Advances in Neuroimmunology Vol. 6 pp. 179-190 1996 Copyright 0 1996 Elsevier Science Ltd.

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Psychoneuroimmunology and cancer: Historical perspectives and current research

Alison Fife*, Pamela J. Beasley and Debra L. Fertig
Brigham and Women s Hospital, 75 Francis Street, Boston, MA 02115, USA

Division of Psychiatry,

Summary The belief that cancer might be related to temperament or distress has been emphasized throughout the history of medicine. The field of psychoneuroimmunology has its origins in psychosomatic medicine, and has evolved to the investigations of complex interactions between the psyche and the nervous, immune, and endocrine systems. Such interactions may have implications in both cancer risk and survival. Copyright 0 1996 Elsevier Science Ltd Introduction Defined by the American Cancer Society, cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. The potential etiologies include external causes such as chemicals, radiation and viruses, and internal causes such as hormones, immune system abnormalities and inherited mutations. These potential causes do not necessarily act in isolation; more than one may be present at any one time. The enormity of the cancer problem is evident in recent statistics. In the United States this year the number of new cases of cancer is estimated to be 1,252,OOO (American Cancer Society, 1995). Research into the causes of cancer is one of the most important medical agendas of our time. This paper will focus on research in the area of neuroimmunology, specifically as it relates to psychiatric and emotional conditions, and their potential effects on the immune system and the development of cancer. Historical perspectives on psychological factors and the development of cancer The concept that emotions may play a role in cancer onset can be traced back to the 2nd century A.D., when the Greek physician Galen described that melancholic women developed breast cancer more frequently than those of a more sanguine nature. In 1701, Gendton wrote in Enquiries into the Nature, Knowledge and Cure of Cancers of the case of Mrs. Emerson, who upon the death of her daughter, underwent great affliction, and perceived her breast to swell. . .it broke out in a most inveterate cancer. . .she had always enjoyed a perfect state of health . In his 1759 Essay on Scirrous Tumors and Cancers, the surgeon Richard Guy identified women diagnosed with cancer as being of a sedentary, melancholic disposition of mind, (who) meet with such disasters in life as occasion much trouble and grief . In his 1846 treatise on the subject entitled The Nature and Treatment of Cancer Walshe comments on the influence of mental misery, sudden reversals of fortune and habitual gloomings of the temper on the disposition of carcinomatous matter . In 1870, James Paget wrote that the cases are so frequent in which deep

*Corresponding

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The emergence of psychosomatic medicine

anxiety, deferred hope and disappointment are quickly followed by the growth and increase of cancer, that we can hardly doubt that mental deprivation is a weighty addition to the other influences favoring the development of a cancerous constitution (Greer, 1983). The first statistical study of psychological factors and the development of cancer was performed by Herbert Snow in 1893 at the London Cancer Hospital. Dr Snow studied 250 women with breast and uterine cancer, and concluded that the number of instances in which malignant disease of the breast and uterus follows immediate antecedent emotion of a depressing character is too large to be set down to chance, or to the general liability to the buffets of ill fortune which cancer patients, in their passage through life, share with most other people not so afflicted . In her 1926 study, Evans hypothesized that loss of a significant relationship can be an important factor predisposing an individual to the development of cancer. In 1948, Miller and Jones studied six patients with chronic myelogenous leukemia and speculated that the frequent occurrence of emotional difficulty in patients with leukemia may be more than a coincidental finding (Greer, 1983). The history of immunology has been described by Judson and Mackay as consisting of three eras. Throughout the bacteriological and medical era of the late 1800s and early 1900s studies of serotherapy and immunization predominated. The second era, which began after World War 1, focused primarily on the study of antigen-antibody interaction and the study of chemical structures. The era of immunobiology began approximately in the 1960s when Sir Macfarlane Burnet proposed the clonal selection theory of antibody formation, Jacques Miller investigated the role of the thymus in immunity, and Ronald Herberman explored the role of natural killer (NK) cells in immunity (Solomon, 1993). The 1960s was beset with controversy over whether the immune system functioned independently of the central nervous system. Solomon and Moos published Emotions, Immunity and Disease in 1964 in which they proposed an interaction between the brain and the immune

