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20-10-2015 | Nausea and vomiting | Book chapter | Article

37. Chemotherapy-Induced Nausea and Vomiting: Molecular Mechanisms and Clinical Approaches

Author: M.D., Ph.D., F.A.C.P. Rudolph M. Navari

Publisher: Springer International Publishing

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Aprepitant, the first clinically available NK-1 receptor antagonist, has been used effectively as an additive agent to the 5-HT3 receptor antagonists and dexamethasone to control CINV. Rolapitant and Netupitant are other NK-1 receptor antagonists that are currently in phase III clinical trials. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a U.S.-Food and Drug Administration (FDA) approved antipsychotic, has emerged in recent trials as an effective preventative agent for CINV, as well as an effective agent for the treatment of breakthrough emesis and nausea. Clinical trials using gabapentin, cannabinoids, and ginger have not been definitive regarding their efficacy in the prevention of CINV. Additional studies are necessary for the control of nausea and for the control of CINV in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

37.1 Introduction

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life and is perceived by patients as a major adverse effect of the treatment [ 1, 2]. Increased risk of CINV is associated with the type of chemotherapy administered (Table 37.1) and specific patient characteristics (Table 37.2) [ 3, 4]. CINV can result in serious complications such as weakness, weight loss, electrolyte imbalance, dehydration, or anorexia and is associated with a variety of complications, including fractures, esophageal tears, decline in behavioral and mental status, and wound dehiscence [ 1]. Patients who are dehydrated, debilitated, or malnourished, as well as those who have an electrolyte imbalance or those who have recently undergone surgery or radiation therapy, are at greater risk of experiencing serious complications from CINV [ 1, 3, 4].
Table 37.1
Emetic potential of chemotherapy agents
Emetogenic potential
Typical agents
Definition (no CINV prevention)
High
Cisplatin
Emesis in nearly all patients
Dacarbazine
Melphalan (high dose)
Nitrogen mustard
Cyclophosphamide plus an Anthracycline
Moderate
Anthracyclines
Emesis in >70 % of patients
Carboplatin
Carmustine (high dose)
Cyclophosphamide
Ifosfamide
Irinotecan
Methotrexate (high dose)
Oxaliplatin
Topotecan
Low
Etoposide
Emesis in 10–70 % of patients
5-Fluorouracil
Gemcitabine
Mitoxantrone
Taxanes
Vinblastine
Vinorelbine
Minimal
Bortezomib
Emesis in <10 % of patients
Hormones
Vinca alkaloids
Bleomycin
Table 37.2
Patient-related risk factors for emesis following chemotherapy
Major factors
Minor factors
Female
History of motion sickness
Age <50 years
Emesis during past pregnancy
History of low prior chronic alcohol intake (<1 oz of alcohol/day)
 
History of previous chemotherapy-induced emesis
 
The use of 5-hydroxytryptamine-3 (5-HT 3) receptor antagonists plus dexamethasone has improved the control of CINV [ 5, 6]. Recent studies have demonstrated some improvement in the control of CINV with the use of three new agents, palonosetron, a second generation 5-HT 3 receptor antagonist [ 5, 6], aprepitant, the first agent available in the drug class of neurokinin-1 (NK-1) receptor antagonists [ 7, 8], and olanzapine, an antipsychotic which blocks multiple neurotransmitters in the central nervous system [ 912].
The primary endpoint used for studies evaluating various agents for the control of CINV has been complete response (no emesis, no use of rescue medication) over the acute (24 h post-chemotherapy), delayed (24–120 h), and overall (0–120 h) periods [ 3, 4]. Recent studies have shown that the combination of a 5-HT 3 receptor antagonist, dexamethasone, and a NK-1 receptor antagonist have improved the control of emesis in patients receiving either highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) over a 120 h period following chemotherapy administration [ 7, 8]. Many of these same studies have measured nausea as a secondary endpoint and have demonstrated that nausea has not been well controlled [ 13].
Emesis is a well defined event which is easily measured, but nausea may be more subjective and more difficult to measure. There are, however, two well defined measures of nausea which appear to be effective measurement tools which are reproducible: the Visual Analogue Scale (VAS) and the Likert Scale [ 14]. The VAS is a scale from 0 to 10 or 0 to 100 with zero representing no nausea and 10 or 100 representing maximal nausea. The Likert Scale asks patients to rate nausea as None, Mild, Moderate or Severe. Many studies have reported the secondary endpoint of “no significant nausea” or “only mild nausea” [ 38]. Studies that have reported “no nausea” may be more useful in identifying the most effective available antinausea agents [ 14].
Despite the introduction of more effective antiemetic agents, emesis and nausea remain a significant complication of chemotherapy. The purpose of this chapter is to evaluate the clinical agents available for the prevention and treatment of chemotherapy induced emesis and nausea. The use of these agents in various clinical settings is described using the recently established guidelines from the Multinational Association of Supportive Care in Cancer (MASCC) and the European Society of Medical Oncology (ESMO) [ 15], the American Society of Clinical Oncology (ASCO) [ 16] and the National Comprehensive Cancer Network (NCCN) [ 17]. The literature cited in the report consists of the primary clinical trials used for the U.S. FDA approval of the various agents as well as recent comprehensive reviews.

