Chemotherapy-Induced Nausea and Vomiting

PRACTICE OF ONCOLOGY:RECENT ADVANCES

Lisa Lohr, PharmD, BCPS, BCOP

uncontrolled symptoms are more likely to suffer from depres- Abstract: Chemotherapy-induced nausea and vomiting (CINV) af- sion and fatigue. fects many cancer patients and has a great inﬂuence on quality of There have been substantial advances in antiemetic life. CINV involves coordination of several organs of the gastroin- therapy in the last 2 decades. Research into underlying testinal tract, the peripheral and central nervous systems. Many mechanisms in the pathways triggering nausea and vomiting neurotransmitters are involved in this process, and the predominant has led to medications targeting neurotransmitters. The use of receptors are serotonin, neurokinin-1 and dopamine receptors. Risk these antiemetics in combination can provide complete con- factors for CINV include patient gender and age, past history of trol of nausea and vomiting in most patients who receive CINV, plus the emetogenicity and administration schedule of che- chemotherapy. Highly effective antiemetic therapy has al- motherapy. Recommended antiemetic regimens for highly emeto- lowed administration of high-dose chemotherapy regimens genic chemotherapy and moderately emetogenic chemotherapy with and has allowed administration of chemotherapy in the am- a high risk of delayed CINV include a serotonin antagonist, dexa- bulatory, outpatient care setting. methasone and aprepitant. Other moderately emetogenic chemotherapy requires a serotonin antagonist and dexamethasone. Medications for breakthrough symptoms include dopamine antagonists, loraz- PATHOPHYSIOLOGY epam, metoclopramide, haloperidol, droperidol and other agents. Multiple organs and multiple neurotransmitters are in- Options for treatment of refractory CINV include olanzapine, dron- volved in the response to emetic triggers. Incoming signals abinol, nabilone, gabapentin. New evidence from non-controlled from the chemoreceptor trigger zone, GI tract, cerebral cor- studies supports the use of olanzapine, casopitant and gabapentin in tex, and other areas are collected in the emetic center in the controlling the symptoms of CINV. central nervous system. The vomiting center sends out coor- dinating signals to effector organs such as the esophagus, Key Words: chemotherapy-induced nausea and vomiting (CINV), stomach, and abdominal muscles to complete the emesis. The antiemetic, chemotherapy, serotonin antagonist, corticosteroid, neu- predominant neurotransmitter receptors involved in this sig- rokinin-receptor antagonist, olanzapine, casopitant, gabapentin naling are serotonin (the 5-hydroxytryptamine type 3 [5HT3]) (Cancer J 2008;14: 85–93) receptors, neurokinin-1 receptors, and dopamine receptors. Other receptors include corticosteroid, histamine, cannabinoid, acetylcholine, GABAminergic, and opiate receptors. astrointestinal (GI) side effects such as nausea and vom- Effective antiemetic therapies target these receptors. Combi- Giting are common adverse effects from many cancer nations of antiemetics are needed in most situations to target chemotherapy regimens. Having uncontrolled nausea and multiple receptors. vomiting still remains one of the greatest fears of patients Chemotherapy can initiate nausea and vomiting by stimulating the release of neurotransmitters from areas of the undergoing therapy for cancer. Symptoms can range from GI tract and the chemoreceptor trigger zone. The chemore- mild queasiness to violent, repetitive vomiting and retching. ceptor trigger zone lies outside the blood-brain barrier and Uncontrolled nausea and vomiting can lead to physical ef- senses potential toxins such as chemotherapy agents. The fects such as dehydration, electrolyte abnormalities, malnu- enterochromafﬁn cells in the GI tract release serotonin in trition, gastrointestinal tears and bleeding, wound dehiscence, response to damage from chemotherapy, leading to stimula- and aspiration pneumonia. Persistent nausea and vomiting tion of the emetic response. Other areas of the central nervous can have an even greater effect on the quality of life of the system such as the limbic system, the vestibular system, or the patient. Effects include decreased morale, and decreased cerebral cortex can stimulate emesis through states such as pain, ability of the patient to participate in activities of daily life, depression, vertigo, motion sickness, or conditioned responses work, personal care, or recreational activities. Patients with (anticipatory nausea and vomiting.) The neurotransmitters involved in these pathways are less well understood. From the University of Minnesota College of Pharmacy, Minneapolis, MN. Not all nausea and vomiting in cancer patients is caused Reprints: Lisa K. Lohr, PharmD, BCPS, BCOP, Clinical Pharmacist in by chemotherapy. Other common causes include radiation Oncology/BMT, University of Minnesota Medical Center, Fairview, treatments, brain metastases, migraine, viral gastroenteritis, Clinical Assistant Professor, University of Minnesota College of Phar- macy, Minneapolis, MN 55455. E-mail: [email protected] urinary tract infections, bowel obstructions, hypercalcemia, ure- Copyright © 2008 by Lippincott Williams & Wilkins mia, gastroparesis, hyperglycemia, and hyponatremia. Medica- ISSN: 1528-9117/08/1402-0085 tions such as opiates, antibiotics, antifungals, and many others

