Prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting in pediatric cancer patients and hematopoietic stem cell recipients: Clinical practice guideline update.

This 2021 clinical practice guideline update provides recommendations for preventing anticipatory chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. Recommendations are based on systematic reviews that identified (1) if a history of acute or delayed CINV is a risk factor for anticipatory CINV, and (2) interventions for anticipatory CINV prevention and treatment. A strong recommendation to optimize acute and delayed CINV control in order to prevent anticipatory CINV is made. Conditional recommendations are made for hypnosis, systematic desensitization, relaxation techniques, and lorazepam for the secondary prevention of anticipatory CINV. No recommendation for the treatment of anticipatory CINV can be made.

A randomized trial of nurse-administered behavioral interventions to manage anticipatory nausea and vomiting in chemotherapy.

PURPOSE: Chemotherapy side effects diminish quality of life and can lead to treatment delay. Nausea and vomiting can occur prior to chemotherapy because of classical conditioning. We studied the effects of 20-minute behavioral interventions, administered by oncology nurses, of higher intensity (mindfulness relaxation-MR) or lower intensity (relaxing music-RM), on anticipatory nausea and vomiting (ANV). PATIENTS AND METHODS: Patients undergoing chemotherapy for solid tumors were randomized to MR (N = 160), RM (N = 159), or standard care SC (N = 155). Subjects were mostly female (91.8%) and white (86.1%) with breast cancer (85%). Most patients had early stage disease (Stage I: 26%; II: 52.9%; III: 19%; IV: 0.1%). Anticipatory nausea and vomiting were assessed at the midpoint and end of the chemotherapy course using the Morrow Assessment of Nausea and Emesis (MANE). RESULTS: Compared to SC, there was reduced anticipatory nausea at the midpoint of chemotherapy in those receiving MR (OR 0.44, 95% CI 0.20-0.93) and RM (OR 0.40, 95% CI 0.20-0.93), controlling for age, sex, cancer stage, and emetogenic level of chemotherapy. There was no difference between treatment groups in anticipatory nausea at the end of chemotherapy or in anticipatory vomiting and postchemotherapy nausea and vomiting at either time point. CONCLUSION: A brief nurse-delivered behavioral intervention can reduce midpoint ANV associated with chemotherapy.

Oxytocin, social factors, and the expression of conditioned disgust (anticipatory nausea) in male rats.

Disgust has been proposed to have evolved as a means to rid the body and mouth of noxious substances and toxins, as well as to motivate and facilitate avoidance of contact with disease-causing organisms and infectious materials. Nonemetic species, such as the rat, show distinctive facial expressions, including the gaping reaction, indicative of nausea-based disgust. These conditioned disgust responses can be used to model anticipatory nausea in humans, which is a learned response observed following chemotherapy treatment. As social factors play a role in the modulation and expression of conditioned disgust responses in rats, and the nonapeptide, oxytocin (OT), is involved in the modulation of social behavior, the present study examined the effects of an OT antagonist, L-368 899, on the development and expression of socially mediated conditioned disgust in male rats. When administered 10 min before testing in a distinct context (different from the original conditioning context), L-368 899 (5 mg/kg) significantly decreased gaping behavior in rats that were conditioned with a social partner. LiCl-treated rats administered L-368 899 before testing also showed decreased social initiations toward their social partner. These findings suggest that OT may play a role in the modulation and expression of socially mediated conditioned disgust in rats.

Anticipatory nausea and vomiting due to chemotherapy.

As a specific variation of chemotherapy-induced nausea and vomiting, anticipatory nausea and vomiting (ANV) appears particularly linked to psychological processes. The three predominant factors related to ANV are classical conditioning; demographic and treatment-related factors; and anxiety or negative expectancies. Laboratory models have provided some support for these underlying mechanisms for ANV. ANV may be treated with medical or pharmacological interventions, including benzodiazepines and other psychotropic medications. However, behavioral treatments, including systematic desensitization, remain first line options for addressing ANV. Some complementary treatment approaches have shown promise in reducing ANV symptoms. Additional research into these approaches is needed. This review will address the underlying models of ANV and provide a discussion of these various treatment options.