37.1.1 Pathophysiology of Nausea and Vomiting

The sensation of nausea and the act of vomiting are protective reflexes that rid the intestine and stomach of toxic substances. The experience of nausea is subjective, and nausea may be considered a prodromal phase to the act of vomiting [ 14] although significant nausea may occur without vomiting. Vomiting consists of a pre-ejection phase, retching, and ejection and is accompanied by shivering and salivation. Vomiting is triggered when afferent impulses from the cerebral cortex, chemoreceptor trigger zone (CTZ), pharynx, and vagal afferent fibers of the gastrointestinal (GI) tract travel to the vomiting center (VC), located in the medulla (Fig. 37.1). Efferent impulses then travel from the vomiting center to the abdominal muscles, salivation center, cranial nerves, and respiratory center, causing vomiting. It is thought that chemotherapeutic agents cause vomiting by activating neurotransmitter receptors located in the CTZ, GI tract, and vomiting center [ 14].
The mechanisms of emesis are not well defined, but investigations suggest that emesis may be primarily mediated through neurotransmitters (serotonin, dopamine, substance P) in the GI tract and the central nervous system [ 14]. Figure 37.1 shows that chemotherapy agents may directly affect areas in the cerebral cortex, the medulla oblongata, or may stimulate the small intestine of the GI tract via the vagus nerve. A VC, termed the “central pattern generator” by some authors [ 18], appears to be located in the lateral reticular formation of the medulla, which coordinates the mechanism of nausea and vomiting. An additional important area, also located in the medulla, is the CTZ in the area postrema near the fourth ventricle [ 18]. It is strongly suspected that the nucleus tractus solitarius (NTS) neurons lying ventrally to the area postrema initiate emesis [ 19]. This medullary area is a convergence point for projections arising from the area postrema and the vestibular and vagal afferents [ 19]. The NTS is a good candidate for the site of action of centrally acting antiemetics.
The main approach to the control of emesis has been to identify the active neurotransmitters and their receptors in the central nervous system and the GI tract that mediate the afferent inputs to the VC (Fig. 37.2). Agents that may block these neurotransmitter receptors in the CTZ, the VC, or the GI tract may be useful in preventing or controlling emesis (Table 37.3).
Table 37.3
Antiemetic receptor antagonists
Dopamine receptor antagonists
5-HT 3 receptor antagonists
Dopa-5-HT 3 receptor antagonists
NK-1 receptor antagonists
Butyrophenones
Azasetron
Metoclopramide
Aprepitant (MK-869)
Olanzapine
Dolasetron (not recommended for use per FDA)
Fosaprepitant
Phenothiazines
Granisetron
Casopitant
Olanzapine
Netupitant
Ondansetron (intravenous dose restriction per FDA)
Rolapitant
Palonosetron
Ramosetron
Tropisetron
Nausea is a difficult-to-describe, sick or queasy sensation, usually perceived as being in the stomach that is sometimes followed by emesis [ 14]. The experience of nausea is difficult to describe in another person. Nausea and emesis are not necessarily on a continuum. One can experience nausea without emesis and one can have sudden emesis without nausea. Nausea has been assumed to be the conscious awareness of unusual sensations in the VC of the brainstem (Fig. 37.1), but the existence of such a center and its relationship to nausea remain controversial [ 14].
The study of the receptors that are illustrated in Fig. 37.2 has guided the development of the antagonists to the serotonin and the substance-P receptors with relative success in controlling emesis. It is not clear whether the serotonin and/or the substance P receptors are important in the control of nausea. Other receptors such as dopaminergic, histaminic and muscarinic may be the dominant receptors in the control of nausea [ 3, 4, 13].

37.1.2 Types of CINV

Five categories are used to classify CINV: acute, delayed, anticipatory, breakthrough, and refractory. Nausea and vomiting may occur any time after the administration of chemotherapy, but the mechanisms appear different for CINV occurring in the first 24 h after chemotherapy in contrast to that which occurs in the period of 1–5 days after chemotherapy. In order to differentiate these mechanisms, the term acute-onset CINV refers to nausea and/or vomiting occurring within 24 h of chemotherapy administration [ 3, 4]. The incidence of acute emesis and/or nausea reflects several treatment-related factors, including the environment in which chemotherapy is administered, the emetogenicity of the chemotherapy, the dosage of the emetogenic agents, and patient-related factors [ 3, 4, 20].
Nausea and/or vomiting that develop more than 24 h after chemotherapy administration is known as delayed emesis and/or nausea. Typically occurring with administration of cisplatin, doxorubicin, or cyclophosphamide, delayed emesis/nausea is more common in those who experience acute emesis/nausea. Other predictive factors include the dose and the emetogenicity of the chemotherapeutic agent, patient gender and age, and protection against nausea and vomiting in previous cycles of chemotherapy [ 1, 3, 4, 20]. For cisplatin, which has been most extensively studied, delayed emesis reaches peak intensity 2–3 days subsequent to chemotherapy administration and can last up to a week [ 1, 3, 4, 1517, 20].
If patients experience CINV, they may develop a conditioned response known as anticipatory nausea and/or vomiting which occurs prior to the administration of chemotherapy in future chemotherapy cycles and is attributed to the adverse memory of prior CINV. Incidence rates for this type of nausea and vomiting range from 10 % to 45 %, with nausea occurring more frequently [ 1, 3, 4, 20].
Vomiting and/or nausea that occurs within 5 days after prophylactic use of antiemetic agents or requires “rescue” is called breakthrough emesis [ 21]. Vomiting and/or nausea occurring after chemotherapy in subsequent chemotherapy cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles is known as refractory emesis [ 1, 3, 4, 1517, 20].

37.2 Antiemetic Agents

37.2.1 Dopamine Receptor Antagonists

Dopamine receptors are known to exist in the CTZ, and this is the main area of activity of the dopamine antagonists, such as the phenothiazines and the butyrophenones (droperidol, haloperidol). A high level of blockade of the dopamine receptors, however, results in extrapyramidal reactions, as well as disorientation and sedation, limiting the clinical use of these agents. Their current use is primarily to treat established nausea and emesis and not for CINV prophylaxis [ 17].

37.2.2 Serotonin (5-HT3) Receptor Antagonists

Serotonin receptors, specifically the 5-HT 3 receptors, exist in the central nervous system and in the GI tract. The 5-HT 3 receptor antagonists appear to act through both the central nervous system and the GI tract via the vagus and splanchnic nerves. The main toxicities of these 5-HT 3 receptor antagonists consist only of a mild headache and occasional diarrhea [ 22, 23].
The introduction of 5-HT 3 receptor antagonists for the prevention of chemotherapy-induced nausea and emesis, as well as post-operative and radiotherapy- induced nausea and vomiting, has resulted in an improvement in supportive care [ 22, 23]. Treatment guidelines for the prevention of CINV recommended by a number of international groups [ 1517] suggest the use of a 5-HT 3 receptor antagonist and dexamethasone prechemotherapy for the prevention of acute CINV and the use of dexamethasone following chemotherapy for the prevention of delayed nausea and vomiting.

