The Role of Patients Expectations in the Development of Anticipatory Nausea Related to Chemotherapy for Cancer

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1 Vol. 22 No. 4 October 2001 Journal of Pain and Symptom Management 843 Original Article The Role of Patients Expectations in the Development of Anticipatory Nausea Related to Chemotherapy for Cancer Jane T. Hickok, MD, MPH, Joseph A. Roscoe, PhD, and Gary R. Morrow, PhD, MS University of Rochester Cancer Center, Rochester, New York, USA Abstract Although anticipatory nausea (AN), which is reported by one-third of patients receiving chemotherapy for cancer, is thought to develop primarily by classical conditioning, response expectancies may also be important. The role of patients expectations of nausea in the development of AN was examined in 63 female cancer patients receiving their first course of chemotherapy. Twenty women (32%) expected to experience nausea and twelve (19%) reported AN before the third cycle. Pretreatment expectations predicted AN at cycle three (Spearman s r 0.41, P 0.001). AN developed in 40% of patients who expected nausea, 13% of those who were uncertain whether they would develop it, and no patients who did not expect nausea. Logistic regression indicated that expecting nausea was the strongest predictor ( ; P 0.001). Results support a role for cognitive factors in the development of chemotherapy side effects and suggest testing psychologic interventions to modify patients expectations. J Pain Symptom Manage 2001;22: U.S. Cancer Pain Relief Committee, Key Words Cancer, chemotherapy, patient expectations, anticipatory nausea, classical conditioning Address reprint requests to: Jane T. Hickok, MD, MPH, University of Rochester Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, NY USA. Accepted for publication: December 15, Introduction Nausea and vomiting are among the most common adverse effects of chemotherapy for cancer. Despite ongoing improvement in the effectiveness of antiemetic agents, the majority of patients receiving chemotherapy continue to experience one or both of these symptoms. 1 3 Furthermore, many patients who suffer from post-chemotherapy nausea develop symptoms in anticipation of treatment. In most published work, anticipatory nausea is reported by approximately 20% of patients at any one chemotherapy cycle and by 25 30% of patients by the fourth chemotherapy cycle; anticipatory vomiting develops in 8 20% of patients. 1,4 7 These anticipatory symptoms, which can begin a day or more before a patient s clinic appointment, can add significantly to the burden that patients experience while undergoing chemotherapy, increasing their apprehension and prolonging their discomfort. The most generally accepted model for the development of anticipatory nausea and vomiting (ANV) is that they are learned responses that develop through a mechanism of classical, or Pavlovian, conditioning. 4,8 10 A significant body of experimental and clinical work provides evidence for the conditioning model and U.S. Cancer Pain Relief Committee, /01/$ see front matter Published by Elsevier, New York, New York PII S (01)

2 844 Hickok et al. Vol. 22 No. 4 October 2001 highlights the role of post-chemotherapy nausea and emesis (the unconditioned response) after chemotherapy (the unconditioned stimulus) in the causation of anticipatory symptoms (the conditioned response) associated with thoughts or characteristics of the treatment site (the conditioned stimulus). Although the occurrence and severity of post-chemotherapy nausea and vomiting are determined largely by pharmacologic properties of the chemotherapy agents, they may be modified by individual patient characteristics, 4,11 13 such as younger age (less than 50 years), 4 6,14 and a history of motion sickness. 14,15 In addition, feeling warm or hot, sweaty, or generally weak after the last previous chemotherapy infusion have been also associated with a greater likelihood of experiencing AN. 14,16 No previous research has identified significant differences in rates of AN by gender or by racial group. 7 Pharmacologic properties of chemotherapy agents, and demographic, psychologic, and individual difference characteristics presently known to be associated with the development of ANV account for no more than half of the total variance in AN occurrence. 17,18 Several researchers have reported that patients pre-treatment expectations about developing nausea from chemotherapy predict the occurrence of AN, 4,19,20 but it is not entirely clear from previously reported research whether cognitive factors act independently from conditioning to influence side effect development. For example, expectations could interact with the conditioning process by enhancing the development of post-treatment nausea or vomiting. 4,21 Feeling anxious just before a chemotherapy appointment (state anxiety) has been associated with an increased tendency to develop ANV, 22,23 as has a general tendency to feel anxious in a variety of situations (trait anxiety). 6,24 Anxiety at the time of treatment may act to increase the probability of ANV by exacerbating post-treatment nausea and emesis. 25 Anxiety could also promote conditioning by enhancing fear of chemotherapy or increasing the salience of potential conditioned stimuli. 