**6. Management**

Antiemetic guidelines are published by all the cancer organizations including American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC). There are some differences among the guidelines particularly in the choice of the preferred 5-HT3 receptor antagonist and the use of cannabinoids. The general scheme for antiemetic protocols is similar for the various guidelines.

Prevention of CINV is the primary treatment to avoid subsequent episodes of CINV and anticipatory CINV. Due to physiopathology of CINV, 5-HT3 and NK1 receptor antagonists are the main classes of drugs Management include also both pharmacologic and nonpharmacologic agents such as steroids, dopamine antagonists, benzodiazepines, cannabinoids, antipsychotics. The primary issue is the prevention and treatment of moderately and highly emetogenic chemotherapy.

## **6.1 5-HT3 antagonists**

Selective 5-HT3 receptor antagonists have revolutionized the management of CINV. They are indicated in preventing and treating N/V induced by chemotherapy with moderate and high emetic potential. The 5-HT3 receptor antagonists include both first-generation drugs such as ondansetron (Zofran), dolasetron (Anzemet) and granisetron (Kytril) with half-life between 3–9 hours and second-generation drugs such as palonosetron (Aloxi) with half-life of approximately 40 hours. According to their half-life they are used in different indication with more use in acute CINV for first-generation drugs and delayed CINV for second-generation drugs. The first-generation antiemetic drugs are equivalent in efficacy [20–22] and they have few adverse events. The most common adverse events of 5-HT3 receptor antagonist include headache, constipation, transient high levels of hepatic enzymes

and QT prolongation [23]. The oral and intravenous formulation are therapeutically equivalent [24]. The first-generation drugs are more active in acute CINV and appear little active and modest active in delayed N/V induced by cisplatin and moderately emetogenic chemotherapeutic agents, respectively. The second-generation 5-HT3 receptor antagonist has a longer half-life and a greater binding affinity for the specific receptor. Three randomized prospective trials compared palonosetron with a first-generation antiemetic drug in patients receiving moderately and highly emetogenic chemotherapy. The noninferiority of palonosetron in term of complete response was demonstrated [25–27]. Some international guidelines consider palonosetron the preferred 5-HT3 antagonist for moderate emetogenic chemotherapy regimens but there are no prospective trials demonstrating the superiority of palonosetron compared to first-generation agents.

### **6.2 NK1 antagonists**

In the past 10 years, antiemetic treatment has greatly advanced with the availability of NK1 receptor antagonists. The NK1 receptor antagonists are the most recent class of antiemetic agents and include aprepitant (emend) fosaprepitant (ivemend), rolapitant (varuby) and netupitant (akynzeo). Aprepitant was the first approved agent in the class and is formulized as oral drug. In acute CINV the NK1 receptor antagonists are usually administered in combination with a 5-HT3 receptor antagonists and dexamethasone. 3-days aprepitant can also be administered in delayed CINV [28]. Three randomized prospective trials compared the combination of ondansetron plus dexamethasone plus aprepitant versus ondansetron and dexamethasone in patients receiving highly emetogenic chemotherapy. Aprepitant was administered before chemotherapy and continued along with dexamethasone. The addition of aprepitant led to an approximate 50% reduction in the risk of emesis or need for rescue medications [29–31]. These evidences underline the crucial role of aprepitant in the management of CINV induced by highly emetogenic chemotherapy. A randomized prospective trial investigated the use of aprepitant in moderately emetogenic chemotherapy in almost a thousand of patients with breast cancer. A significantly higher rate of complete response in the aprepitant group was reported [32]. Fosaprepitant is an intravenous NK1 receptor antagonist. In is a water-soluble phosphoryl prodrug of aprepitant converted to aprepitant within 30 minutes after administration. A randomized double-blind study reported that a single dose of fosaprepitant after ondansetron and dexamethasone was noninferior to a standard aprepitant 3-days regimen in preventing CINV in more than 2 thousand patients receiving cisplatin [33]. This evidence suggests that a single dose of fosaprepitant enhances the antiemetic effects provided by conventional 5-HT3 receptor agonists and corticosteroid therapy over conventional therapy alone and may provide a level of efficacy similar to that of the recommended 3-days aprepitant regimen. Rolapitant is a highly selective competitive long-acting NK-1 receptor antagonist demonstrating efficacy in randomized phase III trials. A single oral dose of rolapitant was effective in preventing delayed CINV compared with placebo, when each was used in combination with a 5-HT3 receptor antagonist plus dexamethasone in patients receiving highly or moderately emetogenic chemotherapy [34]. Netupitant is formulated with palonosetron in a fixed-dose combination. Complete response rates during the acute and delayed CINV were significantly higher with single-dose netupitant plus palonosetron than with single-dose palonosetron in highly and moderately emetogenic chemotherapy in phase II and III trials [35].