medicine emerged as a means of scientifically investigating interactions between mind and body. The physician and psychoanalyst Francis Dunbar, founder of the American Psychosomatic Society, speculated in the late 1930s that various disease processes such as peptic ulcer disease, essential hypertension, asthma and rheumatoid arthritis were the result of the discharge of instinctual energy into the vegetative systems of the body . In 1946, Hans Selye described a stressor as a demand that places an adaptational requirement on the organism which leads to a state of stress . The physiological effects of this state of stress are believed to be influenced by regulators such as coping ability and social support. Selye believed the hypothalamic-pituitary-adrenal (HPA) axis had a significant influence in psychosomatic interactions (Solomon, 1993).
Nervous system and immune system

The field of psychosomatic

interactions

Experimental evidence points to the importance of interactions between the nervous and immune systems in the maintenance of homeostasis. Examples of these interactions, which are thought to occur via complex feedback and feedforward systems, include the noradrenergic postganglionic sympathetic innervation of primary and secondary lymphoid organs, the neuroendocrinological regulation of some cells of the CNS, the ability of stimulated lymphocytes to synthesize ACTH, endorphin-like peptides, and neuroendocrine hormones, and the presence of receptors for neurotransmitters on lymphocytes, monocytes, macrophages and granulocytes. Substance P, somatostatin, and vasoactive intestinal peptide are three such neurotransmitters (Ader et al., 1987, 1995). More evidence for the CNS-immune system

Psychoneuroimmunology link was provided by Selye and Hamburg who demonstrated that stress and psychological distress lead to increased steroid hormones, which in turn, are immunosuppressive. Dougherty demonstrated stress-induced morphological alterations of lymphocytes (Solomon, 1993). Catecholamines have been shown to affect lymphocyte metabolism and proliferation via cyclic AMP-induced maturation and differentiation of immature lymphocytes and inhibition of mature immunocompetent cells (Peteet, 1987). Korneva and Khai lesioned the dorsal hypothalamus of the rabbit and demonstrated decreased formation of complementfixing antibodies (Rogers et al., 1979). There is evidence that lesions in the preoptic and anterior hypothalamus can prevent anaphylaxis, decrease response to T-cell mitogens, and decrease NKcell cytoxicity and antibody production (Ader et al., 1995). In addition, peripheral antigenic stimulation has been shown to induce CNS electro-physiological changes (Ader, 1987). Potential pathways between the brain and immune system include neuroanatomic links and noradrenergic projections to lymphoid tissue. Corticotropin releasing factor (CRF) is hypothesized to be a primary mediator in the system s response to stress. The highest concentrations of CRF immunoreactive cells in the brain are found in the paraventricular nucleus of the hypothalamus and the median eminence. Numerous studies have documented increased CRF in the cerebral spinal fluid (CSF) of patients with depression, and a decrease in lymphocyte proliferation and NK cell activity in depressed patients (Irwin, 1994). A recent meta-analysis reviewed a number of studies linking stress to the number and percent of white blood cells and depressed lymphocyte response to mitogens. Overall, stress that was determined to be objective seemed to tend toward more change in immunological parameters than stress that was self-reported (Herbert and Cohen, 1993). The immune system also communicates with the central nervous system via cytokines which, when released by immune cells, influence activation of the HPA axis. Cytokines are thought to have behavioral, endocrinological and electrophysiological activity, as well as influence on sleep,

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That the neuroendocrine system is critical for the normal development of the immune system has been shown in animal studies in which neonatal thymectomy leads to disturbances in cellular immunity, sexual maturation, and adrenal hypertrophy (Rogers et al., 1979). Selye provided evidence in 1955 that accelerated thymic involution was an important consequence of the stress response syndrome , characterized physiologically by adrenal hypertrophy and elevated corticosteroid levels (Rogers et al., 1979). Ader et al. described a complex balance of environment, behavior, CNS, endocrine and immune systems that is involved in the regulation of homeostasis (Ader, 1987). Disruption of any component of the equation can have consequences on all other elements of the system. Depression and stress have been shown to produce disturbances in function of both the immune and neuroendocrine systems. Converging lines of evidence suggest a biological causal model for depression and stress-related influences on the development or prognosis of a physical disease. In this model, environmental factors (such as stressful life events or biological factors that may result in psychiatric illness or mood alterations) may result in endocrine system dysregulation. The endocrine system changes may mediate immune system alterations which then could impact on the clinical prognosis and/or development of a physical disease. Bereavement and immune function