26 Three published studies have examined the role of cognitive factors, particularly patients expectations, in the onset of anticipatory symptoms. All have involved women receiving chemotherapy for breast cancer: two reported on different subsets of the same sample, and one of these, 4 did not identify a significant role for expectations. Andrykowski and colleagues, studying 77 women, found that although those who subsequently developed AN had expressed greater expectations of developing nausea, the independent contribution of patient expectations to AN occurrence beyond the contribution of the severity and duration of post-treatment nausea was not statistically significant; only greater severity and duration of post-chemotherapy nausea (PN), predicted the subsequent occurrence of AN. In this study, patients were receiving chemotherapy on a weekly basis and, although strict definitions of AN and PN were employed, it is conceivable that some of the nausea measured as AN may in fact have been delayed or persistent post-chemotherapy nausea, which can last as long as seven days after a chemotherapy infusion. Inclusion of persistent symptoms may have contributed to a spuriously high AN frequency of 57% and could explain, at least in part, the lack of significant association between expectations and AN. 4 In a more recent report involving a subset of the same sample (n 59), the authors determined that expectations made an independent contribution to the development of AN when contingency, previously found to be the strongest predictor of conditioning, 27 was statistically controlled. 19 Watson and colleagues reported results of a prospective study of 100 women, that showed that patients expectations and trait anxiety predicted the occurrence of AN before cycle three when the effect of the strongest predictor, previous experience of chemotherapy-related nausea, was accounted for. 20 In this article, we report on the relationship between patients pre-treatment expectations of developing nausea and the occurrence of anticipatory nausea before the third chemotherapy treatment in 63 female patients receiving their first course of chemotherapy for a variety of cancer diagnoses. We hypothesized that greater pretreatment expectations of developing nausea would be significantly related to the subsequent development of anticipatory nausea. This prospective study supports previously published results suggesting that expectations may have an independent effect on development of AN separate from that of conditioning and extends the application of previous work by including women with malignancies other than breast cancer. To assure that

3 Vol. 22 No. 4 October 2001 Patient Expectations and Anticipatory Nausea 845 any occurrence of AN would be separate from that of PN, a more precise measure of AN was employed than the one used by previous authors: only patients receiving cyclic intravenous chemotherapy with a break of at least two weeks between the last day of chemotherapy in one cycle and the first day of treatment in the next cycle were enrolled. Methods Patients Study subjects were patients at the University of Rochester Cancer Center, two local affiliated hospitals and a private oncology practice in Rochester, NY, between December 1994 and September The design of this study, to monitor over a 24-hour period the response of patients autonomic nervous system to chemotherapy, stipulated that anticipatory and postchemotherapy nausea and vomiting be assessed only prior to patients first chemotherapy treatment (baseline) and at their first and third chemotherapy cycles. At the time of the study, cyclical chemotherapy with two or more weeks between chemotherapy infusions without concurrent use of radiation therapy (RT) was being given only for a few types of cancer, of which breast cancer was the most common. All subjects were being treated with an initial course of chemotherapy, were not receiving RT concurrently with the scheduled chemotherapy, did not have any primary malignancy or metastatic disease affecting the brain, and were at least 19 years of age. Chemotherapy cycles were either 21 or 28 days in length and patients typically received all chemotherapy agents by intravenous infusion over a period of several hours on the first day of the cycle. A few patients with 28-day cycles received chemotherapy on the first and eighth days of the cycle. All patients received standard antiemetics as prescribed by the treating oncologist. The protocol was approved by the Institutional Review Board of each participating site. Of the 70 patients who provided complete data at baseline and at their first and third chemotherapy cycles, only 7 were male. Thus, results are reported only for the 63 women for whom complete data is available. The mean age of the women was 52.5 years (range years). Fifty-three subjects (84%) were Caucasian and ten (16%) were African-American. Sixty-two percent were married, 25% divorced or separated, 10% single, and 3% widowed. Sixty percent had graduated from or attended college and an additional 22% were high school graduates. Forty-four patients (70%) were being treated for breast cancer, twelve (19%) for cancer of the genitourinary tract, five (8%) had lymphoma, and two (3%) had lung cancer. Twenty women (32%) self-reported being susceptible to motion sickness, generally comparable to figures available for the general population. 