Anticipatory Nausea and Vomiting in Pediatric Cancer Patients

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Vol. 75 No. 3 March 1985




and Vomiting

in Pediatric




J. Dolgin,



R. Katz,




RN, and

Stuart E. Siegel,


From the Division of Hematology-Oncology, Chlldrens Hospital of Los Angeles, and Department of Pediatrics, University of Southern California, School of Medicine, Los Angeles

ABSTRACT. The purpose of this study was to determine

the prevalence and correlates of anticipatory nausea and vomiting in a sample of pediatric patients with cancer

who were receiving outpatient chemotherapy. Forty male and female patients representing a broad range of

diag-noses were interviewed with their parents concerning

nausea and vomiting before and after chemotherapy.

Anticipatory nausea was reported by 28.8% ofthe sample; anticipatory vomiting was present in 20% of the sample.

An additional 9% had experienced anticipatory nausea and vomiting in the past but not currently. Anticipatory nausea and vomiting was positively correlated with the emetic potential of chemotherapeutic regimens and the severity of nausea and vomiting after chemotherapy;

anticipatory nausea and vomiting most often developed within the first 4 months of treatment. Onset of

antici-patory nausea and vomiting usually occurred two to four

hours before treatment and was most severe at the actual

time of drug administration. Considerable interpatient

variability was observed, with treatment-related factors accounting for only 22% of the variance in the occurrence of anticipatory nausea and vomiting. These findings are considered within a behavioral framework for under-standing conditioned aversions in pediatric patients with

cancer. Implications for patient education, future re-search on the prediction of children at risk, and interven-tion are discussed. Pediatrics 1985;75:547-552; anticipa-tory nausea and vomiting, conditioning, cancer therapy,


Treatment-induced nausea and vomiting are among the most distressing side effects that pa-tients with cancer encounter in battling their dis-ease. Although the physiology of

chemotherapy-Received for publication Dec 5, 1983; accepted April 24, 1984. Portions of this paper were presented at the Fifth World Con-ference on Behavior Therapy, Washington, DC, Dec 8-11, 1983. Reprint requests to (M.J.D.) Psychosocial Program, Childrens Hospital of Los Angeles, P0 Box 54700, Los Angeles, CA 90054. PEDIATRICS (ISSN 0031 4005). Copyright © 1985 by the American Academy of Pediatrics.

induced nausea and vomiting is not fully under-stood, various CNS and peripheral sites have been proposed as the sources of the emetic action of chemotherapeutic agents.”2 No such physiologic ex-planation has been offered for the occurrence of anticipatory reactions, ie, nausea and vomiting that occur prior to the administration of emetic drugs. Such anticipatory reactions have been conceptual-ized as the result of classical conditioning in which various temporal, spatial, sensory, and cognitive cues associated with chemotherapy acquire similar nausea/emesis-eliciting properties.3’4

Standard antiemetic therapy has been unsuccess-ful in controlling anticipatory nausea and vomiting

in adult patients. In contrast, recent studies using behavioral interventions such as deep muscle relax-ation, guided imagery, hypnosis, and systematic desensitization have produced promising results in adult populations, further reinforcing the notion of a behavioral etiology.57

Anticipatory nausea and vomiting are of clinical significance in that they add to the overall averse-ness of therapy and may contribute to patient non-compliance and treatment termination.8 For the patient, anticipatory nausea and vomiting not only indicates high levels of stress and anxiety with regard to therapy, but also promotes further dis-turbance because of others’ reactions, family and

staff avoidance, and patient self-deprecation.9 An-ticipatory nausea and vomiting may directly

inter-fere with treatment by compromising the patient through nutritional debilitation and metabolic de-rangement.1#{176} Additionally, patients who reflexively

regurgitate oral medication may not be receiving

maximal therapeutic doses.

