Volume 104
`Number 3
`
`flight © 1933
`American
`psychological
`Association, Inc.
`
`Psychological
`Bulletin
`
`Review Articles
`
`307 Etiology and Treatment ofthe Psychological Side Effects Associated With Cancer Chemotherapy:
`A Critical Review and Discussion
`
`Michael P. Carey and Thomas‘G. Burish
`
`326 Stress Management During Noxious Medical Procedures: An Evaluative Review of Outcome
`Studies
`
`Robin Ludwick—Rosenthal and Richard W. J. Neufild
`
`343 Atypical laterality and Retardation
`Margaret-Ellen Pipe
`
`348 Elucidating the Effects of Reinforcement Magnitude
`Marilyn Bonem and Edward K. Crossman
`
`363 The Amplitude Transition Function and the Manual and Oculomotor Control Systems
`Nicholas C. Barrett and Denis J. Glencrass
`
`373 Coronary Heart Disease and Type A Behaviors: Update on and Alternative to the Booth—Kewley
`and Friedman (1987) Quantitative Review
`Karen A. Matthews
`
`381 Validity of the Type A Construct: A Reprise
`Howard S. Friedman and Stephanie Booth-Kewley
`
`Quantitative Methods in Psychology
`
`385 Data Analysis Using Item Response Theory
`David Thissen and Lynne Steinberg
`
`396 Heterogeneity of Variance in Experimental Studies: A Challenge to Conventional Interpretations
`Anthony S. Brylc and Stephen W Raua'enbush
`
`405 Validity Inferences From Interobserver Agreement
`John S. Uebersax
`
`417 Random Monotone Data Fit Simple Algebraic Models: Correlation Is Not Confirmation
`Scott Parker; Jay Casey: John M. Ziriax, and Alan Silberberg
`
`'
`
`Other
`
`347 Calls for Nominations for JCCR Educational, JPSP: Attitudes, and JPSP: Interpersonal
`
`425 Editorial Consultants
`
`395 Hunt Appointed Editor of JEP: General. 1990—1995
`
`This issue completes Volume 104 and contains the author index for the volume.
`
`(Contents continued on next page)
`
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`Important Announcement About Your Subscription
`306
`424 Instructions to Authors
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`362 Mineka Appointed Editor ofJournal ofAbnormal Psychology 1990—1995
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`384 Split of JCCP—New Section on Assessment
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`Rayner Appointed Editor of JEP: Learning, Memory,
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`The Publications and Communications Board of the American Psychological Association an-
`nounces the appointment ofKeith Rayner, University ofMassachusetts, as editor ofthe Journal
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`1990. As of Ianuary l, 1989, manuscripts should be directed to
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`volume.
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`Keith Rayner
`Department of Psychology
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`Manuscript submission patterns for JEP: Learning, Memory and Cognition make the precise
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Psychological Bulletin
`1988, Vol. 104, No. 3. 307-325
`
`Cwyright 1988 by the American Psychological Association, Inc.
`0033-2909188/300JS
`
`Etiology and Treatment of the Psychological Side Effects
`Associated With Cancer Chemotherapy:
`A Critical Review and Discussion
`
`Michael P. Carey
`Syracuse University
`
`Thomas G. Burish
`Vanderbilt University
`
`Cancer patients receiving chemotherapeutic treatments routinely experience a wide range of dis-
`tressing side effects, including nausea, vomiting and dysphoria. Such symptoms often compromise
`patients’ quality of life and may lead to the decision to postpone or even reject future, potentially
`life-saving, treatments. In ihis article, we discuss the hypotheses that have been offered to explain
`the development of such symptoms. We also review, in greater detail, the research evidence for the
`eflicacy offive treatments for such symptoms: hypnosis, progressive muscle relaxation training with
`glided imagery, systematic desensitization, attentional diversion or redirection, and biofeedback.
`We discuss the implications ofthis treatment research, paying particular attention to factors associ-
`ated with treatment outcome, mechanisms of treatment efi‘ectiveness, and issues associated with
`clinical application.