28 Procedures Each patient was asked to participate in the research study prior to receiving their first chemotherapy treatment for histologically confirmed cancer. After providing informed consent and receiving standard verbal and written information about chemotherapy, including possible adverse effects, from clinic nursing and medical staff, but before beginning treatment (baseline), patients completed a questionnaire assessing their expectations of developing five common adverse effects of chemotherapy (nausea, vomiting, nervousness, fatigue, and sleep problems). Adverse events were assessed on separate fivepoint Likert-type semantic rating scales anchored at one end by 1 I am certain I will NOT have this, and at the other end by 5 I am certain I WILL have this. No written descriptors were associated with the intermediate numbers. Patients who indicated a response of either 4 or 5 were scored as expecting the symptom. Women in this sample appeared to consider each of the five potential side effects queried on the questionnaire separately. Only three subjects had high expectations of experiencing all five adverse effects. The form was adapted from one initially designed by Cassileth and colleagues, 29 and used by our group in previously published studies. 30,31 At baseline, patients also completed the anxiety portion of the Autonomic Perception Questionnaire (APQ). This form measures patients awareness of 21 separate, specific bodily reactions to feeling anxious on a scale of 0 to 9, with 0 indicating no awareness of reactions or of change in specific responses such as heart rate or respiration, and 9 indicating maximum awareness of presence of or change in possible responses to feeling anxious. The total score is obtained by adding up the answers to all 21 questions and can range from zero to Sus-

4 846 Hickok et al. Vol. 22 No. 4 October 2001 ceptibility to motion sickness (yes/no) was also assessed at baseline. Nausea was measured and characterized using the Morrow Assessment of Nausea and Emesis (MANE). 35 The MANE was designed to measure in detail the occurrence, duration, and severity of post-chemotherapy and anticipatory nausea and vomiting. Anticipatory nausea is assessed using three separate questions, Did you experience nausea before your first (or most recent, depending on which cycle was being assessed) chemotherapy treatment? (yes/no); How would you describe the nausea at its worst before treatment? (indicated by circling a number from 1 to 6 with 1 very mild, 2 mild, 3 moderate, 4 severe, 5 very severe and 6 intolerable ); and How many hours before treatment did the nausea first occur? (total number of hours written in). Post-chemotherapy nausea was also assessed with appropriately worded questions, Did you experience nausea during or after your first (or most recent, depending on which cycle was being assessed) chemotherapy treatment? (yes/no); How long did the nausea last? (total number of hours written in); and How would you describe the nausea at its worst? (choices the same as for anticipatory symptoms). Patients were given the MANE by study personnel prior to the first and third chemotherapy infusions and were asked to complete the questions about anticipatory symptoms at that time. They were requested to complete the remainder of the questions at home on the fourth day after treatment and return them by mail. A reminder telephone call was made asking the patient to complete the forms and mail them in if they were not received by one week after treatment. Reliability and validity of the MANE have been demonstrated in patients with cancer. 35,36 The tendency of specific chemotherapy regimens administered to cause vomiting (emetogenicity) was classified by historic frequency of acute emesis according to the method proposed by Hesketh and co-investigators (1997) with level 1 representing 10% frequency, level % frequency, level %, level % and level 5 90% frequency of emesis. 37 No equivalent rating system is available for nausea. and twelve (19%) reported that they experienced anticipatory nausea (AN) prior to the third chemotherapy cycle. The average severity of AN was grade 2.3 (range 1 6), representing nausea of mild to moderate intensity. Onset of anticipatory nausea ranged from one hour or less (three patients) to 48 hours (two patients) before chemotherapy began (mean onset 16.5 hours before treatment commenced). Six patients (10%) reported feeling nauseated prior to their first chemotherapy treatment (mean duration 7 hours, range 1 30 hours; mean severity grade 2.2, range 1 3). Non-parametric correlation showed that the occurrence of AN before the third treatment was significantly associated with three variables: occurrence of nausea before the first cycle of chemotherapy (Spearman s r 0.25, P 0.05), occurrence of nausea following the first cycle of chemotherapy (r 0.30, P 0.02), and patient expectations (discussed below). Duration and severity of PN following the first treatment, emetogenic potential of the chemotherapy regimen being administered, 37 age, anxiety as indicated by total score on the APQ, and susceptibility to motion sickness were not significantly related to Results Twenty of the 63 women (32%) expected to experience nausea as a result of chemotherapy Fig. 1. Percent of patients reporting anticipatory nausea (AN) before cycle three by pre-treatment degree of certainty for expecting nausea.