Numerous studies have investigated the possible effects of bereavement on the immune system. Bereavement can be defined as a state and a reaction to the death or loss of someone to whom the individual had been attached (Andrianopoulos and Flaherty, 1991). Osterweiss et al. (1984) studied bereaved males and reported them to be at higher risk for morbidity: In a prospective study of 4000 widowners, Helsing et al. (198 1) reported an increased mortality rate for the 10 years after the death of a spouse. Among males, rates of death

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in Neuroimmunology multiple parts of the immune system are sensitive. Parkes (1984) suggested that depression related physiological alterations such as hypercortisolism may underlie the immune changes noted in bereavement. Cappel et al. in 1978 showed suppression of phytohemagglutinin-induced lymphocytic proliferation among depressed patients as compared with depressed patients in remission. Studies on hospitalized patients with untreated major depression revealed diminished mitogen-induced lymphocyte proliferation compared with hospitalized age and sex matched controls. No differences were found between ambulatory depressed patients and controls or hospitalized patients with schizophrenia and controls. Of significance is that age-related differences in lymphocyte number and proliferation may influence these results (Schleifer et al., 1985a). Normal ageing is accompanied by a decrease in T-cell number and function. Biological markers in depression have been and continue to be widely studied. The HPA axis has been found to be hyperactive in depression. These changes are marked by high levels of free cortisol in the urine, non-suppression of dexamethasone, diminished ACTH (corticotropin) response to CRF, an increase in the concentration of CRF in the CNS, and adrenal and pituitary hypertrophy. Changes have additionally been documented in the hypothalamic-pituitary-thyroid axis. The response of thyrotropin to thyrotropin-releasing hormone (TRH) is diminished, with increased levels of TRH in the CNS and decreased levels of somatostatin in the CSF. Other neurologic systems including the serotonergic and noradrenergic pathways are affected; volumes of subcortical structures are diminished and sleep architecture is altered. Recent studies have begun to examine lymphocyte P-adrenergic receptor binding in the CNS. Recent studies suggest that alterations in NK cell number and activity, as well as in B cell and T cell subpopulations, may occur in patients with major depression. It has been shown that CRF is increased in some depressed patients, and sup presses NK cell cytotoxicity (Irwin et al., 1990).

were higher than expected from infectious disease, accidents and suicide. Rates of death among women were higher than expected from cirrhosis. Jacobs and Ostfeld (1977) reported that of the 35,000 deaths that occur annually among recently widowed persons, approximately 7000 can be attributed to the death of a spouse. In addition, 67% of widowers reported a decline in health during the year after the death of a spouse. In 1987, Raphael and Middleton reported an association between bereavement and increased rates of hyperthyroidism, diabetes, cancer and cardiovascular disorders. In an effort to explain the increased morbidity and mortality associated with bereavement, Solomon et al. (1982) provided evidence that the risk of cardiovascular disease is highest soon after the death of a spouse, and speculated that this might be related to HPA neuroendocrine activation and subsequent parasympathetic rebound. Schleifer et al. (1983) hypothesize that immune system alteration may mediate the late effects of bereavement, which include increased risk of diabetes and cancer. In addition, a number of studies point to the use of tranquillizers, sedatives and alcohol among the recently bereaved, and speculate that these substances may have immunosuppressive effects. Bereavement has been associated with disturbances in both humoral and cell-mediated immunity. Researchers hypothesize that bereavement somehow suppresses the immune system, either by inducing neurohormonal changes, or by increasing behavior such as smoking or drinking, which may lead to immune changes. Bartrop et al. (1977) showed a decreased T-cell response to mitogens (phytohemagglutinin and concanavalin A) at 6 weeks but not at 1 month after the death of a spouse. Schleifer et al. (1983) demonstrated suppression of mitogen-induced lymphocyte proliferation during the 2 months after the death of a spouse but reported no changes in lymphocyte proliferation prior to the spouse s death, suggesting that the experience of the actual loss was linked to the immune changes. The authors hypothesize that affect states could account for some psychoimmunological effects, and that

