The Biobehavioral Model suggests that stress triggers important biological effects involving the autonomic, endocrine, and immune systems (see arrows from stress to immunity in ). Stress may be routed to the immune system by the central nervous system by means of activation of the sympathetic nervous system (e.g., Felten, Ackerman, Wiegand, & Felten, 1987
) or through neuroendocrine-immune pathways (i.e., the release of steroid hormones, glucocorticoids). The endocrine axes which have been the best characterized are the hypothalamic–pituitary–thyroid axis, the hypothalamic–growth hormone axis, and the hypothalamic–pituitary–adrenal (HPA) axis, although it is the latter that has received the greatest attention in the human stress literature. The few neuroendocrine studies with cancer patients have suggested that they may exhibit the same dysregulation of the HPA axis that is observed in depressed patients (i.e., hypersecretion of adreno-corticotropic hormone and cortisol, adrenal and pituitary hypertrophy; Evans et al., 1986
; Joffe, Rubinow, Denicoff, Maher, & Sindelar, 1986
; McDaniel, Musselman, Porter, Reed, & Nemeroff, 1995
). Also, hormones released under stress (e.g., catecholamines, cortisol, prolactin, and growth hormone) have been implicated in immune modulation (see Maier, Watkins, & Fleshner, 1994
, for a discussion; Rabin, Cohen, Ganguli, Lysle, & Cunnick, 1989
; Sabharwal et al., 1992
). Epinephrine and norepinephrine, for example, regulate lymphocyte levels that can, in turn, alter immune responses such as cellular migration, lymphocyte proliferation, antibody secretion, and cell lysis (Madden & Livnat, 1991
). In vitro work has shown that the addition of catecholamines to human whole blood produced a suppression of interleukin (IL)-12 production yet an increase in IL-10 production (Elenkov, Papanicolaou, Wilder, & Chrosusos, 1996
). This cytokine shift (i.e., suppression of IL-12 yet enhancement of IL-10) causes a T-helper (Th) cell shift from Th1 cells involved with cell-mediated inflammatory reactions to Th2 cells that produce cytokines promoting humoral responses, such as encouraging antibody production. Thus, a stress-related, lower Th1 response might increase susceptibility to infectious pathogens requiring a cellular response (Clerici et al., 1997
). Also, Th1 responses may be more important to antitumor immune responses (e.g., Brunda et al., 1993
Prior to considering stress effects on immunity in cancer patients, it is important to consider the role of immune responses in host resistance against cancer progression (see arrow from immunity to disease course in ). Although the role of immunity in cancer is debated, research has addressed three avenues of influence. The first area examines the capability of the immune system to detect cancer cells and the characteristics of cancer cells that allow their detection (i.e., antigenic processes). Research has centered on the identification of antigens that are selectively expressed by cancer cells and that serve as a basis for their rejection by immune effectors. Classes of antigens identified include mutated oncogenes (p53, Ras), aberrantly expressed fetal and embryonic antigens (e.g., CEA), and tissue-specific antigens (e.g., tyrosinase, mucin; Rosenberg, 2000
The second area examines the capability of the immune system to mount an effective response to particular cancer cells or the cellular characteristics of the cancer cells (i.e., immunogenicity). The NK cell cytotoxic response has been widely explored (Brittenden, Heys, Ross, & Eremin, 1996
), as has the generation of lymphokine-activated killer cells with the administration of recombinant cytokines such as IL-2 and the interferons (IFN; Rosenberg et al., 1993
; Walter et al., 1998
). Other mechanisms are the actions of cytotoxic T cells and antibody-producing B cells. The lytic (killing) activity of antitumor T cells is of obvious importance to the eradication of malignant cells, but high-affinity antibodies with specificity for tumor antigens might also play an important role. These could directly interfere with tumor growth by means of the induction of apoptotic mechanisms (cell death) or the triggering of complement-mediated lysis and antibody-mediated cellular cytotoxity (Cragg, French, & Glennie, 1999
The third area examines the role of the immune system in the eradication of newly formed cancer cells. Low NK cell activity correlates with cancer onset (Imai, Matsuyama, Miyake, Suga, & Nakachi, 2000
). Once diagnosed, NK cell activity is associated with local recurrence (Brittenden et al., 1996
) and distant metastases (Malygin et al., 1993
; Pross & Lotzov’a, 1993
; Yamaguchi, Takashima, Funakoshi, Kawami, & Toge, 1994
). Moreover, survival time without metastasis correlates with NK cell activity (Whiteside & Herberman, 1989
). Finally, immunotherapeutic interventions based on these findings have developed rapidly within the past decade. Examples include therapy with recombinant cytokines (IL-2 and IFN-α
), monoclonal antibodies (anti-HER2/neu), and peptide vaccines (gp100 protein). This research is contemporary and cutting-edge cancer immunology. Consider these immune effector mechanisms when reviewing the measures intervention investigators have chosen.