Reports on the prevalence of anticipatory nausea and vomiting have varied due to the heterogeneity of oncology populations in terms of diagnoses and treatment regimens. In addition to different

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9.1 ± 4.78


40 (50%)/40 (50%)

49 (61%) 18 (23%) 9 (11%) 4 (5%) 43 (53.7%) 4 (5.0%) 1 (1.2%) 8 (10.0%) 4 (5.0%) 4 (5.0%) 2 (2.5%) 1 (1.2%) 5 (6.3%) 2 (2.5%) 1 (1.2%) 1 (1.2%) 4 (5.0%)

pling strategies, the definition and measurement of anticipatory nausea and vomiting have not been

consistent across studies. Overall, recent studies of adult patients with cancer indicate that approxi-mately 25% of these patients experience anticipa-tory nausea and vomiting,” although that figure may be as high as 65% with some chemotherapy protocols.’2

Little is known about factors that predispose patients to the development of such conditioned aversions, although this subject is receiving in-creased attention. Studies of adult patients have

demonstrated that treatment-related

variables-most notably the emetic potency of the chemother-apeutic agents and the severity of postchemother-apy nausea and vomiting-are associated with the development of reactions before treatment.8”3 However, medical factors alone account for only

28% of the variance in the occurrence of anticipa-tory nausea and vomiting,” suggesting that addi-tional explanatory and predictive factors must be sought. Research on demographic variables such as the age and sex of the patient have yielded

conflict-ing results.’3’5 It has been suggested that patients with anticipatory nausea and vomiting tend to be more anxious and depressed than patients without anticipatory nausea and vomiting,9 although it is unclear whether this is a cause or result of their


To date, no published studies have reported on the prevalence and types of anticipatory reactions among pediatric patients, although clinical experi-ence has shown this to be a significant problem for many patients. The purpose of this study was to document the prevalence and patterns of anticipa-tory nausea and vomiting in a pediatric oncology population and to identify medical and demo-graphic variables that contribute to its occurrence.


Setting and Subjects

The study was conducted in the outpatient clinic of the Division of Hematology-Oncology of Chil-drens Hospital of Los Angeles. Approximately 120 patients receive chemotherapy in this clinic each month. This study was approved by the Committee on Clinical Investigations and Publications of

Chil-drens Hospital of Los Angeles (Institutional Review Committee). All patients who received chemother-apy in the Hematology-Oncology clinic from March

15, 1983 through May 15, 1983 were eligible for


Survey data were obtained from 80 consecutive patients. The characteristics of these patients are presented in Table 1. Diagnostic distribution was broadly representative of those pediatric

malignan-cies in which chemotherapy plays a primary role, with a preponderance of acute leukemia. Time since diagnosis ranged from 2 to 98 months (mean 21 ±

22 [SD] months). Of the sample, (72% were in complete continuous remission, 19% had had a single recurrence of their disease, and 9% had had multiple recurrences. Patients had received be-tween one and 37 treatment cycles at the time of the survey (mean 10.7 ± 8.6 [SD]. In most cases, information was obtained jointly from the patient and at least one parent. However, when patients were either too young to respond reliably to the survey items or old enough to attend clinic without an adult present, data were obtained from either the parent or the patient, respectively. The hospi-tal’s translation services were utilized in three in-stances when neither patient nor parent spoke



A structured interview was designed to collect information in the following areas:

Side Effects After Chemotherapy. Items included parent ratings of postchemotherapy nausea and postchemotherapy emesis, and patient ratings of postchemotherapy nausea, emesis, and mood.

Current Symptoms Before Chemotherapy. Items included parent ratings of anticipatory nausea and anticipatory vomiting, and patient ratings of antic-ipatory nausea and anticipatory vomiting. The in-terview also included questions on whether the symptoms were currently being experienced and the time of symptom onset and peak.

Past Symptoms Occurring Before Chemotherapy. This section pertained to patients who were not

TABLE 1. Characteristics of 80 Patients

Age (yr) Mean ± SD Range Sex: M/F Ethnicity White Hispanic Black Asian Diagnoses



currently experiencing anticipatory nausea and vomiting but who had had anticipatory nausea and vomiting at some past point in their treatment course. Items included ratings of anticipatory nau-sea and anticipatory vomiting, the point in the treatment course when anticipatory nausea and vomiting stopped, and perception as to why

antici-patory nausea and vomiting stopped.

Onset and Etiology of Anticipatory Nausea and

Vomiting. Items included the point in the treatment course when anticipatory nausea and vomiting first began and perceptions as to what causes pretreat-ment nausea and vomiting to occur.

Communication About Chemotherapy. Items in-cluded the degree to which the patient talks to a parent about chemotherapy before coming to clinic and the degree to which a parent or other adult

talks to the patient about chemotherapy.