`
`Chemotherapy is the treatment of choice for hundreds of
`thousands of cancer patients diagnosed each year in the United
`States (Silverberg & Lubera, 1986). Its frequent use with cancer
`patients is the result of recent advances in antineoplastic medi-
`cation; new and more effective medications have increased the
`life expectancy for many patients and, in some cases, have re-
`sulted in remission and cure. Unfortunately, such long—term
`gain can come at considerable short-term cost to the cancer pa-
`tient in the form of aversive and debilitating side effects. Among
`the more common drug-induced side efi‘ects are alopecia, sto-
`matitis, immunosuppression, anorexia, nausea, and vomiting.
`In addition to these pharmacological side effects, chemotherapy
`patients also experience psychological side efi‘ects.
`Psychological side effects, which should not necessarily be re-
`garded as abnormal or indicative of psychopathology, are those
`that cannot be attributed directly to the antineoplastic medica-
`tions; instead, such symptoms are believed to result from psy-
`chological processes (e.g., learning) that occur in the chemo-
`therapy context. These symptoms can occur before chemother-
`apy (in which case they are referred to as anticipatory side
`effects) as well as during and alter the actual chemotherapy infu-
`sion. When they occur after chemotherapy has been adminis-
`tered (and while the drugs remain pharmacologically active
`within the system), it is practically impossible to distinguish
`
`We wish to thank Kate B. Carey and the anonymous reviewers for
`their many helpful suggestions on an earlier draft of this review. The
`writing of this manuscript was supported in part by Grant No. 25516
`from the National Cancer Institute, Grant No. PER-29 from the Ameri-
`can Cancer Society, and Grant No. 24 from Syracuse University.
`Correspondence concerning this article should be addressed to Mi-
`chael P. Carey, Department of Psychology, 430 Huntington Hall, Syra-
`cuse University, Syracuse, New York 13244; or to Thomas G. Burish,
`221 Kirkland Hall, Vanderbilt University, Nashville, Tennessee 37240.
`
`such psychological side effects from their pharmacological
`counterparts. Unfortunately, there has been much inconsis-
`tency in the literature concerning the definition of these symp-
`toms and the terminology used to describe them. For the most
`part, however, research with humans has focused on three
`symptoms, namely, nausea, vomiting, and dysphoria. However,
`it should be noted that considerable animal research and recent
`human research have also focused on other side efi‘ects ofcancer
`
`treatments, especially learned side efi‘ects such as conditioned
`taste and food aversions (e.g., Bernstein & Borson, 1986; Smith,
`Blumsack, & Bilek, 1985) and conditioned immunosuppres~
`sion (c.g., Ader, 1981; Ader & Cohen, 1985). These phenomena
`may develop through mechanisms that are similar to those that
`are the focus of this article.
`
`Symptoms such as nausea, vomiting, and dysphoria are not
`only frequent among cancer chemotherapy patients but can also
`be extremely stressful. In addition to the physical and affective
`distress they cause, many patients are embarrassed by their dis-
`play of symptoms (e.g., anticipatory vomiting), and others even
`fear for their sanity. In fact, some patients eventually discon-
`tinue chemotherapy, abandoning the hope for remission and
`cure rather than suffer from such symptoms (Wilcox, Petting,
`Nettesheim, & Abelofi‘, 1982). It has been suggested that still
`other patients will turn to ineffective and expensive “quack"
`treatments rather than tolerate the paradoxical worsening qual-
`ity of life that chemotherapy can bring. Consequently, oncolo-
`gists (e.g., Laszlo & Lucas, 1981), oncology nurses (cg, Oberst,
`1978), and cancer patients themselves (e.g., Cohn, 1982) have
`all implored researchers to identify an effective treatment for
`the side efl‘ects associated with cancer chemotherapy.
`Pharmacological agents (e.g., prochlorpcrazine, delta-9-tet-
`rahydrocannabinol) have been used to control the psychological
`responses to chemotherapy, but standard antiemetics have been
`found largely inefi'ective for this type ofsymptom (Laszlo, 1983;
`
`307
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`308
`
`MICHAEL P. CAREY AND THOMAS G. BURISH
`
`Morrow, Aiseneau, Asbury, Bennett, & Boros, 1982). In addi-
`tion, there is evidence that these medications can actually
`worsen the symptomatology under some conditions (Zeltzer,
`LeBaron, & Zeltzer, 1984a). Moreover, even when antiemetics
`provide some relief, they often have side effects of their own
`(e.g., sedation, dystonic reactions) or administration demands
`(e.g., the need for inpatient hospitalization) that limit their acv
`ceptance or usefulness among some patients. The ineffective-
`ness, the paradoxical worsening of symptoms, and the practical
`limitations of pharmacological agents have all prompted re-
`searchers to consider psychological treatments as an alternative
`method of controlling such symptoms.