The Cancer Journal • Volume 14, Number 2, March/April 2008 85 Lohr The Cancer Journal • Volume 14, Number 2, March/April 2008 commonly used in cancer patients can cause nausea and vom- TABLE 2. Emetogenicity of Chemotherapy Agents iting. It is important to consider these causes, because specific treatments for these conditions will be necessary. Emetogenicity Antineoplastic Agent Brand Name Category Aldesleukin (Ͼ12–15 million Proleukin Moderate CHEMOTHERAPY-INDUCED NAUSEA AND 2 VOMITING units/m ) Alemtuzumab Campath Low Chemotherapy-induced nausea and vomiting (CINV) Altretamine Hexalen High can be described in different phases. Acute CINV starts Amifostine (Ͼ300 mg/m2) Ethyol Moderate within a few hours after chemotherapy administration and can Amifostine (Յ300 mg/m2) Ethyol Low last throughout the first day. Delayed CINV symptoms occur Arsenic trioxide Trisenox Moderate after the acute phase and peak in 2–3 days but can last up to Asparaginase Elspar Minimal 6–7 days. Anticipatory nausea and vomiting can occur even Azacytidine Vidaza Moderate before chemotherapy administration in patients who have Bevacizumab Avastin Minimal developed a conditioned response to chemotherapy. Despite Bexarotene Targretin Low the labels given to these phases, the patient experiences the Bleomycin Blenoxane Minimal same distressing and disruptive symptoms. Bortezomib Velcade Moderate Some patients have a higher risk for developing CINV Busulfan (HSCT doses) Busulfex High symptoms.1,2 Patient-related risk factors for developing acute Busulfan (PO, Յ4 mg/d) Myleran Minimal and delayed symptoms are described in Table 1. Factors Capecitabine (PO) Xeloda Low associated with the chemotherapy itself also determine the Carboplatin Paraplatin Moderate likelihood of CINV.1,3,4 The most predictive factor is the Carmustine (Ͼ250 mg/m2) BiCNu High chemotherapy agent’s inherent propensity to cause CINV. Carmustine (Յ250 mg/m2) BiCNu Moderate Some chemotherapies (eg, cisplatin) cause symptoms in Cetuximab Erbitux Low Ͼ90% of patients (not treated with antiemetics) and are Chlorambucil (PO) Leukeran Minimal labeled as highly emetogenic chemotherapy (HEC). Moder- Cisplatin (Ն50 mg/m2) Platinol High ately emetogenic chemotherapy (MEC) (eg, carboplatin) Cisplatin (Ͻ50 mg/m2) Platinol Moderate causes CINV in 30%–90% of patients. Chemotherapy med- Cladribine Leustatin Minimal ications that cause symptoms in 10%–30% of patients are Clofarabine Collar Moderate called low emetogenicity agents (LEC) (eg, paclitaxel.) Other Ն Ͻ Cyclophosphamide (IV, 1,500 Cytoxan High agents (eg, vincristine) cause CINV in 10% of patients and mg/m2) are called minimally emetogenic chemotherapy agents. Table Cyclophosphamide (IV, Ͻ1,500 Cytoxan Moderate 2 lists the emetogenicity categories for various chemotherapy mg/m2) agents. Various references differ in the estimation of the Cyclophosphamide (PO) Cytoxan Moderate emetogenicity categories for some chemotherapy agents. For Cyclophosphamide/doxorubicin Cytoxan/Adriamycin High some chemotherapy medications, the emetogenicity risk de- combination pends on the dose. Cyclophosphamide/epirubicin Cytoxan/Ellence High Other chemotherapy-related factors increase the risk of combination 2 CINV. Chemotherapy regimens with higher doses and faster Cytarabine (Ն2 g/m ) Cytosar-U High 2 infusion times increase the risk of symptoms. CINV symp- Cytarabine (1–2 g/m ) Cytosar-U Moderate 2 toms tend to get worse with increasing numbers of cycles. Cytarabine (100–200 mg/m ) Cytosar-U Low With chemotherapy regimens administered over multiple Dacarbazine DTIC High days, the symptoms peak on about the third to fourth days. In Dactinomycin Cosmegen High these situations, the delayed CINV symptoms from the first Dasatinib Sprycel Minimal days of chemotherapy overlap with the acute symptoms from Daunorubicin Cerubidine Moderate the later day’s doses. Daunorubicin liposomal DaunoXome Moderate Decitabine Dacogen Moderate Denileukin diftitox Ontak Minimal Dexrazoxane Zinecard Moderate TABLE 1. Patient-Related Risk Factors for CINV Docetaxel Taxotere Low Acute-Phase CINV Delayed-Phase CINV Doxorubicin (Ն20 mg/m2) Adriamycin Moderate Younger age Female sex Doxorubicin (Ͻ20 mg/m2) Adriamycin Low Female sex Poor control of symptoms Doxorubicin liposomal Doxil Low Poor control of symptoms in in the acute phase Epirubicin Ellence Moderate prior cycles Erlotinib (PO) Tarceva Minimal History of motion sickness or Etoposide (PO) VePesid Moderate nausea with pregnancy Etoposide (IV) VePesid Low Anxiety/depression Fludarabine Fludara Low Absence of alcoholism Fluorouracil Adrucil Low Data from Refs. 1 and 2. (Continued)

