It is already known that behavioral interventions for cancer patients, including psychoeducational support groups and psychotherapy, can reduce anxiety, depression, and cancer-related distress and improve quality of life [155
]. The evidence reviewed thus far also points to the potential for behavioral interventions that can reduce stress and mood disturbance to serve an adjunctive role to conventional treatments in improving outcomes for cancer patients. An early behavioral intervention trial found that women with metastatic breast cancer randomized to a year-long weekly support group survived an average of 18 months longer than women assigned to a control group [159
]. However, there has been significant controversy over the meaning of the results [e.g. 161
], and attempts to replicate in other samples of breast cancer patients have not been successful [164
]. Results from studies of other behavioral interventions have also been mixed. While several trials have shown no survival effect [170
], three randomized clinical trials have shown positive results [160
]. One of the most striking findings was that an average of 7 hours of supportive psychotherapy improved survival among patients undergoing surgery for gastrointestinal malignancies, effects that were sustained at 2 and 10-year follow-ups [174
Such findings have catalyzed interest in the potential mechanisms by which behavioral interventions could affect cancer outcomes. Most studies have focused on the roles of NK cell activity, lymphocyte proliferative response, and other markers cellular immune functioning. Indeed, there is evidence from a handful of large, well-designed randomized clinical trials that behavioral interventions that enhance social support and target stress management and other coping skills can improve neuroendocrine and cellular immune functioning.
For example, cognitive-behavioral stress management (CBSM) is a 10 session behavioral program conducted in a supportive group format and aims to assist patients in developing of coping skills, utilizing social support, expressing emotions, and learning relaxation strategies. CBSM reduced anxiety and depression and appeared to normalize neuroendocrine functioning in breast cancer patients; women randomized to the intervention displayed a significant decline in cortisol over a 12-month follow-up period, while women in the control group did not show this decline [158
]. CBSM participants also demonstrated better lymphoproliferative responses at a 3-month follow-up and better Th1 responses at a 6-month follow-up as indicated by greater Th1 cytokine production (IL-2 and IFNγ) and a higher IL-2 to IL-4 ratio; however, these differences were not sustained at a 12-month follow up [68
]. The effect of CBSM on clinical outcomes has not yet been reported.
Another behavioral intervention that was provided in a supportive group format and targeted coping skills, stress management, health practices, and adherence to treatment demonstrated similar benefits for women with early-stage breast cancer in a randomized clinical trial. In addition to reducing distress and improving social support, the intervention also appeared to be protective with respect to immune functioning. T cell proliferative responses to phytohemagglutinin and concanavalin A remained stable or increased during the 4-month intervention period for participants randomized to the intervention while declining during the same time frame for women in the control group, an effect that was maintained at a 12-month follow-up [180
]. Women who reported clinically significant depressive symptoms were especially likely to benefit; in addition to improvements in mood and quality of life, they also showed reductions in markers of inflammation (operationalized as white blood cell count, neutrophil count, and T helper to T suppressor cell ratio) [182
]. Importantly, the intervention also improved clinical outcomes, including initial benefits in performance status, functional status, and overall health status [181
]. Perhaps the most notable finding was that after a median of 11 years of follow up, women randomized to the psychological intervention showed a reduced risk of breast cancer recurrence and mortality [173
]. The authors report plans to investigate whether improvements in cellular immune functioning or reduced inflammation in the intervemtion participants may be responsible for the survival differences.
A key component of these interventions appears to be the acquisition of specific skills to reduce the impact of stress both psychologically and physiologically. Mindfulness-Based Stress Reduction (MBSR) is an 8-week program that includes a number of such skills including mindfulness meditation, gentle yoga, and progressive muscle relaxation techniques. MBSR has shown promising effects in cancer patients including reduced distress, improved quality of life, declines in cortisol, enhanced NK cell functioning, and a quicker restoration of the balance of Th1 to Th2 cytokines to pre-treatment levels [183
]. Other work has demonstrated benefits from brief training in relaxation techniques and guided imagery, including decreased cortisol; greater numbers of mature and activated T cells, NK cells, and lymphokine-activated killer subsets; improved NK cell activity; and enhanced lymphocyte proliferative responses [187
Effects of psychosocial interventions on cellular immune functioning have not been found in all studies [e.g. 192
], and the findings have not been uniformly positive in the studies reviewed above, with effects demonstrated for some parameters of immune functioning but not others. Nonetheless, there is compelling evidence from at least two large, randomized clinical trials for breast cancer patients that behavioral interventions can optimize cortisol regulation and cellular immune functioning. Follow-up work is needed to replicate and extend these findings, to examine effects of behavioral interventions on tumor growth pathways described above, and to determine whether the changes in physiology are of the type and magnitude necessary to alter clinical outcomes.
Targeting specific quality of life concerns, such as insomnia, is another promising avenue [145
]. For example, a cognitive-behavioral intervention for chronic insomnia among early-stage breast cancer patients not only improved sleep and fatigue, but also increased INFγ and IL-1β from pre- to post-treatment, with IL-1β changes maintained at a 1-year follow-up, effects the authors characterized as immune-enhancing. Lymphocyte counts also increased from post-treatment to later follow-up time points [195
]. Interventions focusing on sleep further have the potential to modulate disease-induced alterations in circadian rhythms, which have been closely linked to neuroendocrine and immune regulation relevant to tumor growth [196
Pharmacologic interventions that can modulate the stress response pathways described in this review also hold promise. There is already evidence that SSRIs can be effective in addressing cancer-related quality of life symptoms [198
]. The role of antidepressants on tumor growth outcomes has been mixed, with both positive and negative effects reported, depending on the population and the antidepressant [200
]. Based on evidence that stress-induced alterations in the tumor microenvironment appear to be mediated by beta-adrenergic signaling pathways, beta blockers have been proposed as a potential therapeutic strategy to attenuate these effects. Beta blockers have already been shown to reduce the effects of stress on suppression of NK cell activity and tumor development in animal models [202
], and there is epidemiological evidence that beta blocker use reduces risk for the development of prostate cancer in humans [204
]. Pilot clinical studies to examine the potential preventative effects of beta blockers are underway. Along similar lines, an innovative cocktail of catecholamine- and prostaglandin-blockers has been successfully used in an animal syngenic tumor model along with the immuno-stimulant poly-I-C to prevent peri-operative immunosuppression [205