37.2.2.1 First Generation Serotonin (5HT3) Receptor Antagonists

Table 37.4 shows the 5-HT 3 receptor antagonists currently in use. The first generation serotonin (5-HT 3) receptor antagonists, dolasetron, granisetron, and ondansetron, tropisetron [ 24], azasetron [ 25] and ramosetron [ 26], are equivalent in efficacy and toxicities when used in the recommended doses and compete only on an economic basis [ 27]. The most commonly reported adverse events being mild headache, constipation, and occasionally mild diarrhea [ 3, 4]. Azasetron and ramosetron are not available in North America and Europe and have not been compared extensively to the other 5-HT 3 receptor antagonists. They are marketed primarily in southeast Asia.
Table 37.4
Serotonin antagonists and dosage before chemotherapy
Antiemetic
Route
Dosage
Azasetron
IV
10 mg
Dolasetron (not recommended for use per FDA)
IV
100 mg or 1.8 mg/kg
PO
100 mg
Granisetron
IV
10 μg/kg or 1 mg
PO
2 mg (or 1 mg twice daily)
Ondansetron
IV
8 mg (restricted to <16 mg)
PO
24 mg
Palonosetron
IV
0.25 mg
PO
0.50 mg
Ramosetron
IV
0.30 mg
Tropisetron
IV or PO
5 mg
The same doses are used for highly and moderately emetic chemotherapy
A prolongation of cardiac conduction intervals has been reported for this class of compounds with dolasetron being more extensively studied than granisetron and ondansetron [ 28]. In 2006, Canada issued a drug alert for dolasetron, due to the potential of serious cardiovascular adverse events (cardiac arrhythmias) [ 29], stating that dolasetron was not indicated for use in children, but only for prevention of CINV in adults [ 29]. Subsequently, in 2010, the U.S. FDA announced that the intravenous form of dolasetron should no longer be used to prevent CINV in any patient. New data suggests that dolasetron injection can increase the risk of developing a prolongation of the QTc interval which may potentially precipitate life threatening ventricular arrhythmias [ 30, 31].
In 2012, the U.S. FDA placed a restriction on the doses of intravenous ondansetron due to the risk of prolongation of the QTc interval [ 32]. Patients who may be at particular risk for QT prolongation with ondansetron are those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QTc interval. New information indicates that QT prolongation occurs in a dose-dependent manner, and specifically at a single intravenous dose of 32 mg. The lower dose intravenous regimen of 0.15 mg/kg every 4 h for three doses may be used in adults with CINV. However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation. The new information does not change any of the recommended oral dosing regimens for ondansetron, including the single oral dose of 24 mg for CINV [ 32].
The first generation 5-HT 3 receptor antagonists have not been as effective against delayed emesis as they are against acute CINV [ 3335]. The first generation 5-HT 3 receptor antagonists alone do not add significant efficacy to that obtained by dexamethasone in the control of delayed emesis [ 34]. Hickok et al. [ 35] reported that the first generation 5-HT 3s used in the delayed period were no more effective than prochlorperazine in controlling nausea. The antiemetic effects of prochlorperazine can be attributed to postsynaptic dopamine receptor blockade in the CTZ. A meta analysis [ 34] showed that there was neither clinical evidence nor considerations of cost effectiveness to justify using the first generation 5-HT 3 antagonists beyond 24 h after chemotherapy for the prevention of delayed emesis.
A number of recent studies have demonstrated that there has been poor control of delayed nausea by the first generation 5-HT 3 receptor antagonists in patients receiving HEC or MEC [ 10, 13, 36, 37] (Table 37.5). The use of granisetron and dexamethasone in patients receiving HEC resulted in “no nausea” in 25–27 % of patients [ 36]. The use of ondansetron plus dexamethasone in patients receiving MEC resulted in “no nausea” in 33 % of patients and “no significant nausea” in 56 % of patients [ 37].
Table 37.5
Phase II and III trials of various agents for the treatment of chemotherapy induced nausea
Study
Chemotherapy
Phase II or III
No. patients
No nausea, delayed (%)
No nausea, overall (%)
Saito et al. [ 36]
HEC
III
1,114
Palo+Dex: 38*
Palo+Dex: 32*
Gran+Dex: 27
Gran+Dex: 25
Hesketh et al. [ 38]
HEC
III
1,043
No data
Women:
 Aprepitant: 46
 Control: 38
Men:
 Aprepitant: 50
 Control: 44
Warr et al. [ 39]
     
Aprepitant 52*
Aprepitant 48*
Control 44
Control 42
Warr et al. [ 37]
Cyclo+Doxo/Epi
III
866
Aprepitant: 37
Aprepitant: 33
Control: 36
Control: 33
Grote et al. [ 40]
MEC
II
58
APD: 31
APD: 30
Celio et al. [ 41]
MEC
III
334
Palo+Dex1: 57
Palo+Dex1: 52
Palo+Dex3: 62
Palo+Dex3: 57
Aapro et al. [ 42]
Cyclo+Doxo/Epi
III
300
Palo+Dex1: 50
Palo+Dex1: 47
Palo+Dex3: 55
Palo+Dex3: 50
Navari et al. [ 9]
MEC
II
32
OPD: 78
OPD: 78
Tan et al. [ 10]
MEC
III
229
OAD: 83*
OAD: 83*
HEC
III
 
AD: 58
AD: 56
OAD: 70*
OAD: 70*
AD: 30
AD: 28
Navari et al. [ 11]
HEC
III
257
OPD: 69*
OPD: 69*
APD: 38
APD: 38
Cruz et al. [ 43]
HEC
III
80
Gabapentin: 72
Gabapentin: 62
Control: 52
Control: 45
Meiri et al. [ 44]
MEC, HEC
III
61
No difference between dronabinol or ondansetron
Not reported
Palo palonosetron, Dex dexamethasone, Gran granisetron, Cyclo cyclophosphamide, Doxo doxorubicin, Epi epirubicin, APD aprepitant, palonosetron, dexamethasone, OPD olanzapine, palonosetron, dexamethasone, OAD olanzapine, azasetron, dexamethasone, AD azasetron, dexamethasone, Dex1 1 day of dexamethasone, Dex3 3 days of dexamethaone (*p < 0.01)