carboplatin. Chemotherapy regimens that include more than TABLE 2. (Continued) of these agents are very likely to cause delayed nausea and Emetogenicity vomiting, especially in women. Antineoplastic Agent Brand Name Category Most chemotherapy agents are administered in combi- Gefitinib Iressa Minimal nations of multiple agents, instead of singly. Estimating the Gemcitabine Gemzar Low emetogenicity of combinations is difficult. One method esti- Gemtuzumab ozogamicin Mylotarg Moderate mates the total emetogenicity by mathematically accommo- Hydroxyurea Hydrea Minimal dating each of the agents.5 However, no method has been Idarubicin Idamycin Moderate prospectively validated. The best estimate can be obtained Ifosfamide Ifex Moderate from the primary literature describing the chemotherapy com- Imatinib (PO) Gleevec Moderate bination. If these data are not readily available, the antiemetic Irinotecan Camptosar Moderate therapy should be geared to the highest emetogenicity of the Lapatinib Tykerb Low single chemotherapy agent administered on each day.1,4,6 Lenalidomide (PO) Revimid Minimal Lomustine CeeNU High Mechlorethamine Mustargen High SEROTONIN ANTAGONISTS Melphalan (IV, Ͼ50 mg/m2) Alkeran Moderate Serotonin antagonists form the backbone of antiemetic Melphalan (PO) Alkeran Minimal combinations for many situations. There are four available Mercaptopurine (PO) Purinethol Minimal agents, ondansetron, granisetron, dolasetron, and palonose- Mesna Mesnex Minimal tron. Doses and adverse effects of these agents are listed in Methotrexate (Ն250 mg/m2) Trexall Moderate Table 3. A tremendous amount of research has been done for Methotrexate (50–250 mg/m2) Trexall Low the use of these agents. There is a threshold effect at which Methotrexate (PO and IV Ͻ50 Trexall Minimal receptors are fully blocked when a sufficient dose is given. mg/m2) However, a plateau effect has also been found, at which Mitomycin Mutamycin Low larger doses are not more effective. As single agents, the Mitoxantrone Novantrone Low serotonin antagonists have a response rate of 60%–80%, but Nelarabine Arranon Moderate this rate is higher when these drugs used with corticoste- Oxaliplatin Eloxatin Moderate roids.1,4,7–9 Oral forms of serotonin antagonists are as effec- Paclitaxel Taxol Low tive as intravenous forms. All of these agents are well Paclitaxel protein bound Abraxane Low tolerated, causing few side effects other than headache. A Panitimumab Vectibix Low serotonin antagonist should be included in antiemetic com- Pegasparaginase Oncaspar Minimal binations for the acute phase for highly or moderately eme- Pemetrexed Alimta Moderate togenic chemotherapy. These agents are more effective in Pentostatin Nipent Minimal preventing emesis than in preventing nausea. Serotonin an- Procarbazine (PO) Matulane High tagonists are no more effective than other agents (aprepitant, Rituximab Rituxan Low dexamethasone, or prochlorperazine) in the delayed phase Sorafenib (PO) Nexavar Minimal and are not recommended for these situations.10–14 Streptozocin Zanosar High Palonosetron, a serotonin antagonist with a long half- Sunitinib Sutent Minimal life of about 40 hours (compared with 3–9 hours for other Temozolomide (PO) Temodar Moderate serotonin antagonists), is the most recently developed of Temsirolimus Torisel Low these agents. In 2 trials in MEC and one trial in HEC, Teniposide Vumon Low palonosetron was compared with single doses of a compara- Thalidomide Thalomid Minimal tor agent, either ondansetron or dolasetron, given before a Thioguanine Tabloid Minimal single day of chemotherapy.14–16 A complete response was Thiotepa Thiotepa Low defined by no emesis and no need for rescue antiemetics in Topotecan Hycamtin Low the acute or delayed phases. Corticosteroid premedication for Trastuzumab Herceptin Low the acute phase was allowed but not required in 2 of these Tretinoin Vesanoid Low trials and not allowed in the other trial. Corticosteroid admin- Trimetrexate Neutrexin Minimal istration for the delayed phase was not included. By choosing Vinblastine Velban Minimal these comparator groups, palonosetron was compared with Vincristine Oncovin Minimal placebo for the delayed phase. Palonosetron demonstrated Vinorelbine Navelbine Low equivalent or somewhat higher response rates than those of Vorinostat Zolinza Low the comparator agent in the acute and delayed phases. Pal- Data from Refs. 1, 3, and 4. HSCT, hepatic stem cell transplantation; IV, intrave- onosetron has not been compared with antiemetic regimens nous; PO, oral. containing aprepitant or other more accepted regimens for delayed nausea and vomiting. Some chemotherapy medications are more likely to In a noncomparative trial, palonosetron was combined cause delayed CINV symptoms. These include cyclophosph- with aprepitant and dexamethasone in an antiemetic regimen amide, ifosfamide, doxorubicin, epirubicin, cisplatin, and studied in patients receiving MEC.17 Although not compared

