Stressors, Stress Response, and Cancer Recurrence

A Systematic Review

Briana L. Todd, MA, MS; Michal C. Moskowitz, MS; Alicia Ottati, MA; Michael Feuerstein, PhD, MPH

Disclosures

Cancer Nurs. 2014;37(2):114-125. 

In This Article

Discussion

The current study systematically reviewed literature investigating the link between stressor exposure and/or stress response and cancer recurrence published from December 1979 through April 2012. At this time, there is insufficient evidence to conclude that a causal relationship between stressor exposure and/or stress response and cancer recurrence exists. Most of the studies did not find a relationship between stressors/stress response and cancer recurrence. Many of these studies examined multiple measures of stressor exposure/responses, and these studies reported mixed findings (ie, lack of findings, positive findings, and/or inverse findings).

Considering the differences in findings for each dimension of stress (mostly null findings of a relationship between environmental stressor exposure and recurrence, mixed positive and null findings of an association between psychological stress response and recurrence, and very few studies relating biological stress response and recurrence), there is, at best, tentative evidence of a possible relationship between psychological stress response and recurrence. However, further research is needed before any definitive conclusions can be drawn. It is difficult to know whether null findings can be attributed to insufficient power, measurement error, or a true null relationship.

It is important when reviewing evidence for the hypothesis related to stress (stressor exposure and/or stress response) and cancer recurrence that we consider the criteria that have emerged as a framework for determining whether an exposure is likely to be a causal agent of a health outcome.[37] When considering this set of criteria, it is also important to recognize that many chronic illnesses, including cancer, can have a multivariate set of risk factors.[38] Although this review focuses on stressor exposure and/or stress response, the identification of only 1 risk factor for any single disease is highly unlikely. It is often the combination of risk factors that predicts a disease.[39] However, even if a cause-and-effect relationship is observed in a prospective study, for an exposure to be considered a viable "risk factor," a certain pattern of findings should be observed. This pattern of evidence can provide guidance for determining whether there is necessary and sufficient evidence to conclude that exposure to a stressor represents a risk factor with a certain value that predicts cancer recurrence.

The 9 criteria for determining that a certain independent variable (exposure) is a risk factor for a specific health outcome are as follows: (1) strength of the relationship (ie, value of the relative risk ratio); (2) consistency of the association in different locations by different researchers; (3) specificity of the risk factor's association with the disease and not others; (4) temporal relationship of exposure followed by the health outcome; (5) dose-response relationship, where higher levels of the exposure are related to higher levels of the health outcome (disease); (6) plausibility, where an evidence-based biological pathway exists; (7) coherence, where experimental findings reflect epidemiological findings; (8) experimental confirmation, where change in the exposure results in change in the health outcome (disease) based on RCTs; and (9) consideration of alternate hypotheses.[37]

The literature reviewed in this article was not consistent in the strength or direction of the relationship. The specificity criteria may not be appropriate for all health outcomes (eg, chronic illness) as it is with infectious diseases that are often acute in nature. Stress has been reported as a casual factor of several types of illnesses (eg, certain cardiovascular diseases). Although all studies in the present review reported exposure before the potential outcome of recurrence (ie, prospective), the outcomes varied in direction. In addition, there is no evidence of a dose-response relationship between stress and cancer recurrence in humans. Currently, the strongest evidence that stressor exposure and/or stress response may be a causal agent in cancer onset or recurrence is based on biological plausibility.[17]

Our review identified 3 RCTs.[22–24] Andersen and colleagues[24] provided evidence that stress reduction lowers a breast cancer survivor's risk for recurrence. However, Fawzy et al found that a psychosocial intervention aimed at reducing psychological distress (ie, stress response) did not affect malignant melanoma recurrence at 5 to 6 years[23] or at 10 years[22] after treatment. Although the effects may be cancer type specific, the Andersen et al study has met with concern over the analyses of results.[40] There is very little consistent evidence from RCTs that can inform us of the causal effects of stress exposure on recurrence.