37.2.2.2 Second Generation Serotonin (5-HT3) Receptor Antagonist: Palonosetron

Palonosetron is a second generation 5-HT 3 receptor antagonist which has antiemetic activity at both central and GI sites. In comparison to the first generation 5- HT 3 receptor antagonists, it has a higher potency, a significantly longer half-life, and a different molecular interaction with 5-HT 3 receptors [ 5, 6, 45, 46]. Palonosetron has been approved for clinical use, and studies suggest that it may have some efficacy in controlling delayed CINV compared to the first generation 5-HT 3 receptor antagonists.
Palonosetron demonstrated a 5-HT 3 receptor binding affinity at least 30-fold higher than other 5-HT 3 receptor antagonists [ 45]. Rojas et al. [ 46] recently reported that palonosetron exhibited allosteric binding and positive cooperativity when binding to the 5-HT 3 receptor compared to simple bimolecular binding for both granisetron and ondansetron. Additional studies by Rojas et al. [ 46] suggested that palonosetron triggers 5-HT 3 receptor internalization and causes prolonged inhibition of receptor function. Differences in binding and effects on receptor function may explain some differences between palonosetron and the first generation 5-HT 3 receptor antagonists [ 5, 6]. These differences may explain palonosetron’s efficacy in delayed CINV compared to the first generation receptor antagonists [ 5, 6].
Phase III comparative studies [ 4749] suggest that the use of palonosetron alone improves the complete response rate of acute and delayed emesis, when compared with the use of the first generation 5-HT 3 receptor antagonists alone in patients receiving MEC [ 48, 49]. In patients receiving HEC, palonosetron was as effective as ondansetron in the prevention of acute CINV and with dexamethasone pre-treatment, palonosetron was significantly better than ondansetron in the overall 120-h post-treatment period [ 47].
In patients receiving HEC, a recent study showed that palonosetron plus dexamethasone was significantly better than granisetron and dexamethasone in delayed complete response and control of nausea, but there was a low number of patients with no nausea with either regimen (no nausea, overall period: 31.9 % palonosetron group; 25.0 % granisetron group) [ 36] (Table 37.5).
Two recent studies reported that palonosetron plus 1 day of dexamethasone was as effective as palonosetron plus 3 days of dexamethasone in the prevention of acute and delayed CINV in patients receiving MEC [ 41, 42]. Boccia et al. recently demonstrated that oral palonosetron had similar efficacy and safety as intravenous palonosetron for the prevention of acute CINV in patients receiving MEC [ 50].
In a systematic review and meta-analysis of all randomized controlled trials comparing a single dose of palonosetron with other 5-HT 3 receptor antagonists, Borrel et al. [ 51] concluded that palonosetron was more effective than the first generation receptor antagonists in preventing acute and delayed CINV in patients receiving MEC or HEC, regardless of the use of concomitant corticosteroids. In an additional systematic review of the medical literature, Fabi and Malaguti [ 52], reported that palonosetron was the only serotonin receptor antagonist approved for the prevention of delayed CINV caused by MEC.
The safety and tolerability of palonosetron has been well documented in multiple, large phase III trials. There were no clinically relevant differences seen among palonosetron, ondansetron, or dolasetron in laboratory, electrocardiographic, or vital sign changes over multiple cycles of chemotherapy [ 48, 49, 5155]. The adverse reactions reported were the most common reactions reported for the 5-HT 3 receptor antagonist drug class. There have been no reports of any adverse cardiac events with palonosetron, specifically no prolongation of the QTc interval in healthy volunteers or patients receiving repeated cycles of emetogenic chemotherapy [ 5, 6, 5355].
Based on the clinical studies, palonosetron is highly effective in controlling acute and delayed CINV in patients receiving either MEC or HEC. Compared to the first generation 5-HT 3 receptor antagonists, palonosetron has equivalent efficacy in controlling acute CINV and is more effective in controlling delayed CINV.
The published clinical studies on palonosetron have prompted the international guideline groups to recommend palonoseteron as the preferred 5-HT 3 receptor antagonist for the prevention of acute nausea and vomiting for patients receiving HEC and for the prevention of delayed nausea and vomiting for patients receiving MEC [ 17].
Two recent studies have reported that the complete response rates for both acute and delayed CINV were maintained with the single intravenous dose of palonosetron in patients receiving repeated courses of HEC [ 53, 54].
Despite the use of both first generation and second generation 5-HT 3 receptor antagonists, the control of acute CINV, and especially delayed nausea and vomiting, is sub-optimal with the agents listed in Table 37.4. There is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens [ 23, 35, 56].

37.2.3 Dopamine-Serotonin Receptor Antagonists

Metoclopramide has antiemetic properties both in low doses as a dopamine receptor antagonist and in high doses as a serotonin receptor antagonist. The use of metoclopramide may be somewhat efficacious in relatively high doses (≥20 mg orally, three times/day) in the delayed period, but may result in sedation and extrapyramidal side effects [ 22, 23]. Metoclopramide has been used both as a preventative agent for CINV [ 23] as well as a treatment for breakthrough CINV [ 17].

37.2.4 Neurokinin-1 (NK-1) Receptor Antagonists

Substance P is a mammalian tachykinin that is found in vagal afferent neurons innervating the brainstem NTS, which sends impulses to the VC [ 57]. Substance P induces vomiting and binds to NK-1 receptors in the abdominal vagus, the NTS, and the area postrema [ 57]. Compounds that block NK-1 receptors lessen emesis after cisplatin, ipecac, apomorphine, and radiation therapy [ 49]. These observations have recently led to the development of NK-1 receptor antagonists and the study of the role they may play in controlling chemotherapy-induced nausea and emesis.

