Treatment of Nausea and Vomiting During Chemotherapy

Abstract

Nausea and vomiting are two of the most troubling side effects patients experience during chemotherapy. While newly available treatments have improved our ability to manage nausea and vomiting, anticipatory and delayed nausea and vomiting are still a major problem for patients receiving chemotherapy. Many cancer patients will delay or refuse future chemotherapy treatments and contemplate stopping chemotherapy altogether because of their fear of experiencing further nausea and vomiting. The purpose of this article is to provide an overview of the patho-psychophysiology of chemotherapy-induced nausea and vomiting and the recommended guidelines for treatment.

Cancer treatments are quite challenging for cancer patients to endure. The cancer treatments and subsequent side effects patients experience often make them feel worse than the disease itself.^1–3 Chemotherapy-induced nausea and vomiting (CINV) are two of the most common and troublesome side effects experienced by cancer patients. ^1–3 Cancer patients will delay chemotherapy treatments and contemplate refusing future treatments because of fear of further CINV.^1–4 While significant advances have been made in the treatment of acute chemotherapy-induced vomiting (CIV), chemotherapy-induced nausea (CIN), anticipatory nausea and vomiting (ANV) and delayed nausea and vomiting (DNV) remain substantial problems for cancer patients.^{1, 2} Anticipatory nausea is reported by 30% of patients who experienced nausea during earlier chemotherapy treatment cycles.¹ Anticipatory vomiting is reported in 20% who experienced vomiting during earlier chemotherapy treatment cycles.^{5, 6} Anticipatory, acute and delayed CINV lead to poorer chemotherapy adherence, impaired function, increased anxiety and depression, and diminished quality of life (QOL) among patients. ^{4, 7–9} In turn, physicians and patients increase utilization of healthcare resources to manage these side effects, substantially increasing the public health burden of cancer and its effective treatment.^{4, 7–9,2–6}The purpose of this chapter is to provide an overview of the patho-psychophysiology of CINV and the recommended guidelines for treatment of CINV.

Pathophysiology of Chemotherapy-Induced Nausea and Vomiting: The Role of Neurotransmitters

CINV are distinct symptoms; however, they often go hand-in-hand and are one of the most unpleasant side effects of most chemotherapy regimens for cancer patients. It is important to note that nausea can occur without vomiting. CINV can be acute (during the first 24 hours post-treatment) and delayed (after the first 24 hours post-treatment and up to 5–8 days post-treatment). ¹⁰ CINV, once experienced during early chemotherapy cycles, can create a conditioned response that leads to anticipatory nausea in future cycles of treatment.¹¹ Many of the clinical symptoms commonly reported by patients in association with nausea are manifestations of autonomic nervous system activity in response to chemotherapy delivery. For example, physical manifestations such as pallor, sweating, and feeling hot or cold all over commonly precede or accompany nausea.^{7, 12} Vomiting is a reflex triggered by toxic substances, such as chemotherapeutic agents, causing cell damage within the stomach and small intestines. Broadly, these agents are sensed in the gastric or small bowl mucosa and cause stimulation of vagal afferents that interact with the hindbrain of the central nervous system (CNS), resulting in efferent vagal action that ultimately leads to an emetic response.

Numerous classic neurotransmitters affect the emetic response including serotonin, substance P, dopamine, acetylcholine, and γ-aminobutyric acid (GABA). Other chemical messengers, acting as neurotransmitters, that affect emetic response include histamine, endorphins, and cannabinoids.¹³ We know that inhibiting some of these pathways is effective in alleviating chemotherapy-related vomiting, although these same methods have not done a good job of alleviating chemotherapy-related nausea. This suggests that different pathways may play a role in the manifestation of nausea.

The most widely studied compound related to the development of CINV is serotonin, also known as 5-HT. 5-HT is produced by enterochromaffin cells, a unique cell-type dispersed throughout the enteric epithelium. These cells constitutively express 5-HT and 5-HT is expressed more abundantly upon exposure to a chemotherapeutic agent. At elevated levels, 5-HT is released from the basal surface into the lamina propria. There, secreted 5-HT binds to cognate 5-HT₃ receptors located on vagus nerve terminals, thus acting as a neurotransmitter transducing a signal to the hindbrain. In turn, the translated signal triggers a motor response of NV, carried by efferenting vagal nerves.¹⁴