TABLE 3. Antiemetic Medications Medication Indication/Phase Dose Side Effects/Precautions Serotonin antagonists Headache, fatigue, constipation Dolasetron (Anzemet) Acute 100 mg or 1.8 mg/kg IV or 100–200 mg PO Delayed 100 mg PO, days 2–4 Granisetron (Kytril) Acute 1 mg or 0.01 mg/kg IV or 2 mg PO Delayed 2 mg PO daily or 1 mg PO BID days 2–4 Ondansetron (Zofran) Acute 8 mg or 0.15 mg/kg IV (up to 32 mg) or 16–24 mg PO Delayed 8 mg PO BID or 16 mg/d PO days 2–4 Palonosetron (Aloxi) Acute/delayed 0.25 mg IV ϫ 1 dose Corticosteroids GI distress, insomnia, jitteriness, Dexamethasone HEC: Acute 12–20 mg IV/PO hyperglycemia, mood swings, (Decadron) MEC: Acute 8 mg IV/PO increased appetite LEC: Acute 4–8 mg IV/PO Delayed 8 mg daily PO for 2–4 days (when used with Aprepitant increases AUC of aprepitant) dexamethasone Breakthrough 12 mg IV/PO if not already given Methylprednisolone Acute 40–125 mg IV (Solu-Medrol) NK-1 Antagonist Aprepitant (Emend) Acute/delayed 125 mg PO ϫ 1 day 1, 80 mg PO daily days Drug interactions with warfarin, 2–3 corticosteroids, and other medications Dopamine antagonists Drowsiness, dizziness, Droperidol (Inapsine) Breakthrough 0.625–1.25 mg IV every 4–6 h PRN extrapyramidal side effects, anticholinergic side effects, Haloperidol (Haldol) Breakthrough 0.5–1 mg PO/IV/IM every6hPRN jaundice; caution when using Metoclopramide Breakthrough 10–20 mg PO/IV every6hPRN with other medications that (Reglan) cause CNS depression Prochlorperazine Breakthrough 5–10 mg PO/IV/IM every 4–6 h PRN (Compazine) Promethazine Breakthrough 12.5–25 mg PO/IV/IM every 4–6 h PRN (Phenergan) Miscellaneous Caution when using with other medications medications that cause CNS depression Dronabinol (Marinol) Refractory 2.5–10 mg PO TID-QID Sedation, dizziness, confusion, euphoria/dysphoria, dry mouth, abnormal thinking Lorazepam (Ativan) Breakthrough 0.5–2 mg PO/IV/IM/SL every 6 h PRN Sedation, respiratory depression, dizziness, amnesia Nabilone (Cesamet) Refractory 1–2 mg PO BID (up to 2 mg PO TID) Dizziness, drowsiness, vertigo, ataxia, dry mouth Olanzapine (Zyprexa) Acute/delayed/ 2.5–10 mg PO every night Sedation, anticholinergic effects, breakthrough hyperglycemia, extrapyramidal side effects

IV, intravenous; PO, oral; BID, 2 times daily; PRN, as needed; IM, intramuscular; TID, 3 times daily; QID, 4 times daily; SL, sublingual. with other serotonin antagonists in a triple regimen, this study days 1, 3, and 5 of cisplatin, along with varying doses of described high antiemetic response rates, and this regimen dexamethasone. This regimen demonstrated high antiemetic was well tolerated. response rates in both the acute and delayed phases. Although Because of its long elimination half-life, the U.S. Food this regimen was not compared with other serotonin-contain- and Drug Administration approved labeling for palonosetron ing regimens, it was safe and effective. Multiple dose pal- does not recommend repeat dosing of palonosetron in the 7 onosetron was well tolerated, with headache and constipation days after premedication before a single chemotherapy ad- being the most frequently observed side effects. ministration. Recently every other day palonosetron admin- Other serotonin antagonists under development include istration was given before daily cisplatin treatments in a tropisetron, lerisetron, ramosetron, and others.19,20 noncomparative study in testicular cancer patients.18 A dose It is difﬁcult to determine which serotonin antagonist is of 0.25 mg of palonosetron was given intravenously before the most cost effective because acquisition costs can vary