Overshadowing as prevention of anticipatory nausea and vomiting in pediatric cancer patients: study protocol for a randomized controlled trial.

BACKGROUND: Emesis and nausea are side effects induced by chemotherapy. These effects lead to enormous stress and strain on cancer patients. Further consequences may include restrictions in quality of life, cachexia or therapy avoidance. Evidence suggests that cancer patients develop the side effects of nausea and vomiting in anticipation of chemotherapy. Contextual cues such as smell, sounds or even the sight of the clinic may evoke anticipatory nausea and vomiting prior to infusion. Anticipatory nausea and vomiting are problems that cannot be solved by administration of antiemetica alone.The purpose of the proposed randomized placebo-controlled trial is to use an overshadowing technique to prevent anticipatory nausea and vomiting and to decrease the intensity and duration of post-treatment nausea and vomiting. Furthermore, the effect on anxiety, adherence and quality of life will be evaluated. METHODS/DESIGN: Fifty-two pediatric cancer patients will be evenly assigned to two groups: an experimental group and a control group. The participants, hospital staff and data analysts will be kept blinded towards group allocation. The experimental group will receive during three chemotherapy cycles a salient piece of candy prior to every infusion, whereas the control group will receive flavorless placebo tablets. DISCUSSION: If an effectiveness of the overshadowing technique is proven, implementation of this treatment into the hospitals' daily routine will follow. The use of this efficient and economic procedure should aid a reduced need for antiemetics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30242271/

Impairment of lithium chloride-induced conditioned gaping responses (anticipatory nausea) following immune system stimulation with lipopolysaccharide (LPS) occurs in both LPS tolerant and LPS non-tolerant rats.

Anticipatory nausea is a classically conditioned response to a context that has been previously paired with toxin-induced nausea and/or vomiting. When injected with a nausea-inducing drug, such as lithium chloride (LiCl), rats will show a distinctive conditioned gaping response that has been suggested to be an index of nausea. Previous studies have found that immune system activation with an endotoxin, such as lipopolysaccharide (LPS), attenuates LiCl-induced conditioned gaping in rats. The present study examined the acquisition of LiCl-induced conditioned gaping in rats that were either LPS tolerant or LPS non-tolerant, as little is known about the effects of endotoxin tolerance on learning and memory. Male Long-Evan rats were given four systemic injections of LPS (200 µg/kg) or isotonic saline (NaCl) to induce LPS tolerance, indexed with 24 h changes in body weight following treatment. The animals were then given 4 acquisition trials in a LiCl-induced conditioned gaping paradigm. On conditioning days animals were treated with LPS (200 µg/kg) or saline followed 90 min later by injection of LiCl (127 mg/kg) or saline and then placed in a distinctive context for 30 min and their behavior video-recorded. On a drug free test day all animals were again placed in the distinctive context for 10 min and behavior was video-recorded. Gaping responses were scored for all acquisition days and the test day. Spleen and body weights were also obtained for all rats at the end of the experiment. Gaping responses were attenuated in rats treated with LPS in both the LPS tolerant and LPS non-tolerant groups. There were significant negative correlations between spleen weight as well as spleen/body weight ratios, and levels of conditioned gaping responses in LiCl treated rats, but not control rats. These results show that LPS interferes with learning/memory in the anticipatory nausea paradigm in rats that are both LPS tolerant and LPS non-tolerant.

Anticipatory nausea and vomiting.