For approximately 30 years, 5-HT₃ antagonists have been extremely useful for curbing NV in patients receiving chemotherapy.^{1, 15} These drugs exert their anti-emetic potential by competing with 5-HT for binding of 5-HT₃ receptors, thereby blocking a pro-emetic signal to the CNS. The newest 5HT₃ antagonist, palonosetron, has a higher receptor binding affinity than other commonly used 5HT₃ antagonists,⁷ which makes it more effective at preventing NV. Palonosetron also exhibits allosteric positive cooperativity with the 5-HT₃ receptor compared to other 5-HT₃ antagonists (such as ondansetron and granisetron),⁸ and can trigger 5-HT₃ internalization to prolong inhibitory effects of 5HT₃ receptor function.⁹ Moreover, this drug has a half-life of 40 hours, which may allow more effective prevention of delayed NV than achieved with the other 5-HT₃ antagonoists.¹⁶ Additionally, palonosetron may act to also influence the neurokinin-1 receptor (NK-1) pathway as there is downstream crosstalk between 5-HT₃ and NK-1 receptor pathways.¹⁰

Since 5-HT synthesis is increased significantly after chemotherapy, another method of potential therapeutic benefit would decrease 5-HT synthesis in the gut. Since HT synthesis is dependent on tryptophan hydroxylase (TPH), this enzyme may represent a viable and more broadly acting target. Pre-clinical studies have been conducted using an TPH inhibitor to selectively inhibit 5-HT in the gut using a ferret model of chemotherapy-induced emesis.¹⁷

Substance P is another strong regulator of the emetic response; it binds to the NK-1 receptor. Both Substance P compound and NK-1 receptor are found within the CNS and also within the gut. Unlike 5-HT/5-HT₃ receptor interaction, less is known about how and where substance P and neurokinin-1 act in promoting emetic potential, although peripheral and central components may be involved. Pre-clinical studies suggest that antagonizing neurokinin-1 receptor action in the CNS is key to preventing NV, as agents not capable of crossing the blood-brain barrier do not protect against emesis. ¹⁸ Clinically, administration of aprepitant, the first drug devised to antagonize the NK-1 receptor, has proven effective in preventing NV when combined with 5-HT₃ receptor antagonists.^19–21

Other pathways controlling the emetic reflex exist but far less is known about their regulation of the emetic response, especially in CINV. For example, dopamine release and cognate dopamine receptor-2 signaling may also play a role, as dopamine antagonists have been shown to be effective in treating NV. Additionally, while participation of the CNS is clearly a major contributor to the emetic process, it is also possible the enteric nervous system (ENS) itself may be able to control NV effects without CNS interplay. Understanding of the role of mediators in the pathological development of CINV will advance the development of a broader range of more effective anti-emetic treatments for CINV. Further research on the physiological mechanisms involved in the development of nausea and vomiting are needed in order to develop therapies to fully eradicate anticipatory, acute and delayed CINV.

Pathopsychology of Nausea and Emesis: The Role of Conditioning and Cognition

ANV occurs before chemotherapy infusion. ANV is believed to be a conditioned response, such that ANV will only occur after a patient has experienced nausea and/or vomiting in response to chemotherapy treatment.²² However, there are reports of ANV developing without an individual previously experiencing post-treatment nausea (e.g., in children ²³). The general understanding of ANV as a conditioned response is that contextual factors, such as sights, sounds, and smells of the clinic, become conditioned stimuli paired to the unconditioned stimulus (the chemotherapy agent) that produces the unconditioned response (nausea and vomiting). Therefore, the conditioned stimuli come to elicit the conditioned response – nausea and vomiting prior to chemotherapy (ANV). There is support for ANV as a conditioned response through correlational studies ^24–26, as well as through laboratory models in humans ²⁵ and rats ²⁷. ANV has been estimated to occur in roughly 25–30% of patients,^{6, 28, 29} though there is significant variability between studies.^{6, 24, 29} ANV negatively affects patients’ quality of life and may interfere with treatment. ^{6, 24}