Correlational studies have been conducted with endocrine and immune outcomes. Turner-Cobb, Sephton, Koopman, Blake-Mortimer, and Spiegel (2000)
provided data on social support and salivary cortisol in women diagnosed with recurrent breast cancer. Women provided four salivary cortisol samples (i.e., 8 a.m. and 12, 5, and 9 p.m.) for 3 consecutive days. A significant negative correlation (−.17–.19) between the grand mean of the cortisol assessments and three of the four subscales of the Interpersonal Support Evaluation List (Cohen, Mermelstein, Kamarck, & Hoberman, 1985
) was found, yet there was no relationship with a measure of social network size (−.07; Yale Social Support Index; Seeman & Berkman, 1988
). A reanalysis was also reported (Sephton, Saplosky, Kraemer, & Spiegel, 2000
); rather than averaging the four cortisol assessments, the slope of a patient’s four values was examined. A typical profile would be for cortisol values to decline steadily from the morning peak to the evening assessment. Using a Cox proportional model, they showed patients with the more typical declining pattern had better survival (60%) versus those individuals whose slopes had patterns of slower declines, abnormally timed peaks, or increasing levels during the day (77%).
Correlational immune studies have reported consistent relationships between measures of stress and immune outcomes, both quantitative (e.g., cell count) and functional (e.g., NK cell lysis). Tjemsland, Soreide, Matre, and Malt (1997)
studied Norwegian women diagnosed with breast cancer awaiting their surgical treatment. Preoperative depressive symptoms correlated with postoperative lymphocyte, total T cell, and T4 counts, with higher depression scores related to lower counts. Andersen et al. (1998)
examined the relationship between stress and several aspects of the cellular immune response in women with breast cancer following surgery. All completed a measure of traumatic stress about the cancer experience (IES). Multiple regression models, controlling for age, stage of disease, and length of time since surgery, found significant, down-regulating effects for stress, replicated within (across effector to target cell ratios or concentrations) and between assays: NK cell lysis, the response of NK cells to recombinant interferon gamma (rIFN-γ
), and T cell responses including proliferative responses to concanavalin A (ConA), phytohemagglutinin, and a T3 monoclonal antibody. In combination, these studies provided suggestive evidence of the adverse effects of stress on endocrine (i.e., cortisol) and immune responses. The premise of the following studies is that interventions may enhance biologic indicators (i.e., reduce stress hormone levels and increase immune responses).
Immune Lekander, Furst, Rotstein, Hursti, and Fredrikson (1997)
used a static group-comparison design to examine the effects of progressive muscle relaxation during chemotherapy for Swedish women with Stages I–IV of ovarian cancer. Intervention subjects were provided with instruction (1.5 therapy hr) and audiotapes. Two inpatient units, with 22 total patients, were randomized, one unit assigned to the intervention group (n
= 12) and the other to the control (n
= 10). Analyses revealed no differences between groups either on anxiety symptoms or on enumerative cell counts, NK cell lysis, or blastogenesis (ConA).
Endocrine Cruess et al. (2000)
conducted a small-sample study examining the effect of CBSM for women with Stage I or II breast cancer. The intervention consisted of 10 weekly group meetings of 120 min (20 therapy hrs) including cognitive restructuring, coping skills, assertiveness and anger management training, social support, and relaxation training (combination of progressive muscle, meditation, breathing, and guided imagery). Thirty-four women, self referred and part of a larger clinical trial, were randomized to the intervention or wait-list control. Analysis of covariance analyses indicated a significant reduction in cortisol and significant increases in an experimenter-derived measure of positive benefits from cancer for the intervention group. There were no changes in emotional distress (POMS).
Immune Elsesser, van Berkel, Sartory, Biermann-Gocke, and Ohl (1994)
conducted a small randomized study comparing anxiety management training with a wait-list control for a heterogeneous sample of German cancer patients. The treatment consisted of instruction in progressive muscle-relaxation training and cognitive restructuring for anxiety provoking cognitions and was administered in eight individual sessions during a 6-week period. In the predominantly female sample, (85%) of 20 patients had Stage I cancer, but they represented six different disease sites. The sample was recruited from existing self-help groups that had completed their medical therapy. Analyses indicated significant reductions in both state and, surprisingly, trait anxiety (STAI). However, there were no significant differences on measures of depression, quality of life, or cell counts.
Larson et al. (Larson, Duberstein, Talbot, Caldwell, & Moynihan, 2000
) reported on a randomized study comparing an intervention to reduce presurgical anxiety with a no-treatment (standard care) control for breast cancer patients (Stages I–IV). The intervention consisted of two 90-min (3 therapy hr) sessions including information on common somatic and psychological reactions to stress, problem-solving strategies, support, and progressive muscle-relaxation training with audiotapes. The accrual rate was not provided; however 41 women were randomized. Assessments included psychological measures of depressive symptoms, traumatic stress, quality of life, optimism, and NK cell lysis and IFNγ
production. Attrition was substantial (47%), and repeated measures ANOVAs revealed no significant group differences for either the psychological or the immunologic measures.