A commonly reported consequence of post-treatment nausea or vomiting is the development of anticipatory nausea and vomiting (ANV). In most published work, nausea is reported to occur before chemotherapy drugs are administered by approximately 20% of patients at any one chemotherapy cycle and by 25-30% of patients by their fourth chemotherapy cycle. Most studies in adult patients strongly support the view that the development of ANV involves elements of classical conditioning. The best method to avoid development of ANV is to adequately prevent both vomiting and nausea from the first exposure to chemotherapy. If anticipatory side effects develop, behavioral treatment techniques, such as systematic desensitization, have been shown effective. Benzodiazepines used in combination with behavioral techniques or antiemetics may also be useful. The evidence on which these conclusions are based is reviewed in this article.

Risk factors at pretreatment predicting treatment-induced nausea and vomiting in Australian cancer patients: a prospective, longitudinal, observational study.

PURPOSE: Despite significant advances in antiemetic management, almost 50% of cancer patients still experience nausea and vomiting during treatment. The goal of antiemetic therapy is complete prevention of treatment-induced nausea and/or vomiting (TINV); however, realisation of this goal remains elusive, thus supplementary strategies identifying patients at high risk must be employed in the interim. Consequently, we examined TINV incidence and its risk factors, including patient, clinical and pretreatment quality of life (QOL)/psychological factors. METHODS: Two hundred newly diagnosed cancer patients beginning combined treatment participated in this prospective, longitudinal, observational study. QOL (including TINV), psychological adjustment, and patient/clinical characteristics were examined at pretreatment, on-treatment (8 weeks ± 1 week) and post-treatment. RESULTS: Overall, 62% of patients experienced TINV, with TIN incidence (60%) doubling that of TIV (27%). Eight independent risk factors predicted 73% of TIN incidence: high premorbid/anticipatory NV, moderately/highly emetogenic chemotherapy (M/HEC), longer treatment (>3 months), female gender, surgery prior to adjuvant chemotherapy ± radiotherapy, private health insurance and low emotional functioning (pretreatment). Six independent risk factors predicted 77% of TIV incidence: premorbid/anticipatory vomiting, M/HEC, female gender, cancer resection and low role functioning (pretreatment). CONCLUSIONS: TINV still represents a very major concern for patients. Several pretreatment risk factors for the development of TIN and TIV, respectively, were identified. Patients about to undergo cancer treatment, particularly combined treatment involving emetogenic chemotherapy and surgery, should be screened for these factors with a view to modifying standard pretreatment/maintenance antiemetic therapy. Furthermore, and consistent with recent research, it is recommended that more comprehensive interventions combining antiemetics with other effective pharmacological (e.g. anxiolytics) and non-pharmacological approaches (e.g. acupuncture, relaxation techniques) be considered by clinicians in attempts to improve control of TIN and TIV (and overall QOL) for their patients. In this way, optimal holistic care will be ensured for cancer patients by clinicians providing conventional oncology treatment.

Exposure to a context previously associated with nausea elicits conditioned gaping in rats: a model of anticipatory nausea.

Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.

Preoperative hypnotherapy in the management of a child with anticipatory nausea and vomiting.

A six-year-old boy with oesophageal strictures secondary to neonatal repair of oesophageal atresia and requiring six to eight weekly oesophageal dilatations by bouginage developed anticipatory nausea and vomiting. This was effectively managed by a course of preoperative hypnotherapy over four sessions. Resolution of anticipatory nausea and vomiting occurred along with cessation of postoperative nausea and vomiting. This case supports early intervention with preoperative hypnotherapy in children with anticipatory nausea and vomiting that has not responded to other measures.

Anticipatory nausea: the role of individual differences related to sensory perception and autonomic reactivity.