`In recent years, research on the etiology and treatment of an-
`ticipatory and exacerbatory side effects ofcancer chemotherapy
`has burgeoned and has attracted researchers from several
`health-care disciplines. This increasingly widespread interest is
`based on at least two primary factors. First, from a theoretical
`point of view, the psychological side effects of cancer chemo-
`therapy present an unusual opportunity to study the natural
`development of reactions to repeated aversive treatment within
`a clinical population. As we shall see, these reactions share some
`commonalities with other aversive responses but also appear to
`have some notable differences. Second, from a clinical point of
`view, these side effects are quite prevalent and can be aversive
`and debilitating. As a result, they represent an important clini-
`cal problem.
`The primary purpose of this article is to review the research
`evidence on the etiology and treatment of the most common
`psychological side efl'ects associated with cancer chemotherapy,
`namely, nausea, vomiting, and dysphoria. We begin with an
`overview and evaluation of the etiological formulations that
`have been proffered to explain the development of such symp-
`toms. After this discussion of etiology, we review and critique
`the treatment literature, focusing on investigations that provide
`quantitative outcome data. We discuss the implications of this
`research, paying particular attention to patient factors associ-
`ated with outcome, hypothesized mechanisms by which the
`treatments may exert their impact, and clinical issues in the
`application of such interventions.
`
`Etiology of Psychological Side Effects Associated
`With Cancer Chemotherapy
`
`Psychological side efi‘ects are believed to be relatively com-
`mon. For example, prevalence data obtained from prospective,
`longitudinal studies indicate that approximately 45% of adult
`cancer patients experience nausea, vomiting, or both in the 24
`hr preceding their chemotherapy (Burish & Carey, 1986). Al-
`though precise estimates ofthe prevalence ofpostchemotherapy
`psychological side effects in adults are not available, they are
`believed to be even more common (Burish & Carey, 1986).
`Several causal explanations have been ofl‘ered to explain the
`development ofpsychological side effects. One hypothesis is that
`these symptoms “may be surfacing manifestations of underly-
`ing psychological readjustment problems, associated with life-
`threatening illness" (Chang, 1981, p. 707). This view suggests
`that nonpharmacological, symptoms represent the negative
`affect that patients harbor toward their chemotherapy treat-
`
`ments. To date, no data are available to support this assertion.
`A second hypothesis is that patients may display such symp-
`toms in order to gain attention and sympathy. Inconsistent with
`this hypothesis, however, is the observation that the punishing
`side efi‘ects of chemotherapy far outweigh any secondary gains
`that may be realized by cancer patients; moreover, there are no
`data to support the notion that removal of attention can reduce
`nonpharmacological symptoms. A third hypothesis is that the
`observed symptoms may “be produced by brain metastasis or
`local cancer involvement of the gastrointestinal tract” (Chang,
`I981, p. 707). Although this explanation may be accurate for a
`few patients, it has been ruled out as an explanation for most
`patients (e.g., Morrow, 1982).
`In contrast with the first three hypotheses, which are specula-
`tive and lack empirical support, the fourth hypothesis has been
`supported by the research literature. This hypothesis holds that
`nonpharmacological or psychological
`side efl'ects develop
`through an associative learning process. According to the most
`widely accepted conditioning viewpoint, after one or more pair-
`ings, an association is established between the pharmacological
`side effects (the unconditioned responses; UCRs) caused by the
`chemotherapy (the unconditioned stimulus; UCS) and various
`stimuli (e.g., sights, smells, thoughts; the conditioned stimuli;
`CSs) associated with the chemotherapy setting. As a result of
`repeated associations, the CSs begin to elicit nausea, vomiting,
`and dysphoria (the conditioned responses; CRs), even in the ab-
`sence of the UCS. Two variations of the conditioning model
`have also been suggested. The first, proposed by Leventhal, Eas-
`terling, Nerenz, and Love (1988), is that postchemotherapy
`nausea and vomiting might occasionally serve as the UCS, with
`responses to this nausea and vomiting (e.g., anxiety and second-
`ary nausea occurring later in time) being the UCRs. These
`UCRs then become conditioned to various stimuli in the che-
`motherapy environment and thereby take the form of CR5.