37.2.4.1 Aprepitant

Aprepitant is a NK-1 receptor antagonist which blocks the emetic effects of substance-P [ 7, 8, 23]. When combined with a standard regimen of the corticosteroid dexamethasone and a 5-HT 3 receptor antagonist, aprepitant is effective in the prevention of CINV in patients receiving HEC [ 8, 23]. This regimen is recommended in the guidelines of multiple international groups for the control of CINV in patients receiving HEC [ 1517].
Combined data from two large phase III trials of aprepitant plus a first generation 5-HT 3 receptor antagonist and dexamethasone for the prevention of CINV in patients receiving HEC demonstrated an improvement in complete response when aprepitant was added to ondansetron and dexamethasone [ 7, 8]. There was no improvement, however, in nausea when the pooled data was analyzed for gender (no nausea, overall period: 46 % for women, aprepitant group, 38 % for women, control group; 50 % for men, aprepitant group, 44 % for men, control group) [ 38] (Table 37.5). Using the same pooled data, a separate analysis [ 39] showed a statistical, but small improvement in no nausea with the use of aprepitant (no nausea, overall period: 48 %, aprepitant group; 42 %, control group) (Table 37.5).
In a similar study involving breast cancer patients receiving cyclophosphamide and doxorubicin or epirubicin, aprepitant was added to ondansetron and dexamethasone for the prevention of CINV. The addition of aprepitant to the 5-HT 3 receptor antagonist plus dexamethasone improved the complete response, but there was no improvement in nausea (no nausea, overall period: 33 % aprepitant group; 33 % control group) [ 37].
Palonosetron and aprepitant have been combined with dexamethasone for the prevention of CINV in a phase II study of 58 patients who received doxorubicin and cyclophosphamide [ 40]. This three-drug antiemetic regimen was found to be safe and highly effective in preventing emesis and rescue in the acute, delayed, and overall periods, but there was poor control of nausea (no nausea, overall period: 30 %) (Table 37.5).

37.2.4.2 Fosaprepitant

Fosaprepitant (also known as MK-0517 and L-758,298) is a water soluble phosphoryl pro-drug for aprepitant which, when administered intravenously, is converted to aprepitant within 30 min via the action of ubiquitous phosphatases. The pharmacological effect of fosaprepitant is attributed to aprepitant. Due to the rapid conversion of fosaprepitant to the active form (aprepitant) by phosphatase enzymes, it is expected to provide the same aprepitant exposure in terms of area under the curve (AUC) and a correspondingly similar antiemetic effect [ 58].
In a study in healthy subjects, fosaprepitant was well tolerated up to 150 mg (1 mg/ml), and fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg [ 59]. Fosaprepitant in the intravenous dose of 115 mg has been approved by the U.S. FDA (February, 2008) and the European Union (January, 2008) as an alternative to oral aprepitant 125 mg on Day 1 of a 3-day regimen, with oral aprepitant 80 mg administered on Days 2 and 3 [ 58]. Further studies have demonstrated that a single dose of fosaprepitant, 150 mg intravenously, on day 1 of cisplatin chemotherapy was noninferior to a 3-day oral regimen of aprepitant in the prevention of CINV in the 120 h postchemotherapy [ 60].

37.2.4.3 Casopitant

Casopitant is a novel substituted piperazine derivative, which has potential for the treatment of conditions mediated by tachykinins, including substance P and other neurokinins. Casopitant competitively binds to the NK-1 receptor, thereby inhibiting NK-1 receptor binding of substance P and blocking the activity of the receptor [ 61]. Casopitant and its mesylate salt have been developed for the potential treatment of CINV, post-operative nausea and vomiting (PONV), anxiety, depression, and insomnia.
Three phase III clinical trials with intravenous and oral casopitant have been completed [ 6264]. Two of the trials demonstrated that casopitant, when used in addition to dexamethasone plus ondansetron, was more effective in the prevention of vomiting than dexamethasone and ondansetron alone in patients with solid malignant tumors receiving cisplatin-based HEC [ 62] and non-cisplatin-based MEC [ 63].
In the phase III studies, there have been no reported serious adverse events related to casopitant, and the reported common adverse events (neutropenia, constipation, alopecia, fatigue) occurred with comparable frequency across control and treatment groups [ 6264]. In the subsequent application to the U.S. FDA for approval of casopitant, some additional toxicity issues were apparently raised. At this time, there has been no reported further development of casopitant.

37.2.4.4 Rolapitant

Rolapitant is a NK-1 receptor antagonist in clinical trials. A phase II trial for the prevention of CINV in patients receiving HEC demonstrated that rolapitant added to ondansetron and dexamethasone improved the complete response in the delayed and overall periods compared to ondansetron and dexamethasone alone [ 65]. A number of phase III trials for the prevention of CINV in patients receiving MEC or HEC are in progress [ 66].

37.2.4.5 Netupitant

Netupitant is a NK-1 receptor antagonist in clinical trials. Rossi et al. [ 67] reported that positive emission tomography results demonstrate that netupitant is a potent agent targeting NK-1 receptors. It appears to have a high degree of occupancy for a long duration when given as a single dose and appears to be well tolerated.
Recently reported phase III trials demonstrated that the combination of netupitant plus palonosetron significantly improved the complete response in the acute, delayed and overall periods compared to palonosetron alone in patients receiving MEC or HEC [ 68, 69].