The most common adverse events of NK1 receptor antagonists are fatigue, hiccups, dyspepsia and diarrhea. The use of aprepitant requires the evaluation of potential drug interaction due to its mechanism of action moderately inhibiting

**155**

*Chemotherapy-Induced Nausea and Vomiting DOI: http://dx.doi.org/10.5772/intechopen.96194*

effectively used as single antiemetic agent (**Table 3**).

sedation, headache, dry mouth, hyperglycemia, diarrhea.

In CINV with low and moderate emetic potential, synthetic cannabinoids have been recently evaluated. The two known cannabinoid receptors are CB1 and CB2. Blocking of CB1 and CB2 results in emesis. Cannabinoids act as an agonist on the CB1 receptors, resulting in their pharmacologic effect [43]. The use of these agents with a lower therapeutic index is not recommended as first-line treatment for prevention of CINV and should be reserved for patients refractory to or intolerant of standard antiemetics. Evidence remains insufficient for a recommendation regarding medical marijuana for the prevention of nausea and vomiting in patients with cancer who receive chemotherapy or radiation therapy.

**6.4 Other antiemetic treatments**

**6.3 Steroids**

cytochrome CYP3A4. In particularly, aprepitant is related to an increase of plasma dexamethasone levels. Dexamethasone dose should be reduced when used in combination with aprepitant. Some antitumoral agents are also metabolized by CYP3A4 with the risk of increased toxicity when administered in combination with aprepitant. Aprepitant is also a weak inducer of the cytochrome CYP450. In patient receiving warfarin in combination with aprepitant the international normalized ratio (INR) decreases by 15% [36]. Rolapitant is well tolerated and its most common adverse events include neutropenia and dizziness. It inhibits CYP2D6 and it is metabolized by CYP3A4 so CYP3A4 inducers can reduce rolapitant blood levels and efficacy. The most common adverse events of netupitant include asthenia, dyspepsia, erythema and neutropenia. It is contraindicated in patients with severe renal and hepatic failure and it is an inhibitor of CYP3A4 as aprepitant [37–40].

The antiemetic use of corticosteroids dates to the 1980s although the mechanism of efficacy is not yet clear. Dexamethasone is the most effective corticosteroid and it is widely used in combination with other antiemetic drugs both in acute and delayed CINV. In N/V induced by low emetogenic chemotherapy it could also be

A lot of agents including dopamine receptor antagonists, phenothiazines, cannabinoids, olanzapine are currently used to treat CINV induced by low emetogenic potential. Dopamine receptor antagonists such as metoclopramide and butyrophenones were most commonly used in past years and they could still be administered in combination with other antiemetic agents or in low-risk CINV. The efficacy of metoclopramide improves with increasing doses. Dopamine antagonists exhibit many adverse events and the most serious is represented by extrapyramidal symptoms. Dopamine antagonists may be considered when breakthrough CINV occurs. Currently breakthrough CINV is managed with an agent from a drug class that was not used in the prophylactic regimen. The phenothiazines are rarely administered in CINV and mainly in CINV induced by low emetogenic effect or as salvage therapy in breakthrough emesis. Antipsychotics such as olanzapine are sometimes prescribed in CINV not responding to conventional antiemetics. Olanzapine antagonizes several neurotransmitter receptors involved in the antiemetic reflex and it has been reported effective in preventing both and delayed CINV. No robust data comparing olanzapine with other antiemetic agents is available [41, 42]. In clinical practice olanzapine is often added to the standard three-drugs combination but it does not replace any of them. Olanzapine may be considered for the treatment of breakthrough and refractory CINV in addition to a change in the prophylactic antiemetic regimen. The most common adverse events of olanzapine include fatigue,