`Thus, in this first variation of the conditioning model, the mor-
`phology of the CS and CR is similar to that of the original
`model, but the UCS and UCR are not. The second variation
`was suggested by Garcia y Robertson and Garcia (1985), who
`believe that conditioned responses to cancer chemotherapy may
`develop through a process that closely resembles taste aversion
`learning. Although the published literature on conditioned re-
`sponses to cancer chemotherapy has been based almost exclu-
`sively on the first model of conditioning, it should be noted that
`these two variations do provide viable conceptualizations of al-
`ternative, though not necessarily mutually exclusive, processes.
`There are several sources of data that converge to support the
`hypothesis that associative learning is the primary phenomenon
`underlying the etiology of psychological symptoms. In no case
`were the data generated by experimental research that was de-
`signed deliberately to induce conditioned nausea and vomiting
`in cancer chemotherapy patients through controlled experi-
`mental manipulations, a procedure that would be ethically un-
`acceptable. Rather, the data are based on analogous phenomena
`or experimental outcomes that consistently, logically, or exclu-
`sively point to associative learning as the most reasonable expla-
`nation. At least four sources of supporting data can be identi-
`lied.
`
`First, the symptoms that are displayed by chemotherapy pa-
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`PSYCHOLOGICAL SIDE EFFECTS IN CHEMOTHERAPY PATIENTS
`
`309
`
`tients have several topographical similarities to those of labora-
`tory animals that ingest a gastrotoxic substance or that are irra-
`diated while eating a certain food. The animals subsequently
`avoid that substance or food during future feedings, a phenome-
`non referred to as learned taste aversion (for an extended discus-
`sion of the similarities of conditioned nausea and vomiting in
`cancer patients and learned taste aversions, see Garcia y Robert-
`son & Garcia, 1985). The symptoms have been shown to result
`from a learning process that is associative in nature, although
`it deviates, as does the conditioned response of chemotherapy
`patients, from the traditional classical conditioning paradigm
`in some interesting respects (e.g., the symptoms ofien develop
`after only one or a few associations and despite the fact that
`there may be several hours between the UCS and UCR). An-
`other example of documented animal conditioning that bears
`even closer resemblance to the chemotherapy situation was
`demonstrated by Collins and Tatum (1925) and Pavlov (1927).
`These investigators showed that dogs repeatedly injected with
`an emetic drug developed conditioned vomiting in response to
`stimuli associated with the injection.
`Second, several human studies provide data that support an
`associative learning explanation. For example, I. L. Bernstein
`and her colleagues (e.g., I. L. Bernstein, 1978; I. L. Bernstein &
`Webster, 1980) demonstrated experimentally that taste aver-
`sions can develop in chemotherapy patients as a result of the
`emetic properties of the infused drugs. For example, in one
`study the investigators assigned pediatric cancer patients receiv-
`ing emetogenic chemotherapy agents to one of two groups: to
`an experimental group that received a novel-flavored ice cream
`shortly before their scheduled drug treatment or to a control
`group that did not receive the ice cream. A second control
`group of patients receiving nonemetic chemotherapy drugs was
`also included. After 2 or more weeks, patients in all groups were
`offered either some of the novel-flavored ice cream or an oppor-
`tunity to play with a game. Patients in the two control groups
`overwhelmingly chose the ice cream; patients in the experimen-
`tal group showed an aversion to the ice cream, generally prefer-
`ring the game. Similar results were snbsequently demonstrated
`in adult cancer patients (see I. L. Bernstein & Webster, 1985,
`for a review).