5 Vol. 22 No. 4 October 2001 Patient Expectations and Anticipatory Nausea 847 the development of AN before chemotherapy cycle three (all Ps 0.05). Post-chemotherapy nausea (PN) was experienced by 39 patients (62%) after the first chemotherapy cycle, despite normal clinical practice of providing maximum antiemetic prophylaxis prior to treatment. The average duration was 43 hours (range less than one hour to more than four days) and mean severity was grade 3, moderate (range 1 6). Although the MANE was also used to assess vomiting occurrence and characteristics, the frequency of vomiting was very low (only three patients [5%] reported anticipatory vomiting (AV) before the third chemotherapy cycle, with 15 [24%] reporting emesis after the first cycle). This report focuses only on factors associated with the development of anticipatory nausea. Ninety percent of the study subjects were treated with chemotherapy regimens that historically cause emesis in more than 60% of patients (Hesketh levels 4 or 5). 37 Role of Expectations in Development of Anticipatory Nausea Expectations of developing nausea, measured prior to patients first treatment, predicted the occurrence of AN before the third cycle of chemotherapy (Spearman s r 0.41, P 0.001). None of the women who were certain they would not have nausea developed AN, compared to 55% of those who were certain they would have nausea (Figure 1). Parametric and non-parametric correlation showed that three variables, occurrence of nausea following the first cycle of chemotherapy (Spearman s r 0.28, P 0.03, anxiety as indicated by total score on the APQ (Pearson r 0.41, P 0.001) and age (Pearson r 0.36, P 0.01) were significantly associated with expectations of developing nausea as a result of chemotherapy. Measured variables that were not significantly correlated with patient expectation of nausea included: whether or not patients reported nausea prior to the first cycle of chemotherapy, emetogenic potential of the chemotherapy regimen being administered and susceptibility to motion sickness (all Ps 0.05) (Table 1). Logistical regression analyses were used to further explore the relationship between patient expectation and the occurrence of AN. We entered the two variables other than patient expectation that were significantly correlated with AN occurrence before the third treatment (i.e., occurrence of nausea before the first cycle of chemotherapy and occurrence of nausea following the first cycle of chemotherapy) at the first step in an equation predicting AN at that time. These two factors taken together were a significant predictor of AN development prior to the third treatment ( , P 0.02). Nausea expectancy when entered at step two of this equation accounted for significant improvement in the model ( 2 improvement 10.44, P 0.001). In a similar Table 1 Correlation Among Factors Potentially Related to Anticipatory Nausea (AN) and Patients Expectations Measure Expectations a 2. AN before cycle 3 a.413** 3. AN before cycle 1 a * 4. PN after cycle 1 a.280*.297*.251* 5. PN duration cycle 1 b.259* ** 6. PN severity cycle 1 b **.777** 7. Emetogenicity b Age b.364** * Anxiety b.405** * ** 10. Motion sickness a * *.216 * p 0.05 ** p 0.01 a Spearman s rho b Pearson r Variables: 1. Patients expectations of developing nausea assessed prior to beginning chemotherapy (yes/no); 2. Occurrence of AN before cycle three (yes/no); 3. Occurrence of AN before cycle one (yes/no); 4. Occurrence of post-chemotherapy nausea (PN) after cycle one (yes/no); 5. Duration of PN after cycle one (hours); 6. Severity of PN after cycle one (on a 6-point scale from 1 mild to 6 intolerable); 7. Tendency of particular chemotherapy regimens to cause emesis (on a five point scale ranging from 1 10% frequency to 5 90% frequency of emesis). 8. Age in years; 9. Anxiety represented by total score on the Anxiety Perception Questionnaire (range 0 189); 10. History of motion sickness (yes/no).