*Chemotherapy-Induced Nausea and Vomiting DOI: http://dx.doi.org/10.5772/intechopen.96194*

cytochrome CYP3A4. In particularly, aprepitant is related to an increase of plasma dexamethasone levels. Dexamethasone dose should be reduced when used in combination with aprepitant. Some antitumoral agents are also metabolized by CYP3A4 with the risk of increased toxicity when administered in combination with aprepitant. Aprepitant is also a weak inducer of the cytochrome CYP450. In patient receiving warfarin in combination with aprepitant the international normalized ratio (INR) decreases by 15% [36]. Rolapitant is well tolerated and its most common adverse events include neutropenia and dizziness. It inhibits CYP2D6 and it is metabolized by CYP3A4 so CYP3A4 inducers can reduce rolapitant blood levels and efficacy. The most common adverse events of netupitant include asthenia, dyspepsia, erythema and neutropenia. It is contraindicated in patients with severe renal and hepatic failure and it is an inhibitor of CYP3A4 as aprepitant [37–40].

### **6.3 Steroids**

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

palonosetron compared to first-generation agents.

**6.2 NK1 antagonists**

and QT prolongation [23]. The oral and intravenous formulation are therapeutically equivalent [24]. The first-generation drugs are more active in acute CINV and appear little active and modest active in delayed N/V induced by cisplatin and moderately emetogenic chemotherapeutic agents, respectively. The second-generation 5-HT3 receptor antagonist has a longer half-life and a greater binding affinity for the specific receptor. Three randomized prospective trials compared palonosetron with a first-generation antiemetic drug in patients receiving moderately and highly emetogenic chemotherapy. The noninferiority of palonosetron in term of complete response was demonstrated [25–27]. Some international guidelines consider palonosetron the preferred 5-HT3 antagonist for moderate emetogenic chemotherapy regimens but there are no prospective trials demonstrating the superiority of

In the past 10 years, antiemetic treatment has greatly advanced with the availability of NK1 receptor antagonists. The NK1 receptor antagonists are the most recent class of antiemetic agents and include aprepitant (emend) fosaprepitant (ivemend), rolapitant (varuby) and netupitant (akynzeo). Aprepitant was the first approved agent in the class and is formulized as oral drug. In acute CINV the NK1 receptor antagonists are usually administered in combination with a 5-HT3 receptor antagonists and dexamethasone. 3-days aprepitant can also be administered in delayed CINV [28]. Three randomized prospective trials compared the combination of ondansetron plus dexamethasone plus aprepitant versus ondansetron and dexamethasone in patients receiving highly emetogenic chemotherapy. Aprepitant was administered before chemotherapy and continued along with dexamethasone. The addition of aprepitant led to an approximate 50% reduction in the risk of emesis or need for rescue medications [29–31]. These evidences underline the crucial role of aprepitant in the management of CINV induced by highly emetogenic chemotherapy. A randomized prospective trial investigated the use of aprepitant in moderately emetogenic chemotherapy in almost a thousand of patients with breast cancer. A significantly higher rate of complete response in the aprepitant group was reported [32]. Fosaprepitant is an intravenous NK1 receptor antagonist. In is a water-soluble phosphoryl prodrug of aprepitant converted to aprepitant within 30 minutes after administration. A randomized double-blind study reported that a single dose of fosaprepitant after ondansetron and dexamethasone was noninferior to a standard aprepitant 3-days regimen in preventing CINV in more than 2 thousand patients receiving cisplatin [33]. This evidence suggests that a single dose of fosaprepitant enhances the antiemetic effects provided by conventional 5-HT3 receptor agonists and corticosteroid therapy over conventional therapy alone and may provide a level of efficacy similar to that of the recommended 3-days aprepitant regimen. Rolapitant is a highly selective competitive long-acting NK-1 receptor antagonist demonstrating efficacy in randomized phase III trials. A single oral dose of rolapitant was effective in preventing delayed CINV compared with placebo, when each was used in combination with a 5-HT3 receptor antagonist plus dexamethasone in patients receiving highly or moderately emetogenic chemotherapy [34]. Netupitant is formulated with palonosetron in a fixed-dose combination. Complete response rates during the acute and delayed CINV were significantly higher with single-dose netupitant plus palonosetron than with single-dose palonosetron in highly and

moderately emetogenic chemotherapy in phase II and III trials [35].