BACKGROUND: Anticipatory nausea (AN) during chemotherapy has been difficult to control with conventional antiemetics. AN can lead cancer patients to delay or discontinue chemotherapy, possibly compromising the treatment. PURPOSE: The aim is to investigate the possible influence on the development of AN of individual differences in absorption, somato-sensory amplification, and autonomic perception-measures theorized to be related to sensory perception and autonomic reactivity. METHODS: Prior to treatment, 125 women (M age = 48.5 years) undergoing adjuvant chemotherapy for breast cancer rated their expected severity of side effects and completed the Tellegen Absorption Scale, the Somato-Sensory Amplification Scale, and the Autonomic Perception Questionnaire. AN, as well as anticipatory vomiting (AV), distress, and worry/anxiety, were measured prior to the fourth, sixth, and last cycle of chemotherapy. Posttreatment nausea (PN), vomiting, and fatigue were measured after the first, fourth, sixth, and last cycle. RESULTS: 34% of the women reported AN before 1 or more cycles. When controlling for treatment characteristics and other known predictors, AN was significantly associated with high absorption in addition to severity of PN, pretreatment worry/anxiety, and not receiving radiotherapy between chemotherapy sessions. AV was not associated with any of the variables investigated. Our data suggest that the association is strongest in the early phases of treatment. CONCLUSIONS: Our results partly confirm the results of a previous study showing absorption and autonomic perception as predictors of anticipatory side effects in cancer patients receiving chemotherapy. Individuals high in absorption may be more autonomically reactive to aversive stimuli and, subsequently, more conditionable. Additional radiotherapy could be a competing stimulus, reducing the conditioning of chemotherapy-related nausea. Further studies investigating possible psycho-physiological mechanisms in the development of AN are needed.

Behavioral interventions in treating anticipatory nausea and vomiting.

Anticipatory nausea and vomiting (ANV) is associated with a significant reduction in the quality of life for many chemotherapy patients. The use of 5-hydroxytryptamine type 3 receptor antagonists provides some relief for chemotherapy-induced nausea and vomiting, but does not seem to control ANV. Nonpharmacologic approaches, which include behavioral interventions, may provide the greatest promise in relieving symptoms. Little evidence supports the use of complementary and alternative methods, such as acupuncture and acupressure, in relieving ANV. Behavioral interventions, especially progressive muscle relaxation training and systematic desensitization, should be considered important methods for preventing and treating ANV.

Pavlovian conditioning of nausea and vomiting.

Cancer patients undergoing cytotoxic drug treatment often experience side-effects, the most distressing being nausea and vomiting. Despite antiemetic drugs, 25-30% of the chemotherapy patients report these side-effects when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea and anticipatory vomiting. The present paper summarizes the evidence that anticipatory vomiting is acquired by Pavlovian conditioning, and, consequently, may be alleviated by conditioning techniques. To explore the mechanisms that induce and alleviate conditioned nausea and vomiting further, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea was demonstrated. Cortisol and tumor-necrosis factor-alpha were elevated as endocrine and immunological correlates of nausea. Data in the rotation-induced motion sickness model indicated that gender is an important moderator variable to be considered in further studies. The paper concludes with a review of applications of the demonstrated conditioning principles as interventions to ameliorate distressing anticipatory nausea or anticipatory vomiting in cancer patients undergoing chemotherapy.

The continuing problem of post chemotherapy nausea and vomiting: contributions of classical conditioning.

Despite continuing improvements in antiemetic therapies, nausea and vomiting following chemotherapy treatments for cancer remain significant clinical problems for many patients. The role of classical conditioning in patients' anticipatory nausea is well known, but little attention has been paid to possible conditioning effects on post treatment nausea. The present study statistically examined the contribution of anticipatory (conditioned) nausea to patients' subsequent post treatment nausea. Forty early stage breast cancer patients who developed anticipatory nausea were analyzed. Results revealed a significant correlation between the intensity of anticipatory nausea in the clinic prior to their treatment infusion and subsequent post treatment nausea during the 24 h after the infusion. These results provide support for the hypothesis that, once established, conditioned nausea may contribute to the severity of subsequent post treatment nausea in patients receiving repeated cycles of chemotherapy for cancer. The results suggest the importance of considering the contribution of conditioning process to nausea and other post treatment side effects.