Parental Anxiety. All parents were asked to rate how concerned or worried they usually feel about how their child tolerates chemotherapy treatments.

Demographic and medical data were obtained primarily from the patient’s medical records; infor-mation was supplemented by the patient-parent interview. This included the information shown in Table 1 plus disease stage, Childrens Cancer Study Group (CCSG) treatment protocol, and radiation therapy data. Specific chemotherapeutic agents were recorded for each patient, and assigned an emetic potential value based on a previously vali-dated nurse and physician rating scale of 0 (no emetic potential) to 3 (maximum emetic potential).


Eligible patients and their parents were ap-proached about inclusion in the study during a routine clinic visit. The purpose of the study was explained, and then written consent for participa-tion was obtained. Interviews were conducted

im-mediately in an appropriate clinic room.



of Anticipatory


and Vomiting

The prevalence of anticipatory nausea and antic-ipatory vomiting for the 80 patients is shown in Table 2. Twenty-three patients (28.8%) were ex-periencing anticipatory nausea at the time of the

study. Sixteen of these patients (70% [20% of the entire sample]) were also having mild-to-severe emesis prior to drug administration.

Of the patients who were not experiencing symp-toms before treatment, nine (11.2% of the entire sample) reported having anticipatory nausea and anticipatory vomiting at some past point in their treatment. The proportion of patients who

experi-enced anticipatory nausea and vomiting, either at the time of the study or in the past is shown in Table 3.

Patterns of Anticipatory


and Vomiting

In most cases, onset of anticipatory nausea was two to four hours before treatment and was most

intense during the hour immediately preceding chemotherapy. Three patients reported anticipa-tory nausea beginning 12 to 24 hours before treat-ment. Anticipatory vomiting most often began

within two hours of treatment and was most severe

at the actual time of drug administration. One patient reported having anticipatory vomiting 24 hours before treatment.

Patients reported having first experienced

antic-ipatory nausea and vomiting anywhere from 1 to 48 months into their treatment course (mean 8.3 ±

11.9 [SD] months). However, 62% of those who reported either current or past anticipatory nausea and vomiting first developed it during the initial 4

months of treatment.

Patient and parent perceptions of anticipatory nausea and vomiting were also explored. Treat-ment-related anxiety was most commonly cited as the cause of anticipatory nausea and vomiting (being “worried,” “nervous,” or “scared”). Along similar lines, preoccupation with and expectations of chemotherapy side effects was perceived as the cause of anticipatory nausea and vomiting in five patients: “I think alot about what the medicine is going to do to me.” Specific stimuli associated with treatment (eg, odor of the clinic, taste sensations during infusions) were mentioned by four patients.

TABLE 2. Prevalence of Anticipatory Vomiting in 80 Patients

Nausea and

N %

Anticipatory nausea

None 57 71.2

Mild 12 15.0

Moderate 7 8.8

Severe 4 5.0

Anticipatory vomiting

None 64 80.0

Mild 8 10.0

Moderate 4 5.0

Severe 4 5.0

TABLE 3. Patients with Current or Past Anticipatory Nausea and Vomiting

Antic Na


ipatory usea


Anticipatory Vomiting

N %

Current 23 28.8 16 20.0

Past 9 11.2 9 11.2

Total 32 40.0 25 31.2

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Two parents felt that their children’s symptoms before treatment were an expression of anger at their illness and resistance to their treatment. One mother insisted that her son’s anticipatory nausea

was due to his leukemia and she had helplessly come to accept it. Another parent thought her child’s anticipatory nausea and vomiting was an indication of some psychological disturbance. Three parents reported having no idea what caused their children’s malaise before treatment.

In nine patients who had experienced anticipa-tory nausea and vomiting in the past but not

cur-rently, patient and parents were asked what they perceived to be the reasons for its cessation. Four patients attributed the cessation of anticipatory nausea and vomiting to the termination of a specific chemotherapeutic agent from the treatment regi-men. A formal or informal behavioral intervention was cited by three patients. Two of these patients were referred to a staff psychologist for training in

self-hypnosis and relaxation whereas the third pa-tient responded favorably to the parent’s operant reinforcement of successful coping during chemo-therapy administration. In two cases, neither pa-tient nor parent offered any explanation as to why anticipatory nausea and vomiting had stopped.


of Anticipatory




Anticipatory nausea and vomiting were signifi-cantly correlated with the total emetic potential of the chemotherapy regimen (r = .29; P .005) and

correlated with the level of nausea and vomiting after chemotherapy as reported by patients (r .35; P = .005) and parents (r = .28; P = .005).

