) Minimal

Bortezomib (Velcade) Low

Busulfan (Busulfex, Myleran) Moderate ≥4 mg = Moderate

<4 mg = Minimal

Cabazitaxel (Javtana) Moderate

Capecitabine (Xeloda) Low

Carboplatin (Paraplatin) Moderate with high risk of delayed CINV

Carmustine (BiCNU) >250 mg/m2 = High

≤250 mg/m2 = Moderate

Chlorambucil (Leukeran) Minimal

Cetuximab (Erbitux) Minimal

Cisplatin (Platinol) ≥50 mg/m2 = High

<50 mg/m2 = Moderate

High risk of delayed CINV

Cladribine (Leustatin) Minimal

Clofarabine (Clolar) Moderate

Cyclophosphamide (Cytoxan) >1,500 mg/m2 = High

≤1,500 mg/m2 = Moderate

High risk of delayed CINV

≥100 mg/m2

/d = Moderate

<100 mg/m2

/d = Low

Cytarabine (Ara-C, Cytosar-U) >200 mg/m2 = Moderate

100–200 mg/m2 = Low

<100 mg/m2 = Minimal

Dacarbazine (DTIC) High

Dactinomycin (Cosmegen) Moderate

Dasatinib (Sprycel) Minimal

Daunorubicin (Cerubidine) Moderate

Decitabine (Dacogen) Minimal

Docetaxel (Taxotere) Low

Doxorubicin (Adriamycin) Moderate

High risk of delayed CINV

Doxorubicin liposomal (Doxil) Moderate

Epirubicin (Ellence) Moderate

High risk of delayed CINV

Erlotinib (Tarceva) Minimal

Etoposide (VePeSid) Low Moderate

Everolimus (Afinitor) Minimal

Fludarabine (Fludara) Minimal Low

Fluorouracil (Adrucil) Low

Gefitinib (Iressa) Minimal

Gemcitabine (Gemzar) Low

Hydroxyurea (Hydrea) Minimal

Idarubicin (Idamycin) Moderate

High risk of delayed CINV

Ifosfamide (Ifex) Moderate

Imatinib (Gleevec) Moderate

Interferon α2B (Intron A) ≥10 million units/m2 = Moderate

<10 million units/m2 = Low

Irinotecan (Camptosar) Moderate

Some risk of delayed CINV

Ixabepilone (Ixempra) Low

Lapatinib (Tykerb) Low

Lenalidomide (Revlimid) Minimal

Lomustine (CeeNU) Moderate

Mechlorethamine (Mustargen) High

Melphalan (Alkeran) Moderate Minimal

Mercaptopurine (Purinethol) Minimal

(continued )

104 Section 1 General Care

TABLE 6-2

Emetogenicity of Selected Antineoplastic Agents by Dose and Route of Administration

(Continued)

Chemotherapy Agent Injectable Administration Oral Administration

Methotrexate (Trexall) ≥250 mg/m2 = Moderate

50–249 mg/m2 = Low

<50 mg/m2 = Minimal

Some risk of delayed CINV

Minimal

Mitomycin (Mutamycin) Low

Mitoxantrone (Novantrone) Low

Nelarabine (Arranon) Minimal

Nilotinib (Tasigna) Low

Oxaliplatin (Eloxatin) Moderate

Paclitaxel (Taxol) Low

Paclitaxel Protein Bound (Abraxane) Low

Panitumumab (Vectibix) Minimal

Pazopanib (Votrient) Low

Pegasparaginase (Oncaspar) Minimal

Pemetrexed (Alimta) Low

Pentostatin (Nipent) Low

Pralatrexate (Folotyn) Moderate

Procarbazine (Matulane) High

Rituximab (Rituxan) Minimal

Romidepsin (Istodax) Low

Sorafenib (Nexavar) Minimal

Streptozocin (Zanosar) High

Sunitinib (Sutent) Minimal

Temozolamide (Temodar) Moderate >75 mg/m2

/d = Moderate

≤75 mg/m2

/d = Low

Temsirolimus (Torisel) Minimal

Teniposide (Vumon) Low

Thalidomide (Thalomid) Minimal

Thioguanine (Tabloid) Minimal

Thiotepa (Thiotepa) Low

Topotecan (Hycamptin) Moderate Low

Trastuzumab (Herceptin) Minimal

Tretinoin (Vesanoid) Low

Vinblastine (Velban) Minimal

Vincristine (Oncovin) Minimal

Vinorelbine (Navelbine) Minimal

Vorinostat (Zolinza) Low

High = >90% (of patients would experience chemotherapy-induced nausea and vomiting [CINV] without antiemetic

premedication); Moderate = 30%–90%; Low = 10%–30%; Minimal = <10%.