Overshadowing and latent inhibition of context aversion conditioning in the rat.

A review is presented of experimental studies, using rats as the subjects, that were designed to establish an animal model of the clinical phenomenon of anticipatory nausea. Experiments 1 and 2 demonstrated that pairing a distinctive context with an illness-inducing injection of lithium chloride endowed the context with new properties, consistent with the proposal that classical conditioning had established an association between the context as the conditioned stimulus and nausea as the unconditioned stimulus. The conditioned response to the context constitutes a form of anticipatory nausea. Experiment 3 examined overshadowing, showing that the presence of a novel salient cue (a flavour) during context conditioning reduced the magnitude of the aversion conditioned to the context. Experiments 4-7 examined the effects of giving exposure to the context prior to conditioning. They demonstrated a latent inhibition effect, that is, a reduction in the magnitude of the aversion in pre-exposed animals. It is suggested that these ways of modulating conditioned aversions could form the basis of interventions for use in the chemotherapy clinic. Anticipatory nausea is assumed to be a consequence of the formation of an association between the cues that constitute the clinic and the drug-induced nausea experienced in their presence. By restricting the development of this association, latent inhibition and overshadowing procedures should be effective in alleviating the problem of anticipatory nausea.

Anticipatory nausea in cyclical vomiting.

BACKGROUND: Cyclical Vomiting Syndrome (CVS) is characterised by discrete, unexplained episodes of intense nausea and vomiting, and mainly affects children and adolescents. Comprehending Cyclical Vomiting Syndrome requires awareness of the severity of nausea experienced by patients. As a subjective symptom, nausea is easily overlooked, yet is the most distressing symptom for patients and causes many behavioural changes during attacks. CASE PRESENTATION: This first-hand account of one patient's experience of Cyclical Vomiting Syndrome shows how severe nausea contributed to the development of anticipatory nausea and vomiting (ANV), a conditioned response frequently observed in chemotherapy patients. This conditioning apparently worsened the course of the patient's disease. Anticipatory nausea and vomiting has not previously been recognised in Cyclical Vomiting Syndrome, however predictors of its occurrence in oncology patients indicate that it could complicate many cases. CONCLUSION: We suggest a model whereby untreated severe and prolonged nausea provokes anxiety about further cyclical vomiting attacks. This anxiety facilitates conditioning, thus increasing the range of triggers in a self-perpetuating manner. Effective management of the nausea-anxiety feedback loop can reduce the likelihood of anticipatory nausea and vomiting developing in other patients.

Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers.

OBJECTIVES: Pre-exposure to an environment in which a nausea-inducing body rotation will subsequently be given constitutes a latent inhibition procedure that might act to reduce anticipatory and postrotation nausea. METHODS: This was tested in 24 healthy subjects randomly assigned to receive no pre-exposure (group 0), a single pre-exposure (group 1), or three pre-exposures (group 3). Rotation was standardized as 5 x 1 minute rotation, but the subjects could terminate it on request. Nausea was determined on a 7-item symptom rating scale before, during, and after rotation on days 3 and 4, whereas anticipatory nausea was measured before presumed rotation on day 5. Saliva cortisol and tumor necrosis factor alpha (TNF-alpha) levels were determined at baseline before, directly, and 15 and 30 minutes after rotation every day, and before presumed rotation on day 5. RESULTS: Pre-exposure significantly reduced the degree of anticipatory nausea on day 5. Cortisol levels increased with rotation and were higher at baseline on days 4 and 5, but subjects habituated from day 3 to day 4; levels were lower in women than in men. In contrast, TNF-alpha decreased with rotation but showed no habituation. For both cortisol and TNF-alpha, no effects on postrotational nausea were found. CONCLUSION: It is concluded that repetitive pre-exposure (latent inhibition) reduces anticipatory but not postrotation nausea; behavioral measures (rotation time) and measures of acute stress (cortisol, TNF-alpha) do not respond to latent inhibition. Thus, Pavlovian conditioning rules are effective in healthy humans with anticipatory nausea but not with postrotation nausea. Hormonal responses--TNF-alpha decrease with stress, compensatory cortisol increase--and gender-related effects on learning and habituation are discussed with regard to psychophysiological and psychoimmunological processes.