88 © 2008 Lippincott Williams & Wilkins The Cancer Journal • Volume 14, Number 2, March/April 2008 Chemotherapy-Induced Nausea and Vomiting between the inpatient and outpatient settings and between days after chemotherapy. If aprepitant is not used, the dose different clinics and because costs continue to change. Total should be increased to 8 mg orally 2 times daily for 2–4 days. treatment costs of different antiemetic regimens should be determined to decide which regimen is preferred. NEUROKININ-1 ANTAGONIST Aprepitant is the only currently available neurokinin-1 CORTICOSTEROIDS receptor antagonist. Its antiemetic action occurs through in- Corticosteroids like dexamethasone are potent anti- hibition of the action of substance P in the emetic pathways emetics, especially in combination with other agents. The in both the central and peripheral nervous systems. Aprepi- precise antiemetic mechanism of action of corticosteroids is tant is orally available and is recommended in a dose of 125 unclear but may involve a reduction of serotonin release or mg orally before day 1 of chemotherapy plus 80 mg orally activation of corticosteroid receptors in the central nervous daily on days 2 and 3. Its action is best seen when it is used system (CNS).21 The antiemetic activity of corticosteroids in combination with a serotonin antagonist and dexametha- has been well demonstrated in a large number of studies.21,22 sone. It is well tolerated. Only mild adverse effects of fatigue, The complete response rates are about 15%–20% higher hiccups, headache, and diarrhea are generally seen.25–28 when dexamethasone is added to serotonin antagonists. The cytochrome P450 3A4 system is responsible for the Dexamethasone is effective in prevention of CINV in the metabolism of aprepitant. Aprepitant is also an inhibitor and acute phase and is particularly active in the delayed phase. an inducer of 3A4, as well as an inducer of CYP2C9. Because Corticosteroids are sometimes underutilized because of of these effects, aprepitant can cause a number of significant concern regarding the potential adverse effects.21 Its short drug interactions.1,29,30 The elimination of dexamethasone term use as an antiemetic is actually well tolerated. The most and other corticosteroids is reduced, and a dose reduction is common CNS side effects include insomnia, jitteriness, and needed in most cases.1,29–32 However, when the corticoste- increased appetite. Some patients, especially those with un- roid is used as an antineoplastic agent, it is not recommended derlying diabetes, will experience hyperglycemia. These pa- that the dose be reduced.4 Through its altering of 3A4 tients should be advised to check their blood glucose levels activity, aprepitant has the potential for changing the metab- more frequently in the days after dexamethasone administra- olism of several chemotherapy agents, among them pacli- tion and treat the hyperglycemia appropriately. Other patients taxel, etoposide, ifosfamide, irinotecan, and many others. The may experience heartburn or other GI distress. Because the true significance of these potential interactions is unclear antiemetic use of corticosteroids is short term, tapering the because some of these chemotherapy agents were used in the dose is rarely needed. original aprepitant trials. Aprepitant induces the metabolism When corticosteroids are used as part of the antineo- of warfarin, causing low international normalized ratio val- plastic regimen for lymphoid cancers and myeloma, it is not ues.33 The international normalized ratio values of patients necessary to add additional dexamethasone as an antiemetic. treated with both warfarin and aprepitant should be monitored It is important to withhold corticosteroids if interferon or carefully and the warfarin dose adjusted appropriately. In interleukin-2 is part of the chemotherapy regimen because the addition, aprepitant has the potential for interacting with corticosteroids could potentially reduce the effectiveness of other medications such as phenytoin, itraconazole, terfena- the cancer treatment. dine, and oral contraceptives.29,30,32 The most appropriate dexamethasone dose for MEC The value of aprepitant in prevention of CINV with was explored in a 4-arm study comparing a single 8-mg dose HEC was demonstrated in 2 trials with cisplatin-based che- with other regimens using larger and more protracted admin- motherapy.25,26 Aprepitant was given in the standard dose and istration.23 The larger and longer dexamethasone dosing did was added to ondansetron (given on day 1) and dexametha- not improve the antiemetic efficacy of the regimen over that sone (given on days 1–4.) The patients in the aprepitant arms of the lower dose. So, for MEC, the recommended regimen is fared better, with a higher rate of complete antiemetic re- a single 8-mg dose before chemotherapy. sponse in the acute and delayed phases. It seems that aprepi- In another trial, there was some evidence for a dose- tant is even more effective in women than in men.34 response relationship in HEC.24 Prechemotherapy doses rang- Aprepitant was also studied in the context of MEC ing from 4 to 20 mg were studied. The higher doses of 12 and administration.27 All patients received ondansetron and dexa- 20 mg were superior to the lower 4- and 8-mg doses but were methasone before chemotherapy administration. Patients in not statistically different from each other, although there was the aprepitant arm also