`Third, there have been reports of cancer chemotherapy pa-
`tients becoming conditiOned to antiemetic treatments. In these
`situations, the antiemetic was apparently given each time the
`patient became nauseated or was vomiting; as a result, it be—
`came associated with nausea and vomiting and later was able
`to elicit, on its own, nausea and vomiting. For example, Kutz,
`Borysenko, Come, and Benson (1980) reported the case of a
`patient with neurofibrosarcoma who smoked marijuana to alle-
`viate severe nausea and vomiting. After chemotherapy was dis-
`continued, the smell of marijuana in social situations elicited
`nausea and vomiting. In another case reported by the same au-
`thors, the marijuana was administered in brownies and cookies.
`For a year after the chemotherapy was discontinued, the taste
`or sight of these foods produced nausea. Similar conditioning
`to antiemetics has been reported by other investigators (e.g.,
`Morrow et al., 1982).
`Fourth, research has shown that factors related to the devel-
`opment of conditioned symptoms in cancer chemotherapy pa-
`
`tients conform to the principles of associative learning. For ex-
`ample, Andrykowski et al. (in press) and Andrykowski, Redd,
`and Hatfield (1985) conducted two longitudinal studies of the
`development of anticipatory nausea in cancer chemotherapy
`patients. In these investigations, which together involved the
`study of over 150 patients, the authors found that anticipatory
`nausea never occurred without the prior occurrence ofpostche-
`motherapy nausea, that is, consistent with the principles of as-
`sociative learning, the presence of a UCR was necessary for the
`acquisition of a CR. Moreover, afier a careful analysis of other
`factors that contributed to the development of anticipatory
`symptoms, the authors concluded that, consistent with an asso-
`ciative learning model, “all of the factors that reliably predicted
`the development of AN [anticipatory nausea] were either di-
`rectly or indirectly linked to the magnitude” of the uncondi-
`tioned symptoms (Andrykowski et al., in press, p. 11). As has
`been noted elsewhere (Burish & Carey, 1986), other descriptive
`data on the development and nature of conditioned responses
`in cancer chemotherapy patients also consistently conform, in
`prospective as well as retrospective studies, to the principles of
`associative learning.
`In addition to supporting the conditioning model, the avail-
`able data suggest that several factors can serve to mediate or
`potentiate the learning process and thereby produce consider-
`able variation in symptom development. These individual
`difference factors may arise independently of, but nonetheless
`contribute to, the development of conditioned responses.
`One major individual difference may be proneness to nausea
`and vomiting. Research has suggested that patients who have a
`history ofmotion sickness or ofexperiencing nausea and vomit-
`ing to various foods or situations (e.g., pregnancy) are more
`likely to report posttreatment and anticipatory nausea and
`vomiting in response to cancer chemotherapy (Jacobson et al.,
`1988; Morrow, 1985). Morrow (1985) has suggested that there
`is a neurological basis for this relationship. The experience of
`nausea and vomiting is thought to result from‘activation of the
`“vomiting center," located in the lateral reticular formation of
`the medulla oblongata (Borison & McCarthy, 1983). The vom-
`iting center has four major inputs, including one from the yes
`tibular system, which is thought to play a role in motion sick-
`ness. It has been suggested that in addition to affecting the other
`major inputs, chemotherapy may afi‘ect the vestibular system,
`which in patients with a susceptibility to motion sickness may
`lead to additional stimulation of the vomiting center and there-
`fore an increased likelihood of nausea and vomiting (Morrow,
`1985). Redd and his colleagues (Jacobsen et al., 1988; Andry-
`kowski et al., in press) have suggested that there may be consti-
`tutional differences in cancer patients’ susceptibility to gastro-
`intestinal distress, including that due to chemotherapy. Patients
`with a greater constitutional vulnerability to gastrointestinal
`distress may be more likely to respond to chemotherapy with
`high levels ofposttreatment nausea and vomiting, which in turn
`increases the likelihood that they will develop conditioned nau-
`sea and vomiting, in comparison with patients without this di-
`athesis. In summary, the data suggest that patients with a past
`history of nausea and vomiting resulting from motion sickness,
`certain foods, or other experiences are more likely to develop
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`310
`
`MICHAEL P. CAREY AND THOMAS G. BURISH
`
`conditioned nausea and vomiting in response to cancer chemo-
`therapy.
