Women confront much adversity in adapting to diagnosis and treatment for breast cancer. Breast cancer patients with poor cognitive coping skills and a negative outlook (Carver et al., 1993
; Stanton et al., 1993
) and fewer social resources (Alferi et al., 2001
) experience greater anxiety and distress during the stressful period of treatment. How such adaptations can be modulated by psychosocial interventions that improve individuals’ outlook, coping skills and social support has been of interest to clinical researchers for several years (Antoni, 2003
). Reviews based on intervention studies conducted in the past 10 years have revealed that psychosocial and relaxation-based interventions are helpful in terms of improving emotional adjustment and quality of life in cancer patients undergoing medical treatments (e..g., Luebbert, Dahme & Hasenbring, 2001
; Meyer & Mark, 1995
). In one meta-analysis, relaxation-based interventions (including progressive muscle relaxation, imagery, autogenics and other techniques) were found to be especially effective in reducing anxiety, tension, depression, and overall negative mood (Luebbert et al., 2001
). Cognitive behavioral interventions have been shown to be effective in improving depression, anxiety, and quality of life in cancer patients, with anxiety reductions showing the largest effect sizes (Kissane et al; 2003
; Edmonds, Lockwood & Cunningham, 1999
; Larson et al., 2000
; Trask, Paterson, Griffith, Riba, & Schwartz, 2003
). Less is known about whether such experiences relate to physiological changes, which in turn could affect post-adjuvant physical status and possibly even reduce the risk of disease recurrence over the years after surgery and adjuvant therapy (Antoni & Lutgendorf, 2007
). To address this knowledge gap, the present study sought to document whether a well-established psychosocial intervention modulates psychosocial adaptation in parallel with physiological adaptation in women undergoing treatment for BCa.
Previously we showed in two separate trials that a 10-week Cognitive Behavioral Stress Management (CBSM) intervention facilitated psychosocial adaptation in women being treated for BCa. These effects included decreased prevalence of clinically-elevated depression, less thought intrusion, anxiety symptoms, negative affect, and social disruption, and more benefit finding, positive affect, and positive states of mind (Antoni et al., 2001
; Antoni, Wimberly, Lechner et al., 2006
; Antoni, Lechner, Kazi et al., 2006
). All of these findings appeared to hold up to 12 months. This intervention was also found to decrease afternoon levels of serum cortisol immediately after the completion of the intervention in a prior trial (Cruess et al., 2000), and up to 12 month follow-up in the women participating in the present study—results that were published previously (Phillips et al., in press
). Women assigned to CBSM also showed greater cellular immune function (lymphocyte proliferative responses to anti-CD3 stimulation) at 3-month follow-up (McGregor et al., 2004). Other work similarly suggested that psychosocial interventions of this theoretical orientation, format and length were capable of decreasing self-reported stress and cortisol, and modulating immune parameters such as lymphocyte counts and lymphocyte proliferation (Schedlowski et al., 1994
; Andersen et al., 2004
). In one study the size of the immune effect (McGregor et al., 2004a) was greatest in women with the largest psychological improvements.
It is plausible that some of the immunological changes observed in these prior psychosocial intervention studies may have been explained by changes in Th1 and Th2 cytokine regulation, though few prior studies have shown that psychosocial interventions can affect cytokine regulation in cancer patients. A recently published study showed that women with early stage BCa who received a 8-week mindfulness-based stress reduction (MBSR) group intervention starting 10 days after surgery showed a better recovery of IFN-γ production, decreased late afternoon (4 – 6pm) plasma cortisol, and improved quality of life for up to one-month post-intervention compared to a non-MBSR (usual care) control group (Witek-Janusek, Albuquerque, Chroniak, Chroniak, Durazo-Arvizu & Mathews, in press
). In another study, breast and prostate cancer survivors, who had completed treatment 3 months to 20 years prior, who were assigned to MBSR showed increases in Th1 cytokines IFN-γ and tumor necrosis factor (TNF) that were apparent at 6 – 12 month follow-up (Carlson, Speca, Patel & Faris, 2007
). However, since patients in each of these studies were self-selected into treatment conditions one cannot assume that MBSR caused the changes observed over time. The present study sought to add to these findings by testing the effects of a 10-week group-based CBSM intervention on psychological, neuroendocrine and cytokine production indicators using a randomized controlled trial design.