received aprepitant in the acute and a trend to a higher response rate with the 20-mg dose. delayed phases. Patients in the control arm received ondansetron Therefore, for HEC a 12- or 20-mg prechemotherapy dose is in the delayed phase. Those patients in the aprepitant arm did recommended. However, if aprepitant is included in the have a higher complete antiemetic response rate in both the antiemetic regimen, the 12-mg dose is recommended because acute and delayed phases. However, aprepitant was not com- of inhibition of the elimination of dexamethasone by aprepi- pared with dexamethasone, which is one of the most active tant (see also the section on aprepitant).4 agents for delayed CINV symptoms, in the delayed phase. Dexamethasone is highly active in preventing delayed In another trial in patients receiving HEC, a standard nausea and vomiting symptoms and forms the backbone of triple-drug aprepitant-containing regimen was compared with successful preventive regimens. If dexamethasone is used a regimen containing ondansetron and dexamethasone in both with aprepitant, the usual dose is 8 mg orally daily for 2–4 the acute and delayed phases.28 The patients in the aprepitant

© 2008 Lippincott Williams & Wilkins 89 Lohr The Cancer Journal • Volume 14, Number 2, March/April 2008 arm had higher complete response rates in both the acute and sive sedation. It is a useful addition for patients with insom- delayed phases. This study confirmed that an aprepitant/ nia, anxiety, or refractory nausea and vomiting. In addition, dexamethasone regimen is a better choice than a serotonin treatment with lorazepam can reduce symptoms of anticipa- antagonist/dexamethasone combination for preventing de- tory CINV. Lorazepam can also be administered orally or layed CINV symptoms. parenterally. The usual dose and adverse effects of lorazepam are listed in Table 3. DOPAMINE ANTAGONISTS An older class of antiemetics works primarily through CANNABINOIDS inhibition of dopamine receptors. These include phenothia- Cannabinoid medications can act as antiemetic agents zines (prochlorperazine and promethazine,) butyrophenones through their effect at cannabinoid receptors in multiple parts of (haloperidol and droperidol), and metoclopramide. The usual the CNS involved in the emetic response. Cannabinoid receptors doses and adverse effects of these medications are outlined in also help control the effect of serotonin, dopamine, and other Table 3. The routine prophylactic use of these medications neurotransmitters in these pathways. Cannabinoids may also has not been common since the advent of the serotonin have an effect at the enterochromaffin cells in the GI tract. Two antagonists. These agents still have use as medications for cannabinoid medications, dronabinol and nabilone, have been breakthrough CINV symptoms and as adjunctive medications approved for CINV. The usual doses of these medications are in building antiemetic regimens for patients with refractory shown in Table 3. Although there are conflicting data,35–37 nausea and vomiting. All of these medications cause more cannabinoids can be useful agents for patients who do not have sedation and extrapyramidal symptoms and other adverse adequate nausea and vomiting control with standard antiemetic effects than other antiemetics, which limits their use. How- regimens. The use of these agents is limited by their substantial ever, these agents are useful because they are available in oral adverse effects, which include sedation, dysphoria, vertigo, eu- as well as parenteral dosage forms. phoria, dizziness, and dry mouth. There is a subset of patients who respond very well to cannabinoids and who can tolerate the BENZODIAZEPINES side effects. In these patients, nabilone and dronabinol should Lorazepam is widely used as an antiemetic, especially probably be offered as a scheduled medication instead of “as for patients with breakthrough symptoms, but its mechanism needed” because of their slower onset of action. of action is poorly understood. It is an effective treatment for anxiety but may also act as an antiemetic by inhibiting ANTIEMETIC REGIMENS impulses from the cerebral cortex to the emetic center in the Table 4 describes recommended antiemetic regimens CNS. Lorazepam causes a variable amount of CNS depres- for different CINV situations. For multiday chemotherapy sion, but many patients tolerate it quite well without exces- regimens, the antiemetics should be geared toward the che-