Source: Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology. V2.2010. http://www.nccn.org/professionals/

physician gls/pdf/antiemesis.pdf. Accessed September 30, 2010; Grunberg SM et al. Evaluation of new antiemetic agents and

definition of antineoplastic agent emetogenicity—an update. Support Care Cancer. 2005;13:80; American Society of Clinical Oncology

et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006 [published correction appears

in J Clin Oncol. 2006;24:5341]. J Clin Oncol. 2006;24:2932; Roila F 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.

effective for at least a few days, but little data are published using

repeated doses in fewer than 7 days. Palonosetron has been studied in a three-dose regimen (administration on days 1, 3, 5) for

multiday chemotherapy in an uncontrolled trial.26 This regimen

appeared to be safe and effective, but was not compared with any

other regimen. It is not clear that palonosetron would have superior activity compared with repeated doses of the other 5-HT3

antagonists.

It is difficult to identify the 5-HT3 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.

CORTICOSTEROIDS

The mechanism of action of corticosteroids as antiemetics has not

been fully determined. Some suggest that corticosteroids may

decrease serotonin release, antagonize 5-HT3, 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 almost exclusively used. Dexamethasone improves the antiemetic control of 5-HT3 antagonists

by about 15% to 20%.20 In addition to its use in the acute phase

of CINV, 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 controlled trials.27 For moderately

emetogenic chemotherapy in the acute phase, a single 8-mg

dose was as effective as larger 24-mg doses or prolonged administration. 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. If dexamethasone is used with aprepitant

in the acute phase, the lower 12-mg prechemotherapy dose is

105Nausea and Vomiting Chapter 6

recommended because of inhibition of steroid metabolism by

aprepitant (see the NK1 receptor antagonist section).12 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 for delayed CINV

should be reduced to 8 mg daily when used with aprepitant.

Corticosteroids are sometimes underused 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 dexamethasone is infused

too quickly.18,27,28 For most patients, however, dexamethasone

is well tolerated, especially because the therapy is typically short

term at lower doses. Steroid-related hyperglycemia may occur,

especially in patients with pre-existing diabetes.20 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 uncommon. 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 steroid withdrawal-like symptoms may,

however, benefit from a short taper on repeated corticosteroid

courses.

Corticosteroids also have antitumor properties and are a part

of the antineoplastic regimen for some malignancies, such as

lymphoma, lymphoid leukemia, and myeloma, and additional

dexamethasone for the antiemetic protection is not necessary. In

these cases, the corticosteroid should be administered just 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.12

NEUROKININ 1 RECEPTOR ANTAGONISTS

The potential use of NK1 receptor antagonists as antiemetics

became apparent when the role of substance P in the peripheral

nervous system and CNS was recognized in the emetic stimulus

pathway. Aprepitant, the first NK1 receptor antagonist available,

is active in both the acute and delayed phases 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 5-HT3 antagonist, but that it would be used best

in conjunction with corticosteroids and a 5-HT3 antagonist.29

Studies have shown that aprepitant-containing regimens were

TABLE 6-3

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

Medication (Trade Name) Class Indication

Dose in Adults (Doses Should be Given

30–60 Minutes Before Chemotherapy)

Aprepitant (Emend) NK1 antagonist Acute and delayed PO: 125 mg on day 1, 80 mg on days 2 and 3

Dexamethasone (Decadron) Corticosteroid Acute (high emetogenicity) PO/IV: 12 mg (with aprepitant) or 20 mg

(without aprepitant)