The 2010 National Comprehensive Cancer Network Guidelines recommend that ANV be prevented through optimal antiemetic therapy during every cycle of chemotherapy.²² Despite decreases in the frequency of post-treatment emesis over time, decreases in ANV were not observed in a large community study.²⁸ Therefore, ANV continues to be a problem for patients despite advances and aggressive treatment with anti emetics. ²⁸ Unfortunately, pharmacological interventions typically do not reduce ANV; however, cognitive-behavioral interventions, such as systematic desensitization, can be effective.^{30, 31} Additionally, conditioning techniques, such as overshadowing (i.e., pairing a strong flavored beverage with the beginning of infusion for a couple of cycles and then removing the stimulus at the next cycle) can help alleviate ANV.^{25, 32, 36}

The conditioning paradigm does not fully account for the development of ANV, and cognitive factors have been identified as contributors to ANV, including anxiety and response expectations.^{5, 6, 26, 31, 33–37} Anxiety is believed to contribute to ANV, at least in part, through negative expectations.^{34, 38–40} The relationships between anxiety and negative expectations are reciprocally interactive. For example, increased anxiety produces negative expectations and negative expectations increase anxiety. Evidence suggests that patients’ expectations of experiencing nausea strongly predict the actual occurrence of ANV.^{35, 41} It is most likely that a combination of classical conditioning and expectancy theories more fully explain the psychopathology of ANV because conditioning effects are mediated by patient expectations and conditioning effects moderate patient expectations.^42–44

Patients’ expectations of nausea are also a strong predictor of post-treatment nausea even when controlling for other known contributors.^45–51 Individual variation in patient expectations may also explain why the frequency and severity of CINV are different for different patients on the same chemotherapy regimens. These between patient differences cannot be fully accounted for by the properties of the chemotherapy agents or patient demographic characteristics.^{30, 51, 52} Patient and treatment factors associated with CINV include: female gender, younger age, lower alcohol intake history, history of motion sickness, history of emesis during pregnancy, history of CINV, and pre-treatment expectations of nausea.⁵³ Family conflict has been found to be related to post-treatment nausea and ANV for younger adult and female patients.⁵⁴ Additional cognitive and behavioral interventions that focus on changing expectations are needed as adjuncts to standard pharmaceutical anti-emetic therapies to help fully control anticipatory, acute and delayed CINV. Roscoe and colleagues found that using a cognitive manipulation technique to increase beliefs that acupressure bands could prevent CINV resulted in significantly reduced CINV among patients with high initial expectations of experiencing CINV.⁵⁰ These findings enhance our understanding of factors that contribute to CINV and the combined use of techniques like systematic desensitization, overshadowing, and expectation manipulation with pharmaceutical interventions may lead to more effective management of CINV. More research is needed investigating the psychopathology of CINV in order to effectively manage the full spectrum of anticipatory, acute and delayed CINV.

Integrative Medicine Interventions

Integrative medicine approaches, consisting of both complementary and alternative medicine interventions, are commonly used by cancer patients to reduce the toxic side effects of chemotherapy treatment. Patients typically use these types of interventions along side of their traditional allopathic (e.g., pharmaceutical) interventions. Integrative modalities are used by the majority of patients with cancer and are most commonly used by patients with advanced stage disease.^{55, 56} These types of treatments usually do not require a prescription from a physician, can be accessed in the community, and are gaining increasing scientific evidence to support their use.

Herbal Supplements

Ginger is the most abundantly used supplement for the prevention and/or reduction of CINV. Since the 16^th century, the dried aromatic rhizome (underground stem) of ginger (Zingiber Officinale) has been used by practitioners of both Indian (Ayurvedic) and traditional Chinese medicine to treat gastrointestinal upsets such as nausea and excessive flatulence.⁵⁷ Ginger has been thoroughly studied and found useful for nausea and vomiting associated with motion sickness, surgery and pregnancy.^58–66 Although ginger has been approved for use to prevent motion sickness in Europe and its use is recommended,⁵⁷ ginger is not a US FDA-approved medicinal treatment in the United States. However, ginger is readily available over-the-counter and in grocery stores as it is not an FDA regulated substance. The FDA currently classifies ginger as a generally regarded as safe (GRAS) substance if consumption is limited to 4 grams daily. As previously mentioned, current 5-HT antiemetic medications, such as 5-HT, are receptor antagonists for specific neurotransmitters in the gastrointestinal tract.⁶⁷ Likewise, ginger can bind 5-HT₃ receptors to enhance antiemetic effects and can increase detoxification enzymes to counteract oxidative damage to tissues.⁶⁸ For the best results in reducing CINV, ginger should be implemented before the onset of symptoms or before the first chemotherapy treatment cycle. Our research group previously demonstrated, in a 744 patient phase III randomized, placebo-controlled clinical trial, that three different daily doses of ginger (0.5 gram, 1.0 gram, 1.5 grams) plus standard 5-HT₃ receptor antagonists and dexemethasone significantly reduced acute CINV compared to placebo plus standard standard 5-HT₃ receptor antagonists and dexamethasone.^{69, 70} Our findings suggest that cancer patients can achieve greater alleviation of acute CINV by using ginger supplementation of 0.5 to 1.0 gram daily (equivalent to ¼ to ½ teaspoon of ground ginger) along with standard 5-HT₃ receptor antagonists and dexamethasone.^{69, 70} It is important to note that the ginger used in this study consisted of capsules containing a purified liquid extract equivalent to 250 milligrams of ginger. The purified liquid extract concentrated the biologically active components of the ginger root, such as gingerols, zingerones, and shogaols.⁵⁸ Unclear forms of ginger, such as crystallized, raw, tea, or aromatherapy, are thought to have similar effectiveness.