6 848 Hickok et al. Vol. 22 No. 4 October 2001 stepwise logistic regression analysis using the same predictors, expectation of nausea entered first ( , P 0.001). The variable indicating whether or not the patient experienced nausea prior to the first cycle of chemotherapy entered the equation at step two ( 2 improvement 4.60, P 0.04). The third variable, whether or not the patient experienced nausea after the first cycle of chemotherapy, did not add significant improvement to the model. Patients pre-treatment expectations of developing nausea was the strongest predictor of AN occurrence prior to the third chemotherapy infusion. Discussion Patients pre-treatment expectations of experiencing nausea as a result of chemotherapy made a significant and unique contribution to the development of AN at the third chemotherapy cycle in this group of female cancer patients who were receiving their first course of chemotherapy for a variety of cancer diagnoses. Occurrence, severity, and duration of PN, the presumed primary conditioning factor, did not contribute to the occurrence of AN at the third treatment cycle. Our results support the recent findings of Montgomery and colleagues 19 showing a significant relationship between patients expectations for nausea and the development of AN, and those of Watson and associates 20 who found that patients expectations predicted the occurrence of AN at cycle three but failed to contribute uniquely to AN later in the course of chemotherapy (cycle five). In their work, a history of chemotherapy-related nausea or vomiting was the strongest predictor of AN at cycle three and the only significant predictor by cycle five. The results of this study suggest that in this sample, patient expectations may have acted independently from learning, or conditioning, in the production of AN and that patients expectations played a larger role than conditioning in AN that occurred early in the course of cyclic chemotherapy. The work of Watson and colleagues 20 suggests that conditioning may become a stronger predictor as the number of infusions (putative conditioning trials) increases. Inclusion of women with diagnoses other than breast cancer suggests that the role of expectations in AN is not limited to specific diagnoses or treatment regimens. Additional research involving larger and more heterogeneous patient samples comprising subjects of both genders receiving longer courses of chemotherapy for a variety of cancer diagnoses is needed to further examine the potentially complex interactions between patient response expectancies and conditioning in the development of anticipatory symptoms. In our study, anxiety did not predict AN. Anxiety was assessed as a general tendency to experience certain bodily reactions to feeling anxious and measured only at baseline; we did not measure patients anxiety immediately prior to receiving chemotherapy. Studies that have shown a significant relationship between anxiety and characteristics of AN have traditionally measured state anxiety just prior to chemotherapy. No currently available pharmacologic agents are effective in controlling anticipatory nausea once it has developed Systematic desensitization (a behavioral treatment in which muscle relaxation is learned as a response to situations which have previously been associated with AN) can decrease the occurrence as well as the severity and duration of AN, 41 but it is not widely available in most clinical settings and is relatively expensive to administer. Prevention of AN therefore assumes great importance. In a recent publication we reported that 90% of subjects enrolled in this study cited their doctor or nurse as the most frequent source of information about side effects of chemotherapy. 31 Refinement of questionnaires to delineate further the relative impact of previous experience of nausea (from pregnancy, motion sickness, and the like) and learning about side effects from medical and non-medical sources of information in forming expectations of nausea from chemotherapy is needed to clarify further how an individual s expectations are formed. Our findings that patients positive expectations of developing nausea play a small but important role in the development of anticipatory nausea have implications for changing the way in which health care professionals present information about potential side effects of chemotherapy to patients. It is reasonable to suggest that patient expectations might be amenable to modification and that decreasing an individual s expectations of experiencing nausea could reduce the frequency of AN. Before receiving chemotherapy for the first