Involving women with breast cancer in the development of a patient information leaflet for anticipatory nausea and vomiting.

As chemotherapy regimens increase in toxicity and changes in service provision move towards a more ambulatory outpatient basis, patients are often coping with side effects of treatment in isolation. Despite advances in pharmacological control, for some patients nausea and vomiting can be problematic. For some this can develop into anticipatory nausea and vomiting (ANV), which can severely effect the patients physical and psychological well-being. It is well recognised that the giving of realistic and understandable information is paramount to empower patients in their individual coping. A plethora of literature supports the use of Patient Information Leaflets as a means to educate and empower patients within their treatment trajectory. This paper discusses the authors' experiences in developing a Patient Information Leaflet, designed to assist breast cancer patients in understanding and coping with the symptoms of ANV. The patient's needs were sought to add clarity to the development and design of the leaflet. The authors conclude that developing a Patient Information Leaflet was a major undertaking in terms of time and resources.

Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma.

BACKGROUND: Patients may use their past experiences with nausea, as well as information about the incidence of nausea from chemotherapy that other patients have experienced, to form a prediction, or response expectancy, of nausea from their own upcoming chemotherapy. Mounting evidence suggests that these expectancies relating to nausea are significant predictors, and, likely, contributing factors to the development of treatment-related nausea. METHODS: The patients in the current study were participants in the control arm of a multicenter clinical trial conducted between November 1999 and July 2001 by the University of Rochester Community Clinical Oncology Program. All patients in the current report were age >/= 18 years and were about to begin a first cancer treatment regimen containing doxorubicin. RESULTS: Expectancy of nausea assessed before patients received their first doxorubicin-based chemotherapy treatment was found to be a strong predictor of subsequent nausea and in fact was stronger than previously reported predictive factors, including age, nausea during pregnancy, and susceptibility to motion sickness. Women who believed it was "very likely" that they would have severe nausea from chemotherapy were five times more likely to experience severe nausea than fellow patients who thought its occurrence would be "very unlikely." CONCLUSIONS: Further studies confirming an expectancy of nausea as a risk factor are warranted as are studies examining the benefit to a patient's quality of life from modifying antiemetic treatment guidelines to take into account symptom expectancies. Finally, ethically acceptable interventions that are designed to reduce patients' nausea expectancies or increase their expectancies of nausea control should be developed and studied.

The efficacy of behavioral interventions for cancer treatment-related side effects.

The use of increasingly aggressive methods of cancer treatment (e.g., cytotoxic doses of chemotherapy and total body irradiation) has resulted in the need for more effective management of pain, nausea, and other aversive side effects. One of the most promising approaches is nonpharmacologic intervention based on behavioral research and theory. The purpose of this article is to review the efficacy of behavioral intervention methods in controlling aversive side effects of cancer treatments. Sixty-seven published studies were identified for review. Results indicated that: (1) behavioral intervention can effectively control anticipatory nausea and vomiting in adult and pediatric patients undergoing cancer chemotherapy. However, evidence for the efficacy of behavioral intervention to control post-chemotherapy nausea and vomiting is mixed; (2) behavioral intervention integrating several behavioral techniques can decrease levels of anxiety and distress associated with invasive treatments and cancer diagnosis; and (3) although a variety of behavioral methods have been shown to reduce acute treatment-related pain, not all behavioral techniques are equally effective. Hypnotic-like methods involving relaxation, suggestion, and imagery appear to have the greatest impact on cancer-related pain management. The use of behavioral theory and techniques has an important place in the care of patients undergoing invasive cancer treatments.