The most common adverse events of NK1 receptor antagonists are fatigue, hiccups, dyspepsia and diarrhea. The use of aprepitant requires the evaluation of potential drug interaction due to its mechanism of action moderately inhibiting

**154**

The antiemetic use of corticosteroids dates to the 1980s although the mechanism of efficacy is not yet clear. Dexamethasone is the most effective corticosteroid and it is widely used in combination with other antiemetic drugs both in acute and delayed CINV. In N/V induced by low emetogenic chemotherapy it could also be effectively used as single antiemetic agent (**Table 3**).

#### **6.4 Other antiemetic treatments**

A lot of agents including dopamine receptor antagonists, phenothiazines, cannabinoids, olanzapine are currently used to treat CINV induced by low emetogenic potential. Dopamine receptor antagonists such as metoclopramide and butyrophenones were most commonly used in past years and they could still be administered in combination with other antiemetic agents or in low-risk CINV. The efficacy of metoclopramide improves with increasing doses. Dopamine antagonists exhibit many adverse events and the most serious is represented by extrapyramidal symptoms. Dopamine antagonists may be considered when breakthrough CINV occurs. Currently breakthrough CINV is managed with an agent from a drug class that was not used in the prophylactic regimen. The phenothiazines are rarely administered in CINV and mainly in CINV induced by low emetogenic effect or as salvage therapy in breakthrough emesis. Antipsychotics such as olanzapine are sometimes prescribed in CINV not responding to conventional antiemetics. Olanzapine antagonizes several neurotransmitter receptors involved in the antiemetic reflex and it has been reported effective in preventing both and delayed CINV. No robust data comparing olanzapine with other antiemetic agents is available [41, 42]. In clinical practice olanzapine is often added to the standard three-drugs combination but it does not replace any of them. Olanzapine may be considered for the treatment of breakthrough and refractory CINV in addition to a change in the prophylactic antiemetic regimen. The most common adverse events of olanzapine include fatigue, sedation, headache, dry mouth, hyperglycemia, diarrhea.

In CINV with low and moderate emetic potential, synthetic cannabinoids have been recently evaluated. The two known cannabinoid receptors are CB1 and CB2. Blocking of CB1 and CB2 results in emesis. Cannabinoids act as an agonist on the CB1 receptors, resulting in their pharmacologic effect [43]. The use of these agents with a lower therapeutic index is not recommended as first-line treatment for prevention of CINV and should be reserved for patients refractory to or intolerant of standard antiemetics. Evidence remains insufficient for a recommendation regarding medical marijuana for the prevention of nausea and vomiting in patients with cancer who receive chemotherapy or radiation therapy.


#### **Table 3.** *Management of CINV.*

Two commercial forms of synthetic cannabinoids have been approved by Food and Drug Administration (FDA) with CINV indication: nabilone and dronabinol in 2005 and 2016, respectively. Studies with dronabinol and nabilone were performed in the 1970s and 1980s, before the approval of 5-HT3 receptor antagonists, and often included a placebo arm. Tramer et al. published a meta-analysis on the use of cannabinoids for CINV control. The investigators analyzed data from 30 randomized controlled studies from 1975 to 1997; 16 studies were with nabilone, 13 with dronabinol, and 1 with intramuscular levonantradol. Of the 30 studies,

**157**

*Chemotherapy-Induced Nausea and Vomiting DOI: http://dx.doi.org/10.5772/intechopen.96194*

first-line treatment for CINV.

standard antiemetic strategies.

vomiting, or delayed vomiting [49].

10 used a placebo as the comparator, and prochlorperazine was prescribed in 12 trials. Other antiemetic controls included metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. The authors found that cannabinoids were more effective with moderately emetogenic chemotherapy regimens than all of the active controls, but were not more effective with very high or low emetogenic regimens. More side effects were associated with the cannabinoid treatment, and patients were more likely to withdraw from therapy [44]. A 2015 meta-analysis evaluated the role of cannabinoids in chemotherapyinduced nausea and vomiting. 51 trials included in the analysis were conducted between 1975 and 1991 and none involved comparisons with current antiemetic regimens. The authors concluded that cannabis-based medications may be useful for treating refractory CINV. However, methodological limitations of the trials limit any conclusions [45]. Nabilone and dronabinol are orally active synthetic cannabinoid approved for the treatment of CINV in patients who have not experienced adequate response to conventional antiemetic treatments. The restriction is related to the side effects spectrum of this agents. Some of these adverse events are seen as beneficial to the patient. Events such as a feeling of being high or euphoria and drowsiness are seen as potentially beneficial side effects of this agent. Other side effects that are not considered beneficial and are more problematic include ataxia, anxiety, disorientation, hallucinations, depression, and psychosis. Adverse events may persist for a variable and unpredictable period, with adverse psychiatric reactions persisting 48 to 72 hours after the last dose. Orthostatic hypotension has been reported. Use of synthetic oral cannabinoids should be limited to the management of breakthrough and refractory CONV and they have no place as a