7 Vol. 22 No. 4 October 2001 Patient Expectations and Anticipatory Nausea 849 time, patients are provided with detailed oral and written information about treatment procedures and schedules to be employed as well as possible side effects that could develop. At this time, an opportunity exists for health professionals to assess patients expectations of experiencing specific side effects and perhaps attempt to modify them through verbal information or written material. An optimistic, but still realistic, presentation of information for example reassuring patients about the effectiveness of antiemetics to be prescribed might act to reduce patients expectations of developing nausea and thus decrease the probability of anticipatory nausea. The results also suggest a possible line of future research to test in a double-blind fashion the effect of positive enhancement of patient expectations on the frequency of anticipatory nausea and vomiting. Acknowledgments This study was supported by NR01905 from the National Institute of Nursing Research, USA. References 1. Morrow GR, Roscoe JA, Hynes HE, et al. Progress in reducing anticipatory nausea and vomiting: a study of community practice. Support Care Cancer 1998;6: Latreille J, Pater J, Johnston D, et al. Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998;16: Morrow GR, Hickok JT, Rosenthal SN. Progress in reducing nausea and emesis. Comparisons of ondansetron (Zofran), granisetron (Kytril), and tropisetron (Navoban). Cancer 1995;76: Andrykowski MA, Jacobsen PB, Marks E, et al. Prevalence, predictors, and course of anticipatory nausea in women receiving adjuvant chemotherapy for breast cancer. Cancer 1988;62: Morrow GR, Dobkin PL. Anticipatory nausea and vomiting in cancer patients undergoing chemotherapy treatment: prevalence, etiology, and behavioral interventions. Clin Psychol Rev 1988;8: Jacobsen PB, Bovbjerg DH, Redd WH. Anticipatory anxiety in women receiving chemotherapy for breast cancer. Health Psychol 1993;12: Morrow GR, Roscoe JA. Anticipatory nausea and vomiting: models, mechanisms and management. In: Dicato M, ed. Medical management of cancer treatment induced emesis. London: Martin Dunitz, 1997: Bovbjerg DH, Redd WH, Jacobsen PB, et al. An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med 1992;54: Stockhorst U, Klosterhalfen S, Klosterhalfen W, et al. Anticipatory nausea in cancer patients receiving chemotherapy: classical conditioning etiology and therapeutical implications. Integr Physiol Behav Sci 1993;28: Morrow GR, Roscoe JA. Do severity and duration of postchemotherapy nausea vomiting (NV) predict anticipatory NV? Multinational Association of Supportive Care in Cancer: Consensus Conference on Antiemetic Therapy 1997; Montgomery GH, Bovbjerg DH. The development of anticipatory nausea in patients receiving adjuvant chemotherapy for breast cancer. Physiol Behav 1997;61: Sabbioni ME, Bovbjerg DH, Jacobsen PB, et al. Treatment related psychological distress during adjuvant chemotherapy as a conditioned response. Ann Oncol 1992;3: Morrow GR. Prevalence and correlates of anticipatory nausea and vomiting in chemotherapy patients. J Natl Cancer Inst 1982;68: Morrow GR. Clinical characteristics associated with the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy treatment. J Clin Oncol 1984;2: Morrow GR. Susceptibility to motion sickness and the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy. Cancer Treat Rep 1984;68: Morrow GR, Lindke J, Black PM. Anticipatory nausea development in cancer patients: replication and extension of a learning model. Br J Psychol 1991; 82: Cohen RE, Blanchard EB, Ruckdeschel JC, Smolen RC. Prevalence and correlates of posttreatment and anticipatory nausea and vomiting in cancer chemotherapy. J Psychosom Res 1986;30: Pickett M. Determinants of anticipatory nausea and anticipatory vomiting in adults receiving cancer chemotherapy. Cancer Nurs 1991;14: Montgomery GH, Tomoyasu N, Bovbjerg DH, et al. Patients pretreatment expectations of chemotherapy-related nausea are an independent predictor of anticipatory nausea. Ann Behav Med 1998;20: Watson M, Meyer L, Thomson A, Osofsky S. Psychological factors predicting nausea and vomiting in breast cancer patients on chemotherapy. Eur J Cancer 1998;34: Kirsch I. Response expectancy as a determinant of experience and behavior. Am Psychol 1985;40:

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