Endocrine and immune Gruber et al. (1993)
reported a small-sample randomized study comparing “enhanced” relaxation with a wait-list control in women with Stage I breast cancer. Progressive muscle relaxation was enhanced with guided imagery exercises and electromyographic biofeedback, administered in 9 consecutive weekly sessions, followed by monthly sessions for 3 months. Accrual was not described; 13 women were randomized. Psychological measures were not significant, but significantly higher cell counts and blastogenesis (ConA) and significantly lower levels of cortisol were found for the intervention group. There were no group differences on NK cell counts or the antibody (IgA and IgM) assays.
M. A. Richardson et al. (1997)
compared two group treatments, support and imagery–relaxation, with a no-treatment control for Stage I–III breast cancer patients. The support intervention focused on reducing stress, minimizing feelings of isolation, and enhancing self-esteem with 6 weekly sessions (duration not specified). The imagery intervention, also six sessions, provided instructions in relaxation, imaging ability, and breathing, with the use of images to enhance healing and stimulate immune function. Accrual rate was 30%, and 47 women were randomized. There were no significant differences between groups in mood (POMS), quality of life (FACT-B; Brady et al., 1997
), or any biologic variable (i.e., NK cell lysis, IL-1, IL-2, IFNγ
and beta endorphins). The only group differences were found for coping (Ways of Coping; Dunkel-Schetter, Feinstein, Taylor, & Falke, 1992
), which indicated that both intervention groups sought more support from others than did women in the control group. Also, women in the imagery group used positive coping strategies, whereas women in the support group reported distancing themselves from the stressor.
Van der Pompe, Duivenoorden, Antoni, Visser, and Heijnen (1997)
compared experiential– existential group psychotherapy with a wait-list control for Dutch breast cancer patients. The treatment was described as dynamic and included expression of emotions through self-disclosure, body-awareness exercises and relaxation, social support, and conflict resolution skills. Accrual was not described. Women (N
= 31) with Stage II, III, or recurrent breast cancer were randomized; however with attrition (26%), data were analyzed from 23 participants. Regression analyses indicated no intervention effect on the endocrine or immune outcomes, and some immune findings were in the opposite direction (e.g., higher posttreatment NK percentage scores for the wait-list group).
At the time of the prior review, experimental data on stress and immunity in cancer patients came from a single study, Fawzy and colleagues (Fawzy, Cousins, et al., 1990
; Fawzy, Kemeny, et al. 1990
). Specifically, Stage I or II melanoma patients were randomized to a structured, short-term (10 sessions) group-support intervention or control (no intervention). Significant psychological and coping outcomes for the intervention subjects were evident by 6 months posttreatment, as were significant increases in NK cell numbers and IFNα
-augmented NK cell activity.
In the intervening years, some consistencies have emerged. First, contrasting individuals who differ in their level of stressor distress, one finds that higher stress is correlated with higher endocrine (cortisol) and lower immune responses (Andersen et al., 1998
; Sachs et al., 1995
; Vitaliano et al., 1998
). However, data from experimental studies have been less positive; null findings predominate, with the exception of the cortisol data in the Cruess report (Cruess et al., 2000
). Collectively, these studies illustrate the difficulties inherent in intervention research and the added challenge of including biologic measures. Generalization is limited because of the selectivity of the samples and the often high attrition. Data analyses were hampered by small sample sizes (e.g., N
s from 13 to 47), likely resulting in large within-group variability and/or insufficient power. Nevertheless, these reports are resources for investigators wishing to meet the methodologic challenges faced in these pioneering efforts.
Regarding endocrine and immune measures, the ones used thus far are common to the stress and psychoneuroimmunology literatures (e.g., Miller & Cohen, 2001
; Zorrilla et al., 2001
), although many have no particular relevance to cancer, per se. The case can be made for selective ones, such as cortisol (as it is known to be immune down regulating), NK cell lysis, or NK cell responses to cytokines. These assays are familiar and easy to perform. However, they have drawbacks, as they are nonspecific and there are not enough data to show that changes in nonspecific immune responses are paralleled by changes in specific immune responses. For example, NK cell function may improve with an intervention. However, if there are still no tumor-specific T lymphocytes or antibodies to fight the tumor(s), the relevant disease outcomes will not improve.
One of the best ways to prove the hypothesis that psychological interventions effect cancer outcomes by way of the immune system is to evaluate tumor-specific immune responses, such as with specific tumor antigens or other surrogates of tumor-specific responses, as discussed earlier. Examples of antigens include melanoma antigen for melanomas; growth factor receptor HER-2/neu for breast and ovarian cancers; epithelial mucin for breast, pancreas, colon, prostate, lung, and ovarian tumors; CEA for colon cancer; prostate specific antigen and prostatic acidic phosphatase for prostate cancer; oncogene products such as Ras and p53 for a variety of tumors; human papilloma virus type 16 antigens E6 and E7 for cervical cancer; and others (Finn, 2001
). Although these assays are not as easy to perform by generalists, they can be routine in cancer immunology laboratories.