In the anticipatory CINV benzodiazepines are the treatment of choice due to their antianxiety property [17]. Lorazepam or alprazolam are the most used agents in the prevention and management of anticipatory emesis in combination with

Alternative treatments should also be considered particularly for the anticipatory CINV. Behavioral approaches include hypnosis, muscle relaxion, music therapy, acupuncture or acupressure [46]. Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure and other complementary or alternative therapies for the prevention of nausea and vomiting in patients with cancer. The role of ginger in the prevention of CINV has been evaluated evaluated in two trials and a meta-analysis. The first trial compared powdered ginger plus standard of care versus standard of care alone in 60 patients treated with anthracycline-based chemotherapy experienced severe CINV during previous cycles. Patients in the ginger arm reported less severe nausea and fewer vomiting episodes on days 2, 3, and 5. No adverse events were attributable to ginger [47]. The second trial compared three doses of ginger versus placebo in more than 500 patients receiving a 5-HT3 inhibitor and dexamethasone. The two lower doses of ginger produced the largest reductions in nausea intensity [48]. A 2013 systematic review evaluated four trials and reported that ginger did not have a significant effect on the incidence of acute nausea, acute

The use of acupuncture has been evaluated in 70 patients who were randomly

assigned to receive acupuncture in cycle 1 and ondansetron in cycle 2, or the reverse. All patients also received dexamethasone for 3 days. Complete response from 0 to 24 hours was similar with the two treatments, but acupuncture produced higher complete response rates from 24 to 120 hours. Constipation and insomnia were less common with acupuncture than with ondansetron [50]. Two trials evaluated acupressure wristbands and found no significant benefit against nausea and

#### *Chemotherapy-Induced Nausea and Vomiting DOI: http://dx.doi.org/10.5772/intechopen.96194*

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

24 mg day 1 for high-risk (oral) 8 mg twice daily day 1 for moderate-

Aprepitant 125 mg day 1 (oral) 80 mg days 2–3 (oral) Fosaprepitant 115 mg day 1 (intravenous) 80 mg days 2–3 (oral)

12 mg day 1 (oral) with aprepitant

8 mg day 1 for moderate-risk (oral)

Metoclopramide 1–2 mg/kg day 1 (intravenous) 1–2 mg/kg 2 hours after chemotherapy

20 mg day 1 for high-risk (intravenous) without aprepitant 8 mg day 1 for moderate-risk (intravenous) without aprepitant 20 mg day 1 for high-risk (oral)

without aprepitant

without aprepitant

5–10 mg day 1 (oral)

Prochlorperazine 5–10 mg day 1 (intravenous)

Olanzapine 5 mg for 2 days before chemotherapy (oral)

10 mg day 1 (oral)

*Acute CINV Delayed CINV*

8 mg twice daily days 2–3 (oral)

1 mg twice daily days 2–3 (oral)

8 mg days 2–4 for high risk (oral) with

8 mg days 2–3 for moderate-risk (oral)

8 mg twice daily days 2–4 for high risk

8 mg days 2–3 for moderate-risk (oral)

0.5 mg/kg every 6 hours days 2–4

5–10 mg every 6 hours (oral)

10 mg days 2–4 (oral)

aprepitant

with aprepitant

(oral) without aprepitant

without aprepitant

(intravenous)

(oral)

100 mg days 2–3 (oral)

**Antiemetic agent Dose**

Rolapitant Netupitant

Ondansetron 8 mg or 0.15 mg/kg day 1

Dolasetron 100 mg or 1.8 mg/kg day 1

Granisetron 1 mg or 0.01 mg/kg day 1

Palonosetron 0.25 mg day 1 (intravenous)