First we found that women with BCa assigned to the CBSM intervention showed improvements in psychosocial adaptation evidenced by reductions in cancer-specific intrusive thoughts and general anxiety symptoms. Our confidence in these anxiety reduction effects is reinforced by the fact that they were evident in both a self-report measure and in an interviewer rating scale. Physiological adaptation effects associated with participation in the intervention included decreases in afternoon serum cortisol levels, which we have previously described in detail elsewhere (Phillips et al., in press
). Our rationale for collecting blood samples in the late afternoon is detailed in that paper as well as the limitation in using this protocol. Briefly, we decided to use the 4 – 6 pm sampling window in order to (a) replicate the time frame used in a prior study of CBSM in breast cancer patients (Cruess et al., 2000) that we sought to expand upon; (b) because elevated PM cortisol levels may underlie the association between flat di-urnal cortisol ouput pattern and poorer health outcomes in breast cancer (Sephton, Sapolsky, Kraemer & Spiegel, 2000
); and (c) because this was a time frame that best accommodated participants’ schedules and would likely lead to optimal compliance. Caution is in order in interpreting these single afternoon serum samples as being reflective of HPA activity as they represent total (bound and unbound) levels of cortisol rather than free cortisol levels, and fail to capture momentary fluctuations that vary with stressor exposure or across the diurnal cycle (Yehuda, 2003
). Future work should investigate the effects of stress management on serial salivary samples (which reflect free cortisol levels) collected across the di-urnal cycle, which allow for the calculation of multiple indicators of cortisol output and regulation (Fekedulegn, Andrew, Burchfiel et al., 2007
We also observed increases in the production of Th1 cytokines IL-2 and IFN-γ from stimulated PBMCs during the initial 6-month follow-up in the CBSM condition in contrast to apparent IL-2 and INF-γ decreases in those assigned to a psychoeducational control condition. Since most women underwent some form of adjuvant therapy during the time of the intervention these findings suggested that being in a CBSM group seemed to “buffer” women from the ongoing effects of adjuvant therapy. These effects were no longer evident and had receded to baseline levels at 12-month follow-up, a point well after adjuvant therapy had been completed. When we created a ratio of IL-2 to IL-4 production to reflect the Th1:Th2 balance, as hypothesized we found that women assigned to CBSM showed significant increases in the ratio of IL-2 to IL-4 production compared to controls who showed declines. These effects were also only evident between T1 and T2. Thus all of the effects of CBSM on immune effects were concentrated in the initial 6 month follow-up. During this period women received no further therapeutic contact once their 10 week groups had ended. It is plausible that had we offered a longer intervention or periodic maintenance sessions, effects on cytokine production may have held up longer.
This pattern of results—intervention-related decreases in psychological distress (anxiety) and cortisol levels over the entire 12-month period and intervention effects on Th1 cytokines out to 6 months only—are hard to explain. Explaining these disparities is challenging as the kinetics of immunologic indicators during and after adjuvant therapy for cancer is poorly understood. As a preliminary step it will be important to carefully map out the changes that occur in Th1 and Th2 cytokine production (and other immune parameters) during the typical course of adjuvant therapies for breast cancer patients and then catalog the time course for each cytokine change during each form of treatment. The present study is not equipped to do so.