`A second major factor that appears to affect the development
`of conditioned responses to chemotherapy is a patient’s anxiety
`level.l Specifically, state anxiety levels have been positively re—
`lated to the presence of conditioned responses in a number of
`retrospective studies (e.g., lngle, Burish, & Wallston, 1984; van
`Komen & Redd, 1985) and prospective investigations (e.g., An-
`drykowski et a1., 1985, in press; Nerenz, Leventhal, Easterling,
`& Love, 1986). For example, Nerenz et a1. (1986) interviewed
`cancer patients before each of their first six treatment cycles.
`The authors found that the incidence of anticipatory nausea
`was related to the level of pretreatment anxiety: for mildly anx-
`ious patients the incidence averaged 9.8%; for highly anxious
`patients the incidence was approximately twice as much, aver-
`aging 18.1%. Andrykowsld et al. (1985) found that a patient’s
`self-reported anxiety level before treatments accounted for
`more variance (13.6%) than any other single variable except
`posttreatment nausea in determining whether a patient devel-
`oped anticipatory nausea.
`Although data from numerous studies appear to suggest that
`heightened anxiety levels facilitate the development of condi-
`tioned symptoms, two questions remain. First, what are the
`temporal parameters that determine the relationship between
`state anxiety and the development of conditioned responses?
`That is, exactly when during the course of chemotherapy do
`elevated anxiety levels produce this relationship? Second, why
`is heightened anxiety associated with conditioned symptoms?
`A number of possible answers have been discussed, although
`none have been tested in the chemotherapy context. in most
`cases, investigators have speculated that anxiety directly or indi-
`rectly affects the associative learning process in ways that lead to
`enhanced conditioning. For example, some of the explanations
`suggest that anxiety levels directly alfect conditioning by influ-
`encing the speed with which associative learning takes place.
`According to this explanation, highly anxious patients condi-
`tion more quickly than do less anxious patients (e.g., Spence,
`1958). Data recently repoited by Andrykowski and Redd
`(1987) conflict with this explanation, however. These authors
`interviewed patients before each of their chemotherapy treat-
`ments to determine pretreatment anxiety levels and pre- and
`posttreatment nausea levels. They found that patients who de-
`veloped anticipatory symptoms late in the course ofchemother—
`apy (i.e., alter their seventh treatment) generally had higher anx-
`iety levels during all treatments than did patients who devel-
`oped anticipatory symptoms early in the treatment course.
`Andrykowski and Redd (1987) also noted that late—onset pa-
`tients generally had lower posttreatment nausea levels until the
`session just before they developed anticipatory nausea, at which
`time their posttreatment levels increased substantially. The au-
`thors speculated that the heightened pretreatment anxiety levels
`eventually led to the increased posttreatment nausea and that
`once posttreatment nausea increased, patients were more likely
`to develop anticipatory symptoms (i.e., the greater the intensity
`of the unconditioned response, the more likely the development
`of a conditioned response).
`Others have focused on dilferent parameters in trying to ex-
`plain the relationship between anxiety and conditioning. Dol-
`
`gin, Katz, McGinty, and Siegel (1985), for example, have sug-
`gested that highly anxious patients tend to show high levels of
`vigilance to their environments and, as a result, tend to notice
`more closely various stimuli in the clinic setting. Such attention
`increases the likelihood that these stimuli will develop into CSs.
`They found that consistent with this hypothesis, pediatric can-
`cer patients with anticipatory symptoms attended to and pro-
`cessed more stimuli in their environments, and habituated to
`these stimuli more slowly, than did matched patients without
`anticipatory symptoms.
`Although most of the speculation about the relationship be-
`tween anxiety and conditioned symptoms focuses on the role of
`anxiety within the learning paradigm, J. H. Fetting (personal
`communication, March 1, 1988) has suggested a neurologically
`based explanation that involves the relationship between anxi-
`ety and neurotransmitter changes. In the first stage ofa hypoth-
`esized two-stage process, a cancer patient’s propensity for expe-
`riencing nausea and vomiting is increased as a result of either
`a decreased nausea/vomiting threshold or enhanced neuronal
`firings, either or both of which might be caused by repeated
`bouts of nausea and vomiting during periods of high anxiety.