Psychoneuroimmunology Irwin et al. (1987) reported reduced NK cell activity in psychiatric inpatients compared to matched normal controls. Further, he has reported that sleep loss independent of mood disturbance reduces NK cell activity (Irwin, 1994). Agerelated changes in NK cell activity have been observed. Naliboff et al. (199 1) describe increases in NK cell activity in young subjects compared to older subjects exposed to stress. Psychosocial factors and cancer The hypothesis that psychological or psychosocial factors may be related to the development of cancer has been explored. Jenkins performed a review of death certificates from the Department of Public Health of Massachusetts for the years 1972 and 1973 (Jenkins, 1983). When the standardized mortality ratio for cancer in men was correlated with 130 sociodemographic variables, poverty, unemployment, rented housing, and unmarried status were positively correlated with a higher rate of cancer mortality. Roud (1986) reported on nine patients with cancer and exceptional survival and speculated that their highly optimistic and positive psychological states were related to their survival. In another prospective study looking at the influence of coping styles on survival times, Rogentine studied patients with malignant melanoma using self-report scales measuring adjustment to illness. The mean score of relapsers was less than that of non-relapsers, and Rogentine concluded that those patients with greater difficulty adjusting to their cancer survived longer. Cassileth ef al. (1985) determined the length of survival of 204 patients with unresectable cancer, as well as the relapse rate of 155 patients with Stage I or II melanoma or Stage II breast cancer. The study used a self-report questionnaire which evaluated psychosocial factors including social ties and marital history, job satisfaction, use of psychotropic drugs, general life satisfaction, view of health, degree of hopelessness or helplessness, and perception of the amount of adjustment required to cope with the diagnosis. The authors concluded that psychological and psychosocial

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factors had no influence on length of survival or rate of relapse. According to Brown and Paraskevas (1982) depression prior to cancer diagnosis may be due to serotonin dysregulation mediated by the immune system (Greer, 1983). Stress and the immune system Links between behavior and the immune system have been described by Ader and Cohen in their 1975 study, which demonstrated diminished antibody response to antigen via behavioral conditioning, using a taste aversion paradigm. Black et al. (1963) used direct suggestion under hypnosis to inhibit the swelling and erythema characteristic of the Mantoux reaction (tuberculin skin test) in subjects known to be positive reactors (Rogers et al., 1979). Conditioning of both antigen-specific and nonspecific immune responses have been documented in animals and humans in recent studies (Ader and Cohen, 1993; BuskeKirschbaum et al., 1992, Cohen et al., 1994). Much work has been done investigating the effects of psychological stress on the immune system. Stress is thought to suppress the immune system and thus render an organism more susceptible to disease, especially those diseases closely linked with immune functioning, such as malignancy, infection, autoimmune disease, and allergy. Rogers et al. (1979) define stress in terms of the stimulus to which an individual responds with psychological strain . Individuals responses to psychological stress are often difficult to interpret, as the meaning of, and thus response to a particular stressor is quite variable. Some factors felt to mediate the effects of stress on the immune system include the adaptive capacity of the individual, which is influenced by perception, past experiences, habitual behaviour patterns, coping styles, social supports, personality characteristics, ego defenses and illness behavior (Dorian and Garfinkel, 1987). Numerous studies have implicated psychological stress as a risk factor for the development of disease. For example, specific correlations between immunoglobulin levels and emotional