Despite the fact that women who received the CBSM intervention showed decreases in anxiety, decreases in serum cortisol, and increases in Th1 cytokines there was no evidence that individual differences in psychosocial adaptation changes tracked in synchrony with physiological adaptation changes. It is likely that anxiety reduction alone may not be affecting the cytokine changes, but rather there may have been effects more proximal to intervention participation that are linked to cytokine changes. Specifically, it may be some combination of skills training (e.g., increased perceived efficacy in using stress management skills) or being in a supportive group (e.g., increased perceived social support and bonding with other cancer patients) that are tied more directly to Th1 cytokine production increases. Future work should examine how changes in CBSM specific skills and non-specific group processes track with anxiety, cortisol and immune changes over time in this population.
Our prior work testing CBSM in other populations (men with Human Immunodeficiency Virus [HIV] infection) has shown that cortisol reductions during CBSM parallel reductions in depressed affect but not decreases in anxiety, while reductions in anxiety during CBSM parallel reductions in norepinephrine (Antoni, 2003b
). Although we measured changes in the negative affect in the present study, the measure used (ABS) did not focus on depressed mood exclusively and was not affected by CBSM. Since we did not measure norepinephrine in these breast cancer patients we are unable to test whether changes in anxiety were associated with changes in this neurohormone in the present study. This precludes our ability to test whether parallel CBSM-associated changes in psychosocial and endocrine variables established in prior work are also evident in breast cancer patients. We did however note that greater decreases in cortisol over the course of the study (from baseline to 12 month, and from 6 to 12 month follow-up) were associated with greater increases in Th1 cytokine production, but only up to the 6-month follow-up for IL-2 and up to the 12-month follow-up for IFN-γ It is possible that stress management effects on IL-2 production may have been greatest when patients were acutely recovering from their treatments (up to the 6 month follow-up), and that thereafter other phenomena (e.g., additional medical treatments) acted to decrease cytokine production in the direction of values evident at study entry. On the other hand, decreases in cortisol during the 6 – 12 month follow-up period were associated with increases in IFN-γ production from study entry to 12 month follow-up. The reasons for the discrepant findings for these two Th1 cytokines are unclear. As mentioned previously it will be helpful in future work to do fine-grained analyses of cytokine fluctuations that occur during and after the period of adjuvant therapy in cancer patients in order to better understand the clinical significance of the findings observed in the present study.
The most consistent immunologic effect of psychosocial interventions conducted to date with BCa patients has been increases in lymphocyte proliferation, suggesting that cell-mediated immune indices may be most sensitive to the stress-reducing effects of these interventions (van der Pompe et al., 1997
; Andersen et al., 2004
; McGregor et al., 2004 In related work one group demonstrated that an 8-week cognitive behavioral therapy intervention focused on improving sleep in BCa patients was associated with better subjective sleep, decreases in quality of life, and decreases in anxiety and depression (Savard, Simard, Ivers, & Morin, 2005a
), and increases in IFN-γ production (Savard, Simard, Ivers, & Morin, 2005b
). The present effects of CBSM on increases in Th1 cytokine production in women treated for Stage I – III BCa mirror these effects and may be relevant for health outcomes given prior associations between Th1-directed immune functions and disease progression in mice and BCa patients (Baxevanis, 1993
; Dighe, Richards, Old, & Schreiber, 1994; Kaplan, Shankaran, Dighe, Stockert, Aguet, Old & Schreiber, 1998
; Street, Cretney & Smyth, 2001
; Whiteside & Herberman, 1989
We also found that women assigned to CBSM showed reductions in serum cortisol, which are in line with prior studies of CBSM in BCa patients (Cruess et al., 2000). In other work, reductions in plasma cortisol paralleled a “normalization” of Th1 and Th2 cytokine production in breast cancer patients receiving MBSR intervention during treatment (Witek-Janusek et al., in press
). Some work has suggested that alterations in cortisol regulation may predict survival in women with metastatic BCa (Sephton et al., 2000