Dexamethasone 12 mg day 1 (intravenous) with aprepitant

(intravenous)

risk (oral)

(intravenous) 100 mg day 1 (oral)

(intravenous) 2 mg day 1 (oral)

Two commercial forms of synthetic cannabinoids have been approved by Food and Drug Administration (FDA) with CINV indication: nabilone and dronabinol in 2005 and 2016, respectively. Studies with dronabinol and nabilone were performed in the 1970s and 1980s, before the approval of 5-HT3 receptor antagonists, and often included a placebo arm. Tramer et al. published a meta-analysis on the use of cannabinoids for CINV control. The investigators analyzed data from 30 randomized controlled studies from 1975 to 1997; 16 studies were with nabilone, 13 with dronabinol, and 1 with intramuscular levonantradol. Of the 30 studies,

Dronabinol 5 mg/mq (oral) 5 mg/mq every 2–4 hours (oral) Nabilone 1–2 mg (oral) 1–2 mg twice daily (oral)

**156**

**Table 3.**

*Management of CINV.*

10 used a placebo as the comparator, and prochlorperazine was prescribed in 12 trials. Other antiemetic controls included metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. The authors found that cannabinoids were more effective with moderately emetogenic chemotherapy regimens than all of the active controls, but were not more effective with very high or low emetogenic regimens. More side effects were associated with the cannabinoid treatment, and patients were more likely to withdraw from therapy [44]. A 2015 meta-analysis evaluated the role of cannabinoids in chemotherapyinduced nausea and vomiting. 51 trials included in the analysis were conducted between 1975 and 1991 and none involved comparisons with current antiemetic regimens. The authors concluded that cannabis-based medications may be useful for treating refractory CINV. However, methodological limitations of the trials limit any conclusions [45]. Nabilone and dronabinol are orally active synthetic cannabinoid approved for the treatment of CINV in patients who have not experienced adequate response to conventional antiemetic treatments. The restriction is related to the side effects spectrum of this agents. Some of these adverse events are seen as beneficial to the patient. Events such as a feeling of being high or euphoria and drowsiness are seen as potentially beneficial side effects of this agent. Other side effects that are not considered beneficial and are more problematic include ataxia, anxiety, disorientation, hallucinations, depression, and psychosis. Adverse events may persist for a variable and unpredictable period, with adverse psychiatric reactions persisting 48 to 72 hours after the last dose. Orthostatic hypotension has been reported. Use of synthetic oral cannabinoids should be limited to the management of breakthrough and refractory CONV and they have no place as a first-line treatment for CINV.

In the anticipatory CINV benzodiazepines are the treatment of choice due to their antianxiety property [17]. Lorazepam or alprazolam are the most used agents in the prevention and management of anticipatory emesis in combination with standard antiemetic strategies.

Alternative treatments should also be considered particularly for the anticipatory CINV. Behavioral approaches include hypnosis, muscle relaxion, music therapy, acupuncture or acupressure [46]. Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure and other complementary or alternative therapies for the prevention of nausea and vomiting in patients with cancer. The role of ginger in the prevention of CINV has been evaluated evaluated in two trials and a meta-analysis. The first trial compared powdered ginger plus standard of care versus standard of care alone in 60 patients treated with anthracycline-based chemotherapy experienced severe CINV during previous cycles. Patients in the ginger arm reported less severe nausea and fewer vomiting episodes on days 2, 3, and 5. No adverse events were attributable to ginger [47]. The second trial compared three doses of ginger versus placebo in more than 500 patients receiving a 5-HT3 inhibitor and dexamethasone. The two lower doses of ginger produced the largest reductions in nausea intensity [48]. A 2013 systematic review evaluated four trials and reported that ginger did not have a significant effect on the incidence of acute nausea, acute vomiting, or delayed vomiting [49].

The use of acupuncture has been evaluated in 70 patients who were randomly assigned to receive acupuncture in cycle 1 and ondansetron in cycle 2, or the reverse. All patients also received dexamethasone for 3 days. Complete response from 0 to 24 hours was similar with the two treatments, but acupuncture produced higher complete response rates from 24 to 120 hours. Constipation and insomnia were less common with acupuncture than with ondansetron [50]. Two trials evaluated acupressure wristbands and found no significant benefit against nausea and

vomiting when wristbands were added to standard antiemetic treatment among patients treated with chemotherapy [51, 52].