Patients who received high-dose cyclophosphamide reported more severe anticipatory nausea and vom-iting than patients whose regimens did not include this drug (t = 2.55; df = 78; P = .01). Anticipatory

nausea and vomiting were not significantly corre-lated with the number of treatment cycles received or the amount of time since diagnosis. No signifi-cant differences in age, sex, or ethnic distributions were found between patients who experienced

an-ticipatory nausea and vomiting and those who did not.

Considerable variability in symptoms before treatment was observed for patients with similar diagnoses and treatment protocols. Five of 20 pa-tients (25%) with moderate-risk acute lymphoblas-tic leukemia (CCSG treatment protocol 162) were experiencing anticipatory nausea and vomiting. Five of eight patients (62%) with high-risk acute lymphoblastic leukemia (CCSG treatment proto-cols 192 and 193) had anticipatory nausea and vomiting whereas the remainder had no symptoms

before treatment. Two of five patients (40%) with bone tumors (CCSG treatment protocols 784 and

785) had anticipatory nausea and vomiting. A sim-ilar proportion of the five patients with non-Hodg-kin lymphoma (CCSG treatment protocol 551) re-ported anticipatory nausea and vomiting.

Parental anxiety was significantly correlated with anticipatory nausea and vomiting (r = .31; P = .003), indicating that higher levels of parental

anxiety were related to more severe pretreatment reactions in their children. However, the retrospec-tive nature of the current study precludes any de-termination as to whether parental anxiety exac-erbated reactions before treatment or vice versa. Communication about clinic visits between parents and children was negatively associated with levels of anticipatory nausea and vomiting, but these re-lationships were not statistically significant.

In order to elucidate further the relative contri-bution of the variables studied to the variance in anticipatory nausea and vomiting, a stepwise mul-tiple regression analysis was performed. Variables found on univariate analysis to be related to antic-ipatory nausea and vomiting were entered into the regression equation using a forward selection pro-cedure. Predictor variables included level of nausea and vomiting following chemotherapy, emetic po-tential of chemotherapy regimen, cyclophospha-mide, time since diagnosis, and parental anxiety. Results of the regression analysis are summarized in Table 4. Together, all five variables accounted for approximately 22% of the variance in group membership (ie, subjects with v subjects without anticipatory nausea and vomiting). Three of these variables, postchemotherapy nausea and vomiting, cyclophosphamide, and parental anxiety, accounted for 19% of the total variance.


Approximately one fourth of the patients in the current sample reported experiencing anticipatory nausea and vomiting, which suggests that this prob-lem may be affecting and contributing to treatment-related distress in a large number of pediatric can-cer patients. The prevalence rates of 28% for antic-ipatory nausea and 20% for anticipatory vomiting

TABLE 4. Regression Summary: Variabl

ing to Anticipatory Nausea and Vomiting


Contribut-Variable Multiple r r2 r2

Nausea and vomiting .318

following chemotherapy

Cyclophosphamide .387

Parental anxiety .432

Time since diagnosis .450

Emetic potential .470


.150 .187 .202 .221



ARTICLES 551 are roughly comparable to findings in adult studies,

most notably the study by Morrow,” which docu-mented anticipatory nausea and vomiting in one quarter of the patients studied. The figures reported for adult populations as well as the findings of the current study may actually underestimate the over-all prevalence of anticipatory nausea and vomiting due to the fact that the figures are limited to out-patient chemotherapy. Many pediatric protocols (eg, osteogenic sarcoma and other advanced solid tumors) call for intensive inpatient chemotherapy with concomitant high levels of toxicity (gastroin-testinal and otherwise). These patients are not rep-resented in the current study, although it is reason-able that such aggressive inpatient treatment regi-mens might promote considerable anticipatory nau-sea and vomiting.