) though it is unclear what health consequences may be associated with cortisol changes in the present sample of non-metastatic patients. Glucocorticoids regulate a wide variety of cellular processes through glucocorticoid receptor-mediated activation or repression of target genes. Glucocorticoids such as cortisol may act in a synergistic fashion with catecholamines to facilitate cancer growth (for review see Antoni, Lutgendorf, Cole et al., 2006
). It is thus plausible that stressful situations characterized by both elevated catecholamine and cortisol levels (e.g., uncontrollable stress) may have the greatest impact on cancer-related processes. It is reasonable then to suggest that interventions such as CBSM, which blends relaxation training with cognitive behavioral techniques, to diminish anxiety and perceived stress and restore a sense of control over life are helpful for women dealing with BCa and its treatment. These psychosocial changes may be able to modulate the production of these neuroendocrine substances and possibly their effects on not only cytokine regulation but also tumor growth processes. The present data support the provocative notion that interventions such as CBSM might be used in conjunction with adjuvant therapy to optimize immunologic recovery during critical periods of medical treatment that may be relevant for optimal disease surveillance (Shakhar & Ben-Eliyahu, 2003
Caution should be exercised in interpreting these findings as evidence that CBSM can improve cancer outcomes, though recent work suggests that similar psychosocial interventions may improve health outcomes in BCa patients by decreasing emotional distress (Andersen et al., 2007
). This study used in vitro cytokine production as an indicator of immune status. It is important to keep in mind that in-vitro production assays may not provide adequate indicators of the processes that occur in-vivo. Although recent work (e.g., Carlson, Speca, Patel & Faris, 2007
; Witek-Janusek et al., in press
) has also shown that psychosocial interventions are associated with increases in in-vitro Th1 cytokine production assays, it is unclear how well these assays represent in-vivo cytokine production and signaling. It is therefore unclear whether the changes in cytokine production observed in these studies are relevant to biological processes or clinical outcomes in women with breast cancer. In fact, the question of the relevance of peripheral indicators of the immune system as they relate to changes in the tumor environment remains controversial. While tumor-specific immune responses to immunotherapy have been demonstrated in-vivo
, contemporary research focuses on subverting immune tolerizing mechanisms in tumors, supplementing immune functions, and suppressing tumor angiogenesis and growth (Zou, 2005
). Future work should examine whether psychosocial interventions are capable of modulating some of these tumor-relevant processes and then tie the changes to neuroendocrine changes, and longer-term health outcomes by following cohorts of women with BCa over time.
Caution is also in order in interpreting the results presented herein as they are based upon a middle-class well-educated sample that was likely motivated to participate in health research. There was also evidence that this sample of women may have been more healthy than prior samples used to demonstrate the effects of CBSM on psychosocial adaptation in breast cancer patients (Antoni et al., 2006
). Finally the use of repeated measure ANCOVA models in the present study eliminated all subjects who had missing data for the outcome studies under investigation. This resulted in analyses based on different sample sizes, and reflect “completer” analyses rather than intent to treat analyses. These factors could have biased our results. We considered using other analytic techniques that we and others have used elsewhere (e.g., Latent Growth Modeling; Muthen, 1997), which use Full Information Maximum Likelihood (FIML) for estimating parameters in the presence of missing data (Enders, 2006
). However, we decided against using LGM due to the small sample size. Results should be considered with these limitations in mind.
The pattern of effects observed in the present study suggested that women with non-metastatic BCa offered a 10-week group-based CBSM intervention evidenced better psychosocial adaptation and physiological adaptation during and after their adjuvant treatment. Effects on psychosocial adaptation indicators (reduced cancer-specific and general anxiety) appeared to hold across the entire 12-month observation period. Th1 cytokine regulation changes were most pronounced in the initial 6-month period then returned to pre-intervention levels. Findings suggest that CBSM intervention may have facilitated a “recovery or maintenance” of Th1 cytokine regulation through the adjuvant therapy period. Psychosocial interventions that address dysregulated neuroendocrine function could play a clinically significant role in optimizing host resistance to cancer during this vulnerable period.