Acute (moderate emetogenicity) PO/IV: 8–12 mg

Acute (low emetogenicity) PO/IV: 4–8 mg

Delayed PO/IV: 8 mg daily days 2–4 or days 2 and 3 or

PO: 4 mg BID days 2–4

Dolasetron (Anzemet) 5-HT3 antagonist Acute PO: 100–200 mg

Dronabinol (Marinol) Cannabinoid Breakthrough PO: 2.5–10 mg PO TID to QID

Droperidol (Inapsine) Butyrophenone Breakthrough IV: 0.625–1.25 mg every 4–6 hours PRN

Fosaprepitant (Emend) NK1 antagonist Acute IV: 150 mg ×1 dose or 115 mg initial dose

(followed by aprepitant 80 mg PO on days 2

and 3

Granisetron (Kytril) 5-HT3 antagonist Acute IV: 1 mg or 0.01 mg/kg

PO: 2 mg

TOP: 3.1 mg/24-h patch applied 24–48 hours

before chemotherapy and kept on until

24 hours after chemotherapy or up to 7 days

Haloperidol (Haldol) Butyrophenone Breakthrough PO/IV/IM: 0.5–1 mg every 6 hours PRN

Metoclopramide (Reglan) Dopamine antagonist Breakthrough PO/IV: 10–40 mg every 6 hours PRN

Lorazepam (Ativan) Benzodiazepine Breakthrough PO/IV/IM/SL: 0.5–2 mg every 6 hours PRN

Nabilone (Cesamet) Cannabinoid Refractory symptoms PO: 1–2 mg BID (max 2 mg TID)

Olanzapine (Zyprexa) Serotonin/dopamine

antagonist

Acute/delayed/breakthrough PO: 2.5–10 mg QHS or 2.5 mg BID or 2.5 mg

TID plus 5 mg QHS

Ondansetron (Zofran) 5-HT3 antagonist Acute (moderate or high

emetogenicity)

Delayed

IV: 8–12 mg or 0.15 mg/kg

PO: 16–24 mg

8 mg PO BID or 8 mg IV daily

Palonosetron (Aloxi) 5-HT3 antagonist Acute/delayed IV: 0.25 mg

PO: 0.5 mg

Prochlorperazine

(Compazine)

Dopamine antagonist Breakthrough

Acute

PO/IV/IM: 5–10 mg (up to 20 mg) every

4–6 hours PRN or

PR: 25 mg every 12 hours PRN

PO/IV: 10 mg

Promethazine (Phenergan) Dopamine antagonist Breakthrough PO/IV/IM/PR: 12.5–25 mg every 4–6 hours

PRN

BID, twice daily; IM, intramuscular; IV, intravenous; NK1, neurokinin 1; PO, oral; PR, rectal; PRN, as needed; QHS, at bedtime; QID, four times daily; TID, three times daily.

Source: Ettinger DS et al. Antiemesis: clinical practice guidelines in oncology. V2.2010. http://www.nccn.org/professionals/physician gls/pdf/antiemesis.pdf.

Accessed September 30, 2010; American Society of Clinical Oncology et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006

[published correction appears in J Clin Oncol. 2006;24:5341]. J Clin Oncol. 2006;24:2932; Roila F 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.

106 Section 1 General Care

more effective in women than in men, which is fortunate because

women have more acute and delayed symptoms than men.29

Aprepitant has been studied in the prevention of CINV with

highly and moderately emetogenic chemotherapy.17,29 These

studies showed improved response rates when aprepitant was

added to antiemetic regimens containing a 5-HT3 antagonist

plus dexamethasone.

Although CINV symptoms tend to worsen from cycle to cycle,

the effects of aprepitant seem to be maintained during four cycles

of chemotherapy in patients receiving moderately emetogenic

chemotherapy.30 The addition of aprepitant to the antiemetic

regimen on cycle 2 (even when omitted from cycle 1) also seems

to improve control of CINV symptoms.31,32 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 of 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)

with a regimen without aprepitant (ondansetron and dexamethasone on days 1 through 4) in patients receiving highly

emetogenic chemotherapy.33 The aprepitant-containing regimen offered superior control of CINV in the acute, delayed, and

overall periods. The study confirmed that aprepitant is superior

to a 5-HT3 antagonist during the delayed phase of CINV.