`As a result of this enhanced propensity, a variety of stimuli will
`more readily cause gastrointestinal upset in the future.
`In the second stage, increased noradrenergic activity, caused
`by the heightened anxiety or stress levels, contributes to the de-
`velopment of anticipatory nausea and vomiting in patients with
`the increased propensity. The process by which the increased
`noradrenergic activity leads to these efi'ects is as yet undeter-
`mined, but J. H. Fetting (personal communication, March 1,
`1988) speculated that with repeated exposure to emetogenic
`chemotherapy, the noradrenergic terminals in areas adjacent to
`the vomiting center in the cortex may show increased activity,
`leading to greater stimulation of the vomiting center. In an ini-
`tial test of this hypothesis, Fetting et a1. (1987) administered
`clonidine, a drug that reduces noradrenergic activity, to 8 chen
`motherapy patients who displayed anticipatory symptoms to
`their chemotherapy. After one trial of clonidine, the anticipa-
`tory symptoms were completely eliminated in 4 (50%) of the
`patients. Postchemotherapy nausea and vomiting appeared to
`be unafl'ected.
`
`Overall, then, it appears that the psychological symptoms
`that occur during cancer chemotherapy, particularly the nausea
`and vomiting that occur prior to drug infusion, are acquired
`through an associative learning process; moreover, the data sug-
`gest that the development of such symptoms is moderated by
`
`‘ For the sake of completeness, it should be noted that in addition to
`anxiety level, a number of other individual diflerence factors have been
`found to be correlated with the presence of anticipatory symptoms, for
`example, experiencing taste sensations during chemotherapy, having an
`inhibitive rather than facilitative coping style, being treated in a large
`group room rather than in a small private room, being younger rather
`than older, experiencing itching sensations during chemotherapy, and
`receiving chemotherapy treatments through long infusions rather than
`through short push injections (see Burish & Carey, 1986, for a review).
`However, most of these factors have been reported in retrospective in-
`vestigations exclusively, have been found in only one or two studies and
`not in others, and have not been linked causally to the development of
`conditioned symptoms.
`
`IMMUNOGEN 2182, pg. 6
`Phigenix v. Immunogen
`|PR2014—00676
`
`IMMUNOGEN 2182, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

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`PSYCHOLOGICAL SIDE EFFECTS IN CHEMOTHERAPY PATIENTS
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`311
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`one’s prior experience with gastrointestinal upset from factors
`such as motion sickness or certain foods and by one’s treat-
`ment-related anxiety level. Thus many writers have concluded
`that the psychological symptoms that occur in the chemother«
`apy setting are conditioned responses. In this regard, it is impor-
`tant to note that conditioned responses to cancer chemotherapy
`are similar, developmentally and phenomenologically, to condi-
`tioned aversive responses that develop routinely in other clinical
`contexts. For example, Garcia y Robertson and Garcia (1985)
`have related the animal and human literature on learned taste
`
`aversions to the research on conditioned nausea and vomiting in
`cancer chemotherapy patients. Conditioned responses to cancer
`chemotherapy can also be viewed as a subset of other condi-
`tioned drug responses (e.g., to morphine or alcohol; Siegel,
`1979). Although the review of the extensive literature on condi-
`tioned aversive responses is beyond the scope of this article, it
`is important to keep these similarities in mind when reviewing
`the treatment literature because many of the procedures that
`have been used to ameliorate or prevent conditioned responses
`in cancer chemotherapy patients are similar to or are based on
`the same principles as those that have been used with other
`types of conditioned aversive responses. Many of the treatment
`advances that have been made in the cancer area are, therefore,
`potentially applicable to other areas as well.
`Although associative learning appears to play an important
`role in the etiology ofpsychological side effects, we propose that
`side effects in the chemotherapy context might also result from,
`or be exacerbated by. a fifth mechanism, namely, psychological
`stress (i.e., the process that occurs when a person appraises a
`situation or stimulus as taxing his or her resources and endan-
`gering his or her well-being; Lazarus & Folkman, 1984). Thus,
`we hypothesize that a person who appraises the chemotherapy
`process as threatening or who is unprepared to cope