Many other herbal supplements, in the form of tea or aromatherapy, have been recommended for the relief of CINV. Cinnamon bark, peppermint, chamomile, fennel, and rosewood are among the most common.⁷¹ Similar to ginger, these herbs have anti-spasmodic activity and promote digestive health. Studies have shown that citrus bioflavonoids can actually cause nausea and vomiting.⁷¹ Chinese medicinal herbs have demonstrated effectiveness against CINV.⁵⁵ Chinese medicinal herbs are highly variable compounds and include any liquid extract of a mixture of herbal compounds used to treat symptoms or diseases. Chinese medicinal herbs are prepared by Chinese medicine practioners to reduce therapeutic toxicity and/or strengthen the body’s resistance and immunity.⁵⁵ Usually, Chinese herbalists determine the combination of herbs on an individual basis depending on patient symptoms and conditions. Therefore a Chinese herbalist, as well as oncologist should be consulted before use of Chinese medicinal herbs. Three published studies favored use of Chinese medicinal herbs for the relief of CINV. Shenqi fuzheng injections (consisting of two herbs),⁷² Aidi injections (consisting of four herbs),⁷³ and Aifukang (consisting of 11 herbs)⁷⁴ reduced CINV in a sample of breast cancer patients.⁵⁵

Acupuncture & Acupressure

Acupuncture is another form of traditional Chinese medicine that has been used for centuries to treat nausea and vomiting. Over the past 20 years, clinical evidence supports acupuncture for CINV.⁷⁵ Acupuncture is a 4000-year-old therapeutic technique that involves inserting and manipulating needles with and without electrical stimulation and providing pressure or electrical stimulation at specific points in the body.⁷⁵ Research suggests that acupuncture works primarily on the nervous system through stimulating brain activation or deactivation as documented by neuroimaging techniques.⁷⁶ Needle insertion points are chosen based on specific anatomical sites associated with specific bodily functions.⁷⁶ The acupuncture points most commonly used for control of nausea and vomiting are the P6 and ST36.⁷⁵ The P6 is located between tendons in the wrist approximately two inches proximal to the crease of the wrist. The ST36 is on the anterior lateral side of the leg. Traditional acupuncture involves manual manipulation of needles, whereas electro-accupuncture involves applying a small electric current to the needles. Acupressure incorporates accu-point stimulation through the use of wrist-worn devices consisting of an elastic band and embedded stud, such as Seabands®.⁷⁷ Electro-stimulation involves accu-point stimulation by an intermittent electrical current similar to units used for pain relief through the use of wrist-worn devices, such as Relief-bands®.⁷⁷ Electro-stimulation units that confer a constant electro-stimulation are not recommended for control of CINV.⁷⁷ Although the overall effect of accupuncture strongly suggests effectiveness against acute and delayed CINV, the data is not conclusive. For example, in 2005, Ezzo published a meta-analysis concluding that acupuncture combined with standard antiemetics significantly reduced acute CINV.⁷⁸ However, in 2007, both Gardani⁷⁹ and Dibble⁸⁰ showed no effect of acupressure on acute CINV. Overall, acupuncture is considered to be a cost-effective, minimal risk, integrative therapy that can be used in conjunction with standard anti-emetic pharmaceuticals for the management of CINV.