37.2.5 Dexamethasone

Dexamethasone has been an effective antiemetic in controlling both acute and delayed CINV, and it is essentially the main corticosteroid used as an antiemetic. Concern has been expressed, however, with the potential toxicity of the use of multiple-day dexamethasone to control CINV [ 70]. Patients receiving dexamethasone as prophylaxis for CINV reported moderate to severe problems with insomnia, hyperglycemia, indigestion, epigastric discomfort, agitation, increased appetite, weight gain, and acne [ 70]. Dexamethasone might be decreased or eliminated in an antiemetic regimen if other agents effective in both the acute and delayed periods are employed.
Dexamethasone added to a 5-HT 3 receptor antagonist improves the control of acute CINV [ 1517], and it has been used as a single agent or in combination with other agents in an attempt to control delayed CINV [ 1517]. The available studies show that for patients receiving cisplatin, dexamethasone combined with a 5-HT 3 receptor antagonist has resulted in only a small reduction in the incidence of delayed CINV [ 23].
Celio et al. [ 71] used palonosetron in combination with a 1-day versus 3 days of dexamethasone to prevent CINV in patients receiving MEC. There was no improvement in complete response (67.5 % versus 71.1 %) or no nausea (52.1 % versus 56.5 %) over the 5-day overall period with the additional days of dexamethasone. A similar study [ 42] using palonosetron plus dexamethasone for 1 day versus 3 days for patients receiving MEC showed similar results: no improvement in complete response (53.6 % versus 53.7 %) or in no nausea (47.0 % versus 49.7 %) over the 5-day overall period (Table 37.5).

37.2.6 Olanzapine

Olanzapine is a U.S. FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT 2a, 5-HT 2c, 5-HT 3, 5-HT 6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors [ 7274]. Common side effects are sedation and weight gain [ 75, 76], as well as an association with the onset of diabetes mellitus [ 77]. Sedation has not been observed with the doses (≤10 mg/day for 3–5 days) administered for the prevention of CINV [ 9, 11]. Weight gain and the onset of diabetes is observed only when olanzapine is given at higher doses (>10 mg/day) for longer time periods (daily for >3 months) [ 7577]. Olanzapine’s activity at multiple receptors, particularly at the D2, 5-HT 2c, and 5-HT 3 receptors which appear to be involved in nausea and emesis, suggests that it may have significant antiemetic properties.
A phase I study demonstrated that olanzapine could be safely used for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin and/or irinotecan [ 78]. Using the maximum tolerated dose of olanzapine in the Phase I trial, a Phase II trial was performed for the prevention of CINV in patients receiving their first course of either HEC or MEC. When olanzapine was added to granisetron and dexamethasone in the acute period and added to dexamethasone in the delayed period, there was a very high complete response (no emesis, no rescue) and excellent control of nausea. The study concluded that olanzapine is safe and highly effective in controlling acute and delayed CINV in patients receiving HEC and MEC [ 79].
An additional phase II trial demonstrated that olanzapine, when combined with a single dose of dexamethasone and a single dose of palonosetron, was very effective in controlling acute and delayed CINV in patients receiving both HEC and MEC [ 9]. There was excellent control of nausea in 32 patients receiving MEC (no nausea: overall period, 78 %) without the use of multiple days of dexamethasone.
A phase III study showed the addition of olanzapine to the 5-HT 3 receptor antagonist azasetron and dexamethasone improved delayed CINV in patients receiving HEC or MEC [ 10]. There was significant improvement in nausea in the olanzapine group compared to the control group for patients receiving both HEC (no nausea, overall period: 70 % versus 28 %) and MEC (no nausea, overall period: 86 % versus 56 %).
A phase III study randomized patients receiving HEC to olanzapine, palonosetron, dexamethasone (OPD) or aprepitant, palonosetron, dexamethasone (APD) for the prevention of CINV [ 11]. The complete response was similar, but no nausea was significantly improved in the OPD group (no nausea, overall period: 69 % versus 38 %). These results were consistent with the previous phase II and phase III studies using olanzapine and suggest that olanzapine is an effective and safe agent for the control of both emesis and nausea (Table 37.5).
A recent study has compared olanzapine to metoclopramide for the treatment of breakthrough emesis and nausea in patients receiving HEC and guideline directed antiemetic prophylaxis. Olanzapine was significantly better than metoclopramide for the treatment of breakthrough emesis and nausea. This was the first phase III study on the treatment of breakthrough emesis and nausea [ 21].

37.2.7 Gabapentin

Gabapentin is a gamma-aminobutyric acid analogue which has been used for the treatment of seizures, chronic neuropathic pain, and postherpetic neuralgia [ 80]. The mechanism of action exerted by gabapentin is unknown. Gabapentin is structurally related to the neurotransmitter GABA, but it does not interact with GABA receptors, is not converted metabolically into GABA or a GABA agonist, and is not an inhibitor of GABA uptake or degradation [ 80].
Guttuso et al. [ 81] reported an improvement in CINV in six of nine breast cancer patients when gabapentin was used to prevent nausea. Cruz et al. [ 43] added gabapentin to ondansetron, dexamethasone, and ranitidine to prevent CINV in patients receiving HEC. The complete response was significantly improved in the patients receiving gabapentin but nausea was not significantly improved (no nausea, overall: 62 % versus 45 %) (Table 37.5).
A phase III clinical trial using gabapentin for the prevention of CINV in patients receiving HEC has been conducted by the North Central Cancer Treatment Group. Gabapentin did not improve delayed nausea and vomiting compared to dexamethasone alone in the delayed period [ 82].

37.2.8 Cannabinoids

Studies in animal models have suggested that delta-9-tetrahydrocannabinoid (dronabinol) selectively acts on CB1 receptors in specific regions of the dorsal vagal complex to inhibit emesis [ 83, 84]. There have been few reported studies that have explored this mechanism in patients [ 44, 85]. Meiri et al. [ 44] looked at the efficacy of dronabinol versus ondansetron in patients receiving chemotherapy for a wide variety of neoplasms. Dronabinol and ondansetron were similarly effective antiemetic treatments in 61 patients receiving MEC and HEC.
Nabilone is a synthetic cannabinoid, a racemic mixture of isomers, which mimics the main ingredient of cannabis (dronabinol). A recent review of the published English literature on the use of oral nabilone in the treatment of CINV concluded that cannabiniods do not add to benefits of the 5-HT 3 receptor antagonists [ 85].
In a recent review of cannabinoids in the prevention of CINV, Todaro [ 86] concluded that cannabinoids are not recommended as first-line use for the prevention of chemotherapy-induced nausea and vomiting, but may be considered for the treatment of breakthrough nausea and vomiting.