TABLE 4. Antiemetic Regimens for CINV HEC Acute phase: single dose serotonin antagonist ϩ dexamethasone (higher dose) ϩ aprepitant Delayed phase: dexamethasone ϩ aprepitant Breakthrough symptoms: provide 2 medications (often a dopamine antagonist plus lorazepam) MEC with a high risk of delayed Acute phase: single dose serotonin antagonist ϩ dexamethasone (lower dose) ϩ aprepitant CINV (cyclophosphamide, Delayed phase: dexamethasone ϩ aprepitant ifosfamide, doxorubicin, epirubicin, cisplatin, carboplatin) Breakthrough symptoms: provide 1–2 medications Other MEC Acute phase: single dose serotonin antagonist ϩ dexamethasone (lower dose) Delayed phase: none Breakthrough symptoms: provide 1 medication LEC Acute phase: either none or single dose of dexamethasone, metoclopramide or prochlorperazine Delayed phase: none Breakthrough symptoms: either none or one medication Minimally emetogenic chemotherapy Acute phase: none Delayed phase: none Breakthrough symptoms: Either none or one medication Anticipatory CINV Lorazepam 0.5–1 mg PO (or alprazolam 0.25–0.5 mg PO) the evening before and the morning of chemotherapy treatment Refer patient for nonpharmacologic treatment such as hypnosis or relaxation techniques Breakthrough CINV Choices include dopamine antagonists (prochlorperazine, promethazine, metoclopramide, droperidol, haloperidol), lorazepam, dexamethasone (if not given prophylactically), olanzapine, cannabinoids (dronabinol, nabilone) Refractory CINV Upgrade prophylactic antiemetics to higher level; add in breakthrough medications on scheduled basis; olanzapine; cannabinoids (dronabinol, nabilone); gabapentin

Data are from Refs. 1, 4, and 6. PO, oral.

90 © 2008 Lippincott Williams & Wilkins The Cancer Journal • Volume 14, Number 2, March/April 2008 Chemotherapy-Induced Nausea and Vomiting motherapy with the highest emetogenicity given on each day. pretreated patients. The olanzapine was well tolerated, with In general, for HEC and MEC, the antiemetic regimen should few side effects seen in these patients. include both a serotonin antagonist and dexamethasone. In a phase II, noncomparative study, 30 patients were Aprepitant should be added for HEC and for MEC that has a treated with olanzapine with a dose of 5 mg daily for 2 days high risk of causing delayed nausea and vomiting. Antiemet- before chemotherapy, followed by 10 mg daily for 4 days.43 ics for breakthrough symptoms should be provided, and the These patients received HEC and MEC and were pretreated patient should be encouraged to take these medications before with a standard antiemetic regimen consisting of granisetron the nausea and vomiting becomes significant. For most pa- and dexamethasone. In the acute phase, all patients demon- tients receiving LEC, no premedication is needed. However, strated a complete antiemetic response. In the delayed phase, if necessary (ie, a past history of significant CINV), a single 80% of patients receiving HEC 85% of patients receiving dose of a dopamine antagonist or dexamethasone may be MEC experienced a complete response. Olanzapine was well offered. No prophylactic antiemetics are needed for mini- tolerated in these patients. Nausea was also well controlled. mally emetogenic chemotherapy. Patients suffering from an- Olanzapine was also studied in another phase II trial in ticipatory nausea and vomiting should be referred for behav- 40 patients receiving HEC and MEC.44 All patients were ioral therapies such as relaxation techniques, hypnosis, and treated with an antiemetic regimen containing palonosetron others. If medication is needed, a benzodiazepine, such as and dexamethasone on day 1. Olanzapine was given at a dose lorazepam or alprazolam, can be offered the night before and of 10 mg orally daily for 5 days starting before chemotherapy the morning of chemotherapy treatment. administration. No other antiemetic agents were given in the delayed phase. For the 8 patients receiving HEC, the complete antiemetic response rate was 100% in the acute phase NEWER ANTIEMETIC RESEARCH and 75% in the delayed phase. For the 32 patients receiving Although modern antiemetic regimens offer complete HEC, the complete response rate was 97% in the acute phase protection for most patients, a significant number of patients and 75% in the delayed phase. This antiemetic regimen was have residual or refractory CINV. Newer agents are being well tolerated, but fatigue, drowsiness, and dry mouth were investigated for activity in preventing nausea and vomiting. reported. The authors concluded that this three-drug regimen Some of these agents are chemically related to currently was very effective in controlling CINV symptoms. available agents and other suggest new mechanisms of action. Olanzapine appears to be an effective alternative treatment for refractory CINV symptoms and is well tolerated in Olanzapine most patients without excessive sedation. Further studies Olanzapine is an atypical antipsychotic medication that comparing olanzapine-containing antiemetic regimens with is usually used to treat mania and schizophrenia. However, it other regimens containing aprepitant in both phases and also antagonizes