Biopsychobehavioral

Biopsychobehavioral interventions such as progressive muscle relaxation, guided imagery, hypnosis, and exercise are also efficacious therapies for the treatment of anticipantory, acute and delayed CINV. Biopsychobehavioral interventions are especially appropriate and most beneficial if implemented in a preventive manner and started before the first chemotherapy treatment cycle and, most importantly, before the first onset of symptoms of CINV.^{81, 82}

Progressive muscle relaxation (PMR) involves the tension and relaxation of muscle groups in sequence to relax physically and mentally.⁸² PMR alone reduces the severity of nausea associated with chemotherapy.⁸³ PMR combined with a 20-minute massage during chemotherapy infusions reduces the severity of nausea.⁸⁴ Guided imagery, a technique used to focus patients’ attention on a particular image and associated sensory experiences, reduces the incidence of vomiting in the 24 hours after chemotherapy.⁸⁵ Patients who use guided imagery combined with an antiemetic regimen versus an antiemetic alone have a more positive chemotherapy experience.⁸⁶ PMR is often combined with guided imagery to treat CINV with consistent, positive outcomes. PMR combined with guided imagery reduces the incidence of nausea^{87, 88} and vomiting ^{85, 87, 88} in the first four days after chemotherapy and the severity of nausea ^{84, 88–92} and vomiting^{88, 90} up to 5 days following chemotherapy. Cognitive distraction and systematic desensitization have been used to successfully reduce the severity of ANV^{93, 94} and CINV.^{89, 94} Overshadowing is also a technique that has been used to help alleviate ANV.^{25, 32, 36} Teaching self-hypnosis, which typically involves using the imagination to suggest feeling good and feeling safe, reduces the incidence of ANV^{93, 95} and the severity of CINV⁹⁶ in children undergoing chemotherapy. Hypnosis has also been used successfully with adults to reduce ANV.⁹⁷ Several researchers have used exercise interventions to aid in reducing CINV. Aerobic exercise has been shown to help reduce the severity of CINV⁹⁸ and yoga has been shown to be beneficial in reducing for reducing CINV.⁹⁹

Anti-emetics

Advances in 5HT₃ antagonists and NK-1 antagonists have dramatically improved control of CINV. Palonosetron (Aloxi) and aprepitant (Emend) are the newest antiemetics.

Palonsetron is a second generation antagonist of 5-hydroxytyptamine receptors (5HT₃). Its main advantages compared to the other 5HT₃ receptors include: its significantly longer half-life (approximately 40h, 10× longer than first generation 5HT₃ antagonists), its higher binding affinity, its high selectivity to the 5HT₃ receptors (with little effect on other receptors), and its excellent safety profile (at even up to three times its FDA approved dose).¹⁰⁰ A single dose (0.25 mg IV) of palonosetron can effectively prevent acute CINV resulting from moderately to highly emetogenic chemotherapy.^{4, 8, 9} Recent studies comparing palonosetron to ondansetron and granisetron suggest the superiority of palonsetron on all days, but particularly between 24–120 hours after chemotherapy. Complete response rates ranged from 48% and 57% using 0.75 mg of palonosetron and only 39% to 45% when not using it.^101–103 Additionally, Saito and colleagues conducted a prospective randomized head-to-head trial between Palosetron and Granisetron for both acute and chronic CINV in 1019 patients. This study showed non-inferiority of Palonosetron compared to a first generation 5HT₃ antagonist in the acute phase of CINV (0–24 hours) and superiority of Palonosetron in delayed CINV (24hrs to 120h).¹⁰² As such, current research supports the use of the second generation 5HT₃ receptor antagonist in control of acute and delayed CINV, over the first generation 5HT₃ receptor antagonists (e.g., ondansetron, granisetron, dolasetron) for moderately emetogenic chemotherapy agents.¹⁰²