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in Neuroimmunology family histories of cancer. No differences in health status or psychological distress were found between those with or without first degree relatives with cancer. Independent of family history, women with higher levels of distress had lower NK cell activity. When the contribution of distressinduced immune suppression was removed, NK cell activity remained lower in women who had a first degree relative with cancer. The authors speculate that heritable defects in the preneoplastic cell and reduction in NK cell activity both contribute to increased cancer risk. The stress response, as observed by Cannon in 1914, has been linked to the release of catecholamines and cortisol; producing the socalled fight-or-flight response. The release of glucocorticoids during both acute and chronic stress, has been linked to immunocompromise. These changes may leave the organism vulnerable to oncogenic viruses, newly transformed cancer cells and other diseases subject to immunologic control (McDaniel et al., 1995). Other studies have examined the direct metabolic effect of stress on biological systems. Depression may in some way impair the cell s ability to repair damaged DNA, thus increasing vulnerability to damage from carcinogens (Dattore et al., 1980). Kiecolt-Glaser et al. (1985) examined the process of DNA repair after exposure to irradiation in high vs low-distressed patients. High and low distress were defined by the subject s score on the depression scale of the Minnesota Multiphasic Personality Inventory (MMPI). Twenty-eight psychiatric in-patients were studied; the high-distress group was found to have significantly poorer DNA repair in lymphocytes . Of note, these patients were not on medication, did not carry a diagnosis of alcohol or drug abuse, and had no known immunologic or hormonal disease. Major depression has been linked to increases in numbers of neutrophils and diminished NK cells, T and B lymphocytes, helper and suppressor/cytotoxic T cells, NK cell activity and lymphocyte response to mitogens (Ader et al., 1995). Stress may also affect the phagocytic function of macrophages (Calabrese and Wilde, 1991).

states in patients with breast cancer and rheumatoid arthritis have been demonstrated. An increased incidence of disease has been reported in individuals experiencing psychological stress in the form of bereavement or loss of job (Rogers et al., 1979). Academic examinations can lead to alterations in the immune system such as impaired mitogen responsiveness of lymphocytes (Glaser J. K. et al., 1986). Several studies, however, have reported improved cellular immune function in response to stress (Monjon and Collector, 1977; Mettrop and Visser, 1969; Folch and Waksman, 1974). Coping and social support seem to buffer the relationship between the immune et al. (1984) system and stress. Kiecolt-Glaser found a significant relationship between stressful life events and decreased NK cell activity in a group of medical students. Dorian et al. (1982) showed that exam stress was more immunosuppressive among those students who reacted with more distress. Loneliness has been associated with decreased NK cell activity among medical students (Kiecolt-Glaser et al., 1984). The effects of stress on the immune system may be related to activation of the HPA axis and subsequent increased levels of corticosterone. Physiological effects of increased corticosterone levels include lymphocytopenia, thymus involution and loss of tissue mass in the spleen and peripheral lymph nodes. These alterations in components of the immune system can lead to impaired immune surveillance and thus increased susceptibility to disease (Vogel and Bower, 1991). Psychiatric illness and stress may compromise a normal healthy functioning immune system. Though the real effect on health and illness in an otherwise healthy person is not well established, data exist to support the hypothesis that emotional stress and illness can affect the cellular immune response. As noted above, psychological stress may increase the organism s vulnerability to certain diseases by exerting an immunosuppressive effect. Bovbjerg and Valdimarsdottir (1993) investigated the possibility that healthy individuals with a family history of cancer have lower levels of NK cell activity. Forty-three healthy women were recruited without regard to their

Psychoneuroimmunology The effects on the immune system of perhaps a more everyday type of stress was studied in a group of healthy young students taking examinations. Distress was measured using the Brief Symptom Inventory (BSI), a self-report measure. This study also reported significant changes in the immune system; the level of production of interferon was decreased as was the total number and activity of NK cells and mitogen responsiveness (Glaser R. e? al., 1986). Holland (1990) has postulated that psychosocial factors may act as promotors of malignant cell division (1990). Sklar and Anisman (1979) reported that experimental animals allowed to escape electrical shock showed reduced growth of transplanted tumors compared to yoked control animals. These studies point to a possible psychological effect on tumor growth. One might hypothesize that a sense of control could enhance host resistance to tumor growth. The pattern of adaptation to reported stress is also crucial. Sklar and Anisman (198 l), based on their work and a review of the literature, have described the following generalities. Typically, acute stress and chronic stress, in which adaptation to the stress does not develop, lead to depletion of norepinephrine (NE) and dopamine (DA) in some brain regions, with increased levels of acetylcholine (Ach) and some HPA axis hormones such as ACTH, P-endorphin and corticosteroids. These changes are associated with immune suppression and enhanced tumor development in a variety of animal models. Conversely, chronic stress paradigms in which animals show adapt.ation to the stress most often lead to enhanced synthesis of NE and DA and a concomitant decrease from acute stress levels of Ach and the above HPA axis hormones toward baseline. This adaptation or ability to effectively cope generally leads to enhanced immune function and deceleration of tumor growth. However, studies of the effects of chronic stress on the immune system have produced conflicting results. Chronic stress and increased glucocorticoid production may not lead to enhanced tumor growth or incidence (Kort, 1994). The nature of the stressor in animal studies varies, thus individual studies may not easily be