37.2.9 Ginger

Ginger is an herbal supplement which has been used for reducing the severity of motion sickness, pregnancy-induced nausea, and post-operative nausea and vomiting [ 87]. The mechanism of action by which ginger might exert antiemetic effects is unclear. Animal studies have described enhanced GI transport, anti-5-hydroxytryptamine activity, and possible CNS antiemetic effects. Human experiments to determine the mechanism of action show varying results regarding gastric motility and corpus motor response [ 87].
Pillai et al. [ 88] added ginger to ondansetron and dexamethasone in children and young adults receiving HEC and reported a reduction in the severity of acute and delayed CINV, but all patients had some nausea in days 1–4 postchemotherapy. Zick et al. [ 89] reported that ginger provided no additional benefit for reduction of the prevalence or severity of acute or delayed CINV when given with 5-HT 3 receptor antagonists and/or aprepitant in 162 cancer patients receiving chemotherapy. Ryan et al. [ 90] gave ginger before and after chemotherapy administration to 644 patients receiving a wide variety of chemotherapy regimens and found a reduction in nausea during the first day of chemotherapy. In total, the available studies do not support ginger as an agent to recommend for the prevention of chemotherapy-induced nausea [ 91].

37.3 Clinical Management of CINV

37.3.1 Principles in the Management of CINV

Antiemetic guidelines have been published by the National Comprehensive Cancer Network (NCCN) [ 17], the American Society of Clinical Oncology (ASCO) [ 16] and the Multinational Association Supportive Care in Cancer (MASCC) [ 15]. These guidelines form the basis of the recommendations for the management of CINV. As new information and new studies emerge, the guidelines will evolve to provide the highest quality, evidence-based clinical practice.

37.3.1.1 Single-Day Chemotherapy

For patients receiving HEC, current evidence suggests the following [ 1517]:
  • Prechemotherapy- Any of the 5-HT 3 receptor antagonists with dexamethasone and oral aprepitant. Fosaprepitant may be administered intravenously on day 1 as an alternative to 3 days of oral aprepitant.
The guidelines suggest that the combination of cyclophosphamide and doxorubicin should be considered as HEC and the appropriate preventative agents should be used.
  • Postchemotherapy- Oral aprepitant on days 2 and 3 (omit if fosaprepitant has been given on day 1) and dexamethasone on days 2–4.
The NCCN guidelines have recently endorsed the regimen of olanzapine, palonosetron, and dexamethasone as an alternative first-line preventative therapy for patients receiving HEC [ 17].
For patients receiving MEC, current evidence suggests the following [ 1517]:
  • Prechemotherapy- The 5-HT 3 receptor antagonist palonosetron plus dexamethasone. If palonosetron is not available, ondansetron or granisetron may be employed.
  • Postchemotherapy- Dexamethasone on days 2–4.
Antiemetic guidelines of the past [ 92] have included the available oral first generation 5-HT 3 receptor antagonists as optional therapy for the prevention of delayed emesis, but the level of evidence supporting this practice is low [ 23, 34, 35]. The first generation 5-HT 3 receptor antagonists are no longer recommended for use post chemotherapy [ 1517].
For patients receiving low emetogenic chemotherapy, a single agent in the form of a 5-HT 3 receptor antagonist, dexamethasone, or a phenothiazine, depending on the clinical situation, should be used prechemotherapy, and an antiemetic following chemotherapy should be given only as needed.

37.3.1.2 Treatment of Breakthrough CINV

A phenothiazine, metoclopramide, dexamethasone, or olanzapine may be effective in the treatment of breakthrough nausea and vomiting [ 17]. A 5-HT 3 receptor antagonist may also be effective unless a patient presents with nausea and vomiting which developed following the use of a 5-HT 3 receptor antagonist as prophylaxis for chemotherapy or radiotherapy-induced emesis. It is very unlikely that breakthrough nausea and vomiting will respond to an agent in the same drug class after unsuccessful prophylaxis with an agent with the same mechanism of action [ 21].
Patients who develop nausea or vomiting postchemotherapy (days 1–5) despite adequate prophylaxis should be considered for treatment with a 3-day regimen of oral olanzapine or oral metoclopramide. A recently completed phase III study demonstrated that oral olanzapine (10 mg/day for 3 days) was significantly better than oral metoclopramide (10 mg TID for 3 days) in controlling both emesis and nausea in patients receiving HEC who developed breakthrough CINV despite guideline directed prophylactic antiemetics [ 21]. The NCCN guidelines [ 17] recommend olanzapine as the preferred agent.
It is important to note that aprepitant has been approved as an additive agent to a 5-HT 3 receptor antagonist and dexamethasone for the prevention of CINV. It has not been studied and should not be used to treat breakthrough nausea and vomiting [ 21, 56].

37.3.1.3 Refractory CINV

Patients who develop CINV during subsequent cycles of chemotherapy when antiemetic prophylaxis has not been successful in controlling CINV in earlier cycles should be considered for a change in the prophylactic antiemetic regimen. If anxiety is considered to be a major patient factor in the CINV, a benzodiazepine such as lorazepam or aprazolam can be added to the prophylactic regimen. If the patient is receiving HEC, olanzapine (days 1–3) can be substituted for aprepitant or fosaprepitant in the prophylactic antiemetic regimen [ 11]. If the patient is receiving MEC, aprepitant or fosaprepitant can be added to the palonosetron and dexamethasone antiemetic regimen [ 93].

37.3.1.4 Anticipatory CINV

In order to prevent the occurrence of anticipatory CINV, patients should be counseled prior to the initial course of treatment concerning their “expectations” of CINV. Patients should be informed that very effective prophylactic antiemetic regimens will be used and that 70–75 % of patients will have a complete response (no emesis, no use of rescue medications). The most effective prophylactic antiemetic regimen for the patient’s specific type of chemotherapy should be used prior to the first course of chemotherapy in order to obtain the optimum control of CINV during the first course of chemotherapy. If CINV is effectively controlled during the first cycle, it is likely that the patient will have effective control during subsequent cycles of the same chemotherapy. If the patient has a poor experience with CINV in the first cycle, it may be more difficult to control CINV in subsequent cycles, and refractory and/or anticipatory CINV may occur. The use of anti-anxiety medications such as lorazepam or another benzodiazepine may be considered for excess anxiety prior to the first course of chemotherapy in order to obtain an optimum outcome and prevent anticipatory CINV. If anticipatory CINV occurs despite the use of prophylactic antiemetics, behavioral therapy might be considered.