Aprepitant and fosapretitant are potent, selective NK-1 receptor competitive antagonists of Substance P, believed to be an essential component in triggering the emetic reflex.¹⁰⁴ They can penetrate the CNS where there is a concentration of NK-1 receptors. Aprepitant is a 3 day regimen, with a recommended dosing of 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80 mg orally once daily in the morning on Days 2 and 3. Fosaprepitent is a pro-drug of aprepitant for injection (115 mg over 15 min) and can be substituted for aprepitant 30 minutes prior to chemotherapy on Day 1 only. In 2003, Hesketh et al.¹⁰⁴ published a randomized, double blind, parallel-group, placebo-controlled trial of 530 patients receiving Cisplatin (a highly emetogenic agent). The Aprepitant group response was superior to standard therapy group in acute and delayed phases,as well as overall.¹⁰⁴ Subsequently, a prospective, randomized, double blind, parallel study of 866 patients receiving moderately emetogenic chemotherapy over multiple cycles demonstrated the efficacy of Aprepitant in prevention of nausea and emesis over all 4 cycles of treatment.¹⁰⁵ This randomized, placebo-controlled trial also evaluated daily Aprepitant with Dexamethasone for 3 days versus a single daily dose of Palonosetron with Dexamethasone for acute and delayed CINV. The study demonstrated no statistical significance between groups, suggesting that one dose of aprepitant with standard anti-emetic regimen has similar effectiveness to a 3 day aprepitant regimen for CINV¹⁰⁵. The use of Aprepitant may also provide an advantage in that patients only have to take one dose of dexamethasone on day 1 with moderately emetic chemotherapy regimens.¹⁰⁶ Fosaprepitant may offer an option for patients who cannot tolerate oral administration of antiemetics, particularly during an episode of severe nausea or vomiting.¹⁰⁷

Guidelines

Clinical practice guidelines for CINV have been developed using evidence-based research by expert panels including the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and the Multinational Association of Supportive Care in Cancer (MASCC).^108–114 Research shows that adherence to these guidelines can improve complete control of CINV by almost 20%.¹¹⁵ Guidelines for antiemetic usage are based on the potential of experiencing CINV for specific chemotherapy regimens and classify regimens into four categories: highly-emetic (>90%), moderately-emetic (both with and without anthracycline and cyclophosphamide [AC]; 30–90%), low-emetic (10–30%), and minimally-emetic (<10%). The guidelines for antiemetic use are broken down further into categories based on the patient’s expectations (anticipatory), time of onset (acute and delayed), and resistance to antiemetic treatment (breakthrough and refractory; see Figure 1). As mentioned previously in this article, anticipatory CINV is an expected or conditioned response that usually occurs just prior to the actual administration of chemotherapy treatment.^{12, 116, 117} Acute CINV usually occurs within the first few hours of chemotherapy administration, peaking between 5–6 hours, and resolving within 24 hours.¹¹⁸ Delayed CINV occurs more than 24 hours after chemotherapy administration and can last up to 7 days. Delayed CINV is common in chemotherapy regimens that involve cisplatin, carboplatin, cyclophosphamide, and/or doxorubicin.¹¹⁹ Patients receiving multi-day chemotherapy regimens are at risk for both acute and delayed CINV depending on the chemotherapeutic agents and the sequence of administration. Breakthrough CINV occurs when prophylactic antiemetic treatment fails and “rescue” antiemetics are required, while refractory CINV occurs when previous antiemetic regimens have failed in prior chemotherapy treatment cycles. These comprehensive clinical practice guidelines are a valuable tool for oncologists in the prevention and treatment of CINV a summary of the recommended treatments are provided in Figure 1.

Figure 1.

Pharmacological Treatment Guidelines for Acute and Delayed Chemotherapy-Induced Nausea and Vomiting

5HT3: serotonin receptor antagonist; DEX: dexamethosone; NK1: neurokinin-1 receptor antagonist; PALO: palononsetron; DRA: dopamine receptor antagonist

Summary

Despite advances in pharmaceutical and behavioral therapies, and the provision of standard clinical guidelines for effectively managing CINV, patients continue to experience CINV. Although introduction of 5-HT₃ and NK-1 antagonists has considerably reduced the incidence of CINV it remains a prevalent side effect among cancer patients. If oncologists follow the ASCO, NCCN or MASCC guidelines for the treatment of CINV, research suggests that control of CINV can be improved by approximately 20%.¹¹⁵ Evidence also suggests that the addition of integrative therapies including herbal supplements, accupuncture, progressive muscle relaxation, guided imagery, hypnosis, and exercise can improve control of anticipatory, acute and delayed CINV above and beyond what is achieved by the use of pharmaceuticals alone. These integrative behavioral interventions need to be included in standard clinical practice guidelines. CINV as a fearsome side effect is more manageable now than years past with the advent of powerful, long-acting agents. Unfortunately, adequate control of nausea remains a challenge and requires increased research focus.