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compared to one another or to other models. It is interesting to note that in adrenalectomized animals, stress-induced immunosuppression is observed, and that hypophysectomy can negate the effects of stress on some of the observed immunological changes, thus, there are clearly other mechanisms at work in addition to the HPA axis (Ader et al., 1995) Corticosteroids are known to modulate immune function generally in a suppressive fashion. There is also evidence that a number of other stressrelated hormones, including endorphins (Morley et al., 1985) enkephalins (Plotnikoff et al., 1985) and prolactin (Bernton et al., 1988), are associated with immune system enhancement. It has been postulated (Plotnikoff et al., 1985) that endogenous opioids may modulate the effects of corticosteroids on immune function during times of stress. Psychosocial studies associated with cancer risk A causal relationship between psychosocial stress and the development of cancer has not been proven, and research in this area is complicated by the effects of the cancer and cancer treatment (Kiecolt-Glaser and Glaser, 1995). One of the most controversial but nevertheless compelling constructs in the literature is that of the Type C personality. This personality type has been characterized by repression of emotions, maintenance of emotional control, and overtly pleasant interpersonal relations despite covert distress (Temoshok and Fox, 1984). This construct was supported by Kneier and Temoshok s retrospective study (1984) which found that patients with malignant melanoma, in comparison to those with cardiovascular disease, showed greater psychophysiological arousal to electrical skin stimulation despite reporting less overall emotional distress response to the stimuli. Kreitier et al. (1993) suggest that repression could be a response posed by the cancer diagnosis and a means for keeping anxiety at a tolerable level rather than a personality trait of cancer patients. Retrospective studies have been criticized on

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in Neuroimmunology social support, fatigue and depression accounted for 5 1% of the baseline variance in NK cell activity. At 3 month follow-up, 30% of the variance was accounted for by these variables. Psychosocial factors were not found to be significantly related to the prognostic indicator of positive nodes, although NK activity was found to be lower and depression higher in women with positive nodes. Gruber et al. (1988) conducted a pilot study looking at the effect of behavioral training on the immune systems of 10 adults with a variety of metastatic tumors. Over 1 year, patients used either guided imagery or progressive muscle relaxation. Correlated with the behavioral intervention were significant increases in measures of T-lymphocyte function, total levels of immunoglobulins G and M, mixed lymphocyte responsiveness, NK activity, and the production of IL-2 by stimulated lymphocytes. A later randomized controlled study (Gruber et al., 1993) looked at the effects of behavioral training in Stage 1 breast cancer patients. Pre-treatment and posttreatment measures included blood samples, psychological testing, and a computerized psychophysiological evaluation. Anxiety levels were reduced after the intervention. The aforementioned immune parameters were significantly improved and directly correlated with the behavioral interventions. A prospective intervention study with metastatic breast cancer patients was performed by Spiegel and colleagues (1989). The patients in the experimental group met weekly in psychological support groups for 1 year. At 12 months, the experimental patients showed significantly less tension, fatigue or confusion and more vigor than the control group. Survival was significantly different, with a mean of 36.3 months in the intervention group compared with 18.9 months in the control group. Lower mood disturbance and higher ratings of vigor on the POMS at the end of the intervention period were associated with greater longevity. Fawzy and colleagues (1993) developed a 6 week structured group intervention for patients with malignant melanoma, who were randomly assigned to a series of six structured support