There is growing evidence that the prechemotherapy dose of

aprepitant (or fosaprepitant) provides the majority of the benefit compared with the postchemotherapy doses.17,34 This first

dose of aprepitant blocks about 80% of the NK1 receptors in

the CNS.17,34 One study compared a single 150-mg IV dose of

fosaprepitant to the standard three-day oral regimen (along with

ondansetron and dexamethasone) in patients receiving highly

emetogenic chemotherapy. There was no difference found in the

antiemetic efficacy between the two groups.35 Ongoing research

is needed to further clarify the optimal dosing regimen.

Aprepitant is generally well tolerated with mild side effects,

including fatigue, hiccups, headache, and diarrhea.29,33 The overall adverse effects in standard aprepitant-containing regimens are

not appreciably different from regimens without aprepitant. An

intravenous prodrug, fosaprepitant, is now available, and an IV

dose of 115 mg can replace the first prechemotherapy 125-mg

PO dose of aprepitant.34

Aprepitant is metabolized by the CYP3A4 enzyme system. It

is a moderate inhibitor and inducer of CYP3A4, and an inducer

of CYP2C9.1,29 Consequently, several drugs potentially interact

with aprepitant. The most commonly encountered interaction

is with the corticosteroids. Aprepitant increases the AUC 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.1,17,29 The interaction is

greatest when the corticosteroid is administered orally. However,

when the corticosteroid is also given as part of the antitumor regimen, the corticosteroid dose should not be reduced because of

concern that the antineoplastic activity might be compromised.12

Aprepitant may also enhance warfarin metabolism by inducing

CYP2C9. International normalized ratio (INR) values in patients

treated with warfarin and the standard aprepitant regimen are

significantly reduced, especially on day 8 of the chemotherapy

cycle.17,29,36,37 The patient’s coagulation status after aprepitant

administration should be monitored, especially during the 7- to

10-day period after aprepitant. The dosage of warfarin should

be adjusted if the INR is out of range. Several chemotherapy

agents (paclitaxel, etoposide, 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 because the clinical

relevance of this potential interaction is not known.29,38 Other

drugs that may interact with aprepitant include oral contraceptives, itraconazole, terfenadine, and phenytoin.29

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 dosages and indications for these agents are shown in Table

6-3. Many of these agents have more side effects than contemporary agents, especially sedation and extrapyramidal side effects,

such as dystonia and akathisia. 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.

Olanzapine is an atypical antipsychotic agent that antagonizes

several serotonin and dopamine receptors as well as other neurotransmitter receptors.39 Its antiemetic action was first described

in patients with refractory nausea or vomiting and advanced cancer. Olanzapine has activity both in the prevention of CINV in

patients at high risk, as well as rescue treatment for patients with

refractory nausea and vomiting. Studies have demonstrated its

efficacy in preventing CINV in the setting of highly and moderately emetogenic chemotherapy. Newer, controlled trials show

improved response rates when added to an antiemetic regimen

of a 5-HT3 antagonist plus dexamethasone, as well as comparable activity to aprepitant.23,36,39,40 The usual dose of olanzapine

used in these trials was 10 mg PO daily on days 1 through 5.

Olanzapine is also active as a rescue agent for patients with

refractory CINV. In this setting, the usual dose of olanzapine

is 2.5 to 10 mg daily in one to four divided doses. The common side effects of olanzapine include sleepiness, dry mouth,

and dizziness, although these were not significant in the preliminary reports.23,36,39,40 Olanzapine is a good choice for control

of highly refractory CINV symptoms, but further study is warranted before it should be routinely recommended for prophylaxis of acute and delayed 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.41 Small trials have

shown conflicting effectiveness in the prevention of CINV.42,43 A

new oral cannabinoid, nabilone, was approved for the treatment

of CINV in patients who do not respond adequately to other

antiemetics.41 Cannabinoids are associated with side effects, such

as drowsiness, dry mouth, dysphoria, vertigo, and euphoria.41,42

Although some patients have a clear preference for, and good