several neurotransmitters involved in the dexamethasone in the delayed phase will be required before CINV pathways. These include several serotonin (including olanzapine can be routinely recommended for prophylactic 5HT3) and dopamine receptors and others including musca- CINV regimens. rinic, histamine, and adrenergic receptors. The antipsychotic dose range starts at 5–10 mg daily, but can be adjusted Gabapentin upward to 20 mg daily. The usual adverse effects seen with Gabapentin is an anticonvulsant medication that is the antipsychotic uses of olanzapine include sleepiness, ex- active in several seizure disorders and in diabetic neuropathy, trapyramidal effects, insomnia, dizziness, weight gain, and postherpetic neuropathy, migraines, and bipolar disorder as dry mouth. well as vasomotor hot flashes. Gabapentin is an analog of The activity of olanzapine as an antiemetic was first ␥-aminobutyric acid, but its mechanism of action involves demonstrated in the hospice/palliative care arena, in patients calcium channels that control neurotransmitter release. The with advanced cancer and refractory nausea and vomit- anticonvulsant dose begins with 300 mg orally 3 times daily but ing.38–40 These studies described good effectiveness from can be advanced slowly up to 2400 mg daily. The neuropathic olanzapine without excessive sedation. pain dose starts at 100 mg orally three times daily and can be In a phase I trial, olanzapine was administered to adjusted up to 1800 mg daily. Gabapentin is renally eliminated, patients receiving HEC and MEC regimens with standard and the dose should be adjusted for patients with reduced renal antiemetics.41 The maximally tolerated dose of olanzapine function to lower the chance of CNS adverse effects. The most was 5 mg orally daily for 9 days, starting 2 days before common adverse effects include sleepiness, dizziness, confu- chemotherapy. Most of the patients receiving HEC and all the sion, tremor, and headache. patients receiving MEC exhibited a complete antiemetic re- In one publication, a group of researchers described the sponse. case of a patient with refractory CINV.45 This patient was Another study described the retrospective chart review given gabapentin in an effort to control her hot flashes and of 28 patients who had received olanzapine for prevention of subsequently her persistent nausea and vomiting resolved. delayed CINV symptoms.42 Most of these patients had re- This same group of researchers then conducted a noncon- ceived HEC or MEC and had received other antiemetics and trolled trial in 9 patients with breast cancer who had experi- had a history of CINV symptoms. Olanzapine had been enced significant nausea with the chemotherapy regimen con- administered in doses from 2.5–5mg daily. These researchers taining doxorubicin and cyclophosphamide every 3 weeks. A noted a fairly low rate of nausea and vomiting in these highly routine antiemetic regimen (containing ondansetron and dexa-

© 2008 Lippincott Williams & Wilkins 91 Lohr The Cancer Journal • Volume 14, Number 2, March/April 2008 methasone) was used, and some of the patients received loraz- both of these preliminary trials. Information about potential epam. The gabapentin dose was 300 mg orally every night for 2 drug interactions with casopitant is not available at this time. days, starting 5 days before chemotherapy. Then gabapentin was continued at 300 mg orally 2 times daily for 2 days and then at 300 mg orally 3 times daily for 6 days. Most of the patients (7 CONCLUSION of 9 patients) experienced improvement in their nausea scores in CINV involves a complex interaction between multiple the acute phase. Eight of the 9 patients had reductions in their organs and multiple neurotransmitters. Likewise, multiple delayed-phase nausea. Most of the patients experienced a sig- antiemetic agents are needed in conjunction to help control nificant reduction, with a median reduction of 3 points on a nausea and vomiting. With our most effective modern anti- 7-point nausea scale. The gabapentin treatment was well toler- emetic regimens, not all patients are completely protected, ated, with only 2 patients having mild to moderate sleepiness. although they may hesitate to tell their caregivers how they Gabapentin was also studied in another noncontrolled are faring. Continued research is needed to provide the trial in patients receiving HEC and MEC treatments.46 These optimal, most cost-effective antiemetic therapy possible. 24 patients had experienced moderate to severe CINV symptoms after previous chemotherapy cycles. A standard anti- REFERENCES emetic regimen with a 5HT3 antagonist and dexamethasone 1. Ettinger DS, Bierman PJ, Bradbury B, et al. Antiemesis: clinical practice was given to all patients. 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