All prospective studies reviewed were characterized by several methodological limitations, including the lack of a consistent measure of stressor exposure and/or stress response and potentially inadequate power to detect differences given the small number of participants. The type of stressor exposure and/or stress response also varied by study, complicating the interpretation of the findings. The studies reviewed assessed only limited aspects of stress; however, stress is a multidimensional phenomenon that can be measured in a variety of ways. Moreover, cancer recurrence was not consistently operationally defined. Whereas some studies clearly defined recurrence,[26–29] the majority lacked a specific definition.[22–25,30–36] The underlying models of stress that were used by the investigators are not always explicit. This type of transparency would greatly help the reader better understand choice of measurement and should be included in the measurement sections of methods. Finally, all studies included in the review measured stress response or stressor exposure at 1 specific point in time, yet stress response and stressor exposure are dynamic and can change over time. In addition to the concerns with the individual studies listed previously, there are limitations of the current review that should also be considered. The selected studies were limited to English only. In addition, most of the articles in the review studied breast cancer survivors. Considering differences between the male and female physiological stress response,[41] it is unknown how gender might affect the findings.

Although the finding of an inverse relationship between stress and recurrence is opposite to the original hypothesis, a plausible biological explanation for this observation has been proposed.[42] Unlike chronic stressors, acute stressors trigger the body to redistribute immune cells such as leukocytes to organs and injured sites to prepare the body for potential injury or infection, thereby improving overall immune response.[42,43]

Future studies should include prospective designs that measure stressor exposure and/or stress response with valid and consistent instruments and that account for confounding variables (eg, time since initial diagnosis, stage of tumor, previous psychiatric history). Although this review was not designed to focus on any specific cancer site, the articles retrieved studied breast cancer and melanoma. Future studies need to focus on many types of cancers to determine whether there may be an interaction with cancer type, treatment exposures, stressors, stress response, and recurrence. Examining cancers that are hormonally mediated, such as prostate and endometrial cancers, or immune mediated, such as leukemia and lymphomas, may be more likely to reveal a link between stress and cancer recurrence because of the relationship among exposure to stressors, immune response, and cancer progression.[18] Future research on stress and cancer recurrence should consider each of the criteria for an evidence-based risk factor.[38]

Although the current review did not find consistent evidence for the relationship between stressor exposure and/or stress response and cancer recurrence, this does not negate the relationship among stressor exposure and/or stress response and long-term and late effects that cancer survivors experience over time.[44] For example, after exposure to a stressor, breast cancer survivors with persistent fatigue differ in cortisol response compared with breast cancer survivors without fatigue, indicating that exposure to stressors plays a role in fatigue.[45] In the general population, excessive exposure to stressors has also been related to cognitive problems (eg, impaired memory), sleep disturbance, and poorer mental health (eg, mood and anxiety disorders).[46]

In response to cancer survivors who may be concerned that stress leads to cancer recurrence, nurses can reassure survivors that at this point, there is no conclusive evidence that exposure to stressors or stress response cause cancer recurrence. However, considering the preliminary evidence that psychological stress response may possibly be a risk factor for cancer recurrence, as well as evidence that excessive stress is deleterious for other health reasons, it is recommended that cancer survivors maintain a healthy level of stress in their lives. Nurses can advise patients to use empirically supported treatments to manage psychological stress. Interventions targeted at attenuating the stress response reduce some measures of symptom burden.

A systematic review of cognitive-behavioral therapy approaches indicated that these approaches were effective in reducing a cancer survivor's anxiety, depression, and quality of life in the short run.[47] In addition, results from another systematic review indicate that when yoga is used as an intervention for emotional and physical health, along with mindfulness-based stress reduction, moderate improvements in stress response levels, quality of life, and mood are observed in a heterogeneous sample of cancer patients and survivors.[48]

Despite the lack of conclusive evidence supporting a relationship between stressor exposure and/or stress responses with cancer recurrence, attending to the reduction in a cancer survivor's stress response can improve emotional well-being and quality of life. Nurses can play a pivotal role in this endeavor by assessing survivor beliefs about causal associations between stressors or stress-reducing behaviors and risk of recurrence.[8,9,11,49] Nurses can also offer guidance about coping with common stressors and posttreatment symptoms.[50]

High-quality evidence is needed to provide a more definitive answer to the question of the role of stressors and/or the stress response in cancer recurrence. The overall evidence to date does not provide support for this hypothesis. The use of various stress management approaches may be more appropriately targeted at symptom management rather that recurrence, although such a relationship was not addressed in the current review.

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