the basis of being open to recall bias, as well as the influence of memory on self-report of depression (Levenson and Bemis, 1994). Studies of this type may fail to control for known risk factors such as smoking and family history of cancer, stage and treatment of cancer, and other demographic variables; hence the results are difficult to interpret (Holland, 1990). Some longitudinal prospective investigations have assessed the level of depression at baseline and subsequent morbidity and mortality from cancer (McGee ef al., 1994). Shekelle and colleagues (198 1) analyzed data obtained from the MMPI given to 2020 Western Electric employees 17 years earlier. A two-fold increase in the odds of death from cancer was found among those employees who had an elevated depression score on the MMPI. Repression was not associated with cancer risk. This study did control for other known risk factors for cancer including age, smoking, use of alcohol, occupational exposure, and family history of cancer. A recent meta-analysis inferred a small but statistically significant link between depression and the development of cancer (McGee et al., 1994). Depression and neuroendocrine dysfunction have been studied in patients with pancreatic cancer, gynecological cancer and gastric cancer. Alterations in the HPA axis in these depressed patients is similar to that seen in depressed patients without cancer (McDaniel ef al., 1995). Psychosocial factors and cancer survival Psychosocial intervention improves mood, adjustment to illness, fatigue, pain and possibly survival time in patients with cancer (Fawzy et al., 1995; Spiegel, 1989). Davis (1986) studied effects of biofeedback and cognitive therapy in 19 newly diagnosed breast cancer patients. The results of this randomized study showed improvement in level of anxiety and reduced urine cortisol in the intervention group. In a semiprospective study of 75 breast cancer patients, Levy et al. (1987) studied psychological factors, NK cell activity, and prognostic indicators of survival. Adjustment to illness, lack of

Psychoneuroimmunology groups encompassing health education, stress management, coping skills and supportive group psychotherapy. In the original study, psychological assessments consisting of affective state and coping were administered, and baseline NK cell functioning was measured. At the end of the 6 weeks, the experimental subjects exhibited lower levels of distress (anxiety, depression, anger, confusion) and more adaptive coping styles than the control group; at 6 month follow-up these group differences were even more pronounced, revealing increases in the treatment group of NK cell cytotoxicity and percentage of NK cells and large granular lymphocytes. At 6 year follow-up, lower rates of recurrence and mortality and greater activity of NK cells were found in the treatment group. Baseline levels of NK cell cytotoxicity predicted later recurrence (Fawzy et al., 1993). Mulder et al. (1992), in their critical review of psychosocial studies with breast cancer patients point out the need to control for clinical, pathological, and intervening behavioral factors in psychosocial intervention research. They suggest that if future correlational studies confirm the putative risk factors for progression, intervention strategies can be further developed in which these factors are addressed specifically. Discussion The belief that emotions play a role in the onset and progression of cancer has been emphasized throughout the history of medicine. In recent years, a substantial literature has emerged supporting the theory that depression and stress can result in altered endocrine and immune system functioning. Whether stress, emotional expression, and depression can exert an influence on the development or course of cancer remains an intriguing question. Methodological problems are a major obstacle in clarifying the true impact of psychological factors on cancer; the physiological impact of these factors, i.e. how a particular individual copes with a particular stressor, is likely to be an important variable. A model for a possible pathway explaining how

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stress and depression could influence the development or course of a medical illness such as cancer has been proposed. Perkins et al. (1991) postulate that the endocrine and immune systems act as mediators. In their model, environmental stressors may have an impact on the development of cancer, these stressors are then buffered by psychosocial variables such as coping and social support. Depressive illness, or possibly an altered mood state, may be associated with changes in the endocrine system that in turn may result in, and interact with, specific alterations in immune function. Such alterations may in turn make an individual more vulnerable to cancer initiation and progression. One approach to studying this phenomenon, which has important clinical ramifications, is through research on the effects of psychological interventions. Psychosocial treatments have been shown to be helpful in improving mood, adjustment, pain and quality of life in cancer patients (Spiegel 1994, Fawzy et al., 1995). However, the impact of these interventions on the endocrine and immune systems in cancer patients is largely unknown. Several recent studies (Spiegel et al., 1989, Fawzy et al., 1993) suggest that such interventions may improve survival. Studies which investigate the effects of different psychosocial interventions on quality of life and prognosis, using measurable neuroendocrine and immunological markers provide an exciting area for future research. References
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