37.3.1.5 Multi-day Chemotherapy and High-Dose Chemotherapy with Stem Cell or Bone Marrow Transplantation

Although there have been significant improvements in the prevention of CINV in patients receiving single-day HEC and MEC, there has been limited progress in the prevention of CINV in patients receiving multiple-day chemotherapy or high-dose chemotherapy with stem cell transplant. The current recommendation is to give a first generation 5-HT 3 receptor antagonist and dexamethasone daily during each day of chemotherapy in patients receiving multiple-day chemotherapy or high-dose chemotherapy with stem cell transplant [ 94]. This regimen appears to be at least partially effective in controlling acute CINV, but is not very effective in controlling delayed CINV. The complete response in most studies of 5 days of cisplatin and in various high-dose chemotherapy regimens is 30–70 % with the majority of studies reporting a complete response of ≤50 % [ 94].
Patients should receive the appropriate prophylaxis for the emetogenic risk of the chemotherapy for each day of the chemotherapy treatment. Both acute and delayed CINV may occur on day 2 or subsequent chemotherapy days and delayed CINV may occur after the last day of the multi-day chemotherapy treatment.
The antiemetic agents palonosetron, aprepitant, casopitant, and olanzapine have shown effectiveness in controlling both acute and delayed CINV in patients receiving single-day MEC and HEC. They may have application in patients receiving multiple-day or high-dose chemotherapy. Palonosetron has been used in one report of patients receiving 5 days of cisplatin [ 95], and Albany et al. [ 96] reported that the addition of aprepitant to a 5-HT 3 receptor antagonist and dexamethasone significantly improved the complete response in patients receiving 5 days of cisplatin.

37.3.1.6 Prevention and Treatment of Nausea

The current data in the literature from multiple large studies suggest that the first or second generation 5-HT 3 receptor antagonists and aprepitant have not been effective in the control of nausea in patients receiving either MEC or HEC, despite the marked improvement in the control of emesis with these agents [ 13]. It appears that neither the serotonin nor the substance P receptors may be important in mediating nausea. Recent phase II and phase III studies with olanzapine have demonstrated very good control of both emesis and nausea in patients receiving either MEC or HEC [ 911]. Preliminary small studies with gabapentin, cannabinoids, and ginger are inconclusive in defining their role, if any, in the prevention of CINV. At this time, olanzapine appears to have high potential for the prevention of both emesis and nausea in patients receiving MEC or HEC [ 10, 11]. If patients are having difficulty with significant nausea, consideration should be given to including olanzapine in their prophylactic antiemetic regimen [ 10, 11]. Olanzapine may also be efficacious in the treatment of breakthrough nausea [ 21].

37.4 Conclusions and Future Directions

The first generation 5-HT 3 receptor antagonists (dolasetron, granisetron, ondansetron, tropisetron, ramosetron, and azasetron) have significant and similar efficacy in the prevention of acute CINV for patients receiving MEC and HEC. However, these agents do not appear to have significant efficacy in the prevention of delayed CINV, and these 5-HT 3 agents compete primarily on an economic basis.
The second generation 5-HT 3 receptor antagonist palonosetron improves the complete response rate of acute and delayed emesis in patients receiving MEC and HEC. The current data in the literature of multiple large studies suggest that neither the first or second generation 5-HT 3 receptor antagonists have been effective in the control of nausea in patients receiving either MEC or HEC, despite the marked improvement in the control of emesis.
The NK-1 receptor antagonist aprepitant significantly improves the control of acute and delayed CINV when added to a 5-HT 3 receptor antagonist and dexamethasone for patients receiving HEC. The appropriate use of aprepitant in patients receiving MEC will be determined by future studies. Aprepitant does not appear to be effective as an antinausea agent.
Rolapitant and netupitant are NK-1 receptor antagonists currently in phase III trials, and they appear to have potential for use in the prevention of CINV.
Recently completed phase II and phase III clinical trials have demonstrated that the use of olanzapine in combination with a 5-HT 3 receptor antagonist and dexamethasone is safe and effective in the prevention of emesis and nausea in patients receiving MEC and HEC.
Olanzapine may be an important agent in the control of chemotherapy-induced nausea. Olanzapine is known to affect a wide variety of receptors including dopamine D2, 5-HT 2C, histaminic, and muscarinic receptors. Any or all of these receptors may be the mediators of chemotherapy-induced nausea.
Olanzapine also appears to be an effective agent in the treatment of breakthrough emesis and nausea.
Preliminary small studies with gabapentin have demonstrated some effectiveness in the control of chemotherapy-induced emesis, but the control of nausea remains to be determined. The studies on the use of cannabinoids and ginger do not support the use of these agents as effective in the prevention of CINV.
Clinicians and other healthcare professionals who are involved in administering chemotherapy should be aware that studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners [ 97], and patients often do not receive adequate prophylaxis [ 56, 98]. A number of international organizations have published extensive guidelines on the use of prophylactic antiemetic regimens as well as directives on the management of patients with breakthrough, refractory, and anticipatory CINV [ 1517]. Oncology practitioners are encouraged to use the evidenced based guidelines for the prevention of CINV.
Palonosetron, aprepitant, and olanzapine have not been studied extensively in multi-day chemotherapy, bone marrow transplantation, or radiotherapy-induced nausea and vomiting. Future studies may address whether these agents would be effective in patients who experience nausea and vomiting during these clinical settings. Future studies may determine not only how these agents should be used and what combinations of new and older agents will be the most beneficial for patients, but may also may provide new information on the mechanism of CINV.
Literature

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