As was noted earlier, anticipatory nausea and vomiting has been conceptualized as a conditioned aversion response to previously neutral stimuli.3’4 Support for this hypothesis comes from animal research in which dogs given repeated injections of morphine sulfate were observed to display signs of malaise and emesis at the sight of the experimenter or the hypodermic syringe.’6 The current study lends further support to the conditioning model. More emetic chemotherapeutic agents and higher levels of nausea and vomiting after chemotherapy were related to more severe reactions before treat-ment. This finding is consistent with findings in studies of adults with anticipatory nausea and vom-iting,8”3 and it is also consistent with the behav-ioral literature showing that the more salient the unconditioned stimulus (ie, emetic potential) and the stronger the unconditioned response (nausea and vomiting before chemotherapy) the more likely that conditioning and stimulus generalization will occur.’7

Anticipatory nausea and vomiting were usually first manifested during the first 4 months of treat-ment, although the percentage of patients who de-veloped anticipatory nausea and vomiting increased with time since diagnosis. Studies of adult patients have also shown that the majority of patients who develop anticipatory symptoms do so by the time oftheir fourth treatment cycle,7 which suggests that a critical period for acquiring this conditioned re-sponse may exist. The intensity of anticipatory nausea and vomiting was reported to increase as the noxious event grew nearer in time, and this avoidance gradient generally reached its peak at the actual time of drug administration. When

antici-patory nausea and vomiting stopped, it was most

commonly due to either the termination of the unconditioned stimulus (ie, the emetic drug) or the use of a behavioral counter-conditioning technique.

Considerable interpatient variability in

antici-patory nausea and vomiting was observed in the current sample, with only 22% of this variance attributed to disease- and treatment-related fac-tors. Although the conditioning model provides an explanation as to why some patients develop

antic-ipatory nausea and vomiting, it does not account for why most patients do not manifest such reac-tions. Under these circumstances, it is difficult to predict which patients are most at risk because many patients with similar diagnoses and treat-ment regimens will not develop anticipatory nausea and vomiting. It is, therefore, of basic scientific and applied clinical relevance to understand the consti-tutional and psychological variables contributing to the development of anticipatory nausea and vom-iting. One interesting avenue for speculation con-cerns the role of endogenous opiates. Previous re-search has shown that the perception of acute

dis-tress in children with cancer is positively correlated

to f-endorphin levels in CSF.’8 Endorphins have also been identified as important neurotransmitters in the chemoreceptor trigger zone.’9 Thus, patients who exhibit high levels of behavioral distress may be at greater risk for increased nausea and vomiting after chemotherapy as well as anticipatory nausea and vomiting.

Other biobehavioral factors that may contribute to the development and/or maintenance of

antici-patory nausea and vomiting include autonomic

reactivity,20 anxiety,2’ stimulus screening,22 and dif-ferential patterns of parental management of chil-dren in stressful situations.23 Our current research

is focusing on these variables as well as the rela-tionship of anticipatory nausea and vomiting to other forms of avoidance conditioning in patients with cancer, eg, learned taste aversions, which have also been observed in adult and pediatric patients receiving chemotherapy.2427 The ultimate aim of such research is to develop a comprehensive model for understanding and predicting conditioned aver-sions and for the early identification of patients at high risk. This would lay the foundation for imple-menting prophylactic and curative behavioral in-tervention strategies and would provide more gen-eral insight into the factors contributing to treat-ment-related distress.

It is important that care givers provide patients and parents with information regarding the causes of anticipatory nausea and vomiting so that further misconceptions, anxiety, and avoidance may be pre-vented. Patients who experience anticipatory nau-sea and vomiting should understand that this rep-resents an adaptive organismic response and that such conditioning serves as a warning mechanism in anticipation of a threatening event. Patients and

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parents can also be encouraged that pretreatment reactions may be reversed. Although no systematic studies of behavioral interventions (eg, hypnosis, guided imagery, relaxation, stress inoculation, op-erant techniques) have been reported to date in pediatric patients with anticipatory nausea and vomiting, several case studies28’29 and our own din-ical experience support their utility. Controlled re-search on these intervention strategies is clearly needed and would be aided by further clarification of individual differences in the etiology of antici-patory nausea and vomiting.


This study was supported by a grant from the Depart-ment of Research, Childrens Hospital of Los Angeles.


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Michael J. Dolgin, Ernest R. Katz, Kathy McGinty and Stuart E. Siegel

Anticipatory Nausea and Vomiting in Pediatric Cancer Patients


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Anticipatory Nausea and Vomiting in Pediatric Cancer Patients

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