Mechanisms of Radiation-Induced Fatigue in Breast Cancer

Institution: University of California, Los Angeles
Investigator(s): Julienne Bower, Ph.D. -
Award Cycle: 2000 (Cycle VI) Grant #: 6KB-0006 Award: $224,991
Award Type: New Investigator Awards
Research Priorities
Community Impact of Breast Cancer>Sociocultural, Behavioral, and Psychological Issues: the human side



Initial Award Abstract (2000)
Breast-conserving surgery followed by radiation to the breast is one of the two treatment options for early stage breast cancer, and is selected by more than half of women diagnosed with breast cancer today. While this treatment minimizes surgical intervention, it does have side effects that can affect both physical and emotional well-being. One of the most common side effects of radiation therapy is fatigue. Although typically not debilitating, fatigue can cause significant impairment in quality of life among women undergoing radiation, interfering with daily activities, mood, and social relations at a time when women may already be struggling to cope with the demands of cancer diagnosis and treatment. Fatigue can sometimes persist for months or even years following completion of radiation treatment, causing more significant and enduring disruption in women’s lives.

Despite the prevalence of this symptom, the causes of radiation-induced fatigue are not known. The primary goal of this study is to identify factors that contribute to fatigue in breast cancer patients undergoing radiation treatment. We are particularly interested in how psychological and behavioral responses to breast cancer may impact fatigue. For example, women who feel distressed, out of control, and expect the worst following a breast cancer diagnosis and who make few active efforts to cope with their disease may be more likely to experience symptoms of fatigue. Biological factors may also contribute to fatigue and will be considered here, including changes in the immune system induced by radiation. Physical symptoms and health behaviors that have been linked to fatigue in previous studies will also be examined.

Women diagnosed with early-stage breast cancer who are scheduled to receive radiation therapy will be invited to participate in this research study. Participants will be assessed before they begin treatment, at three time points during treatment, and at two follow-up appointments. At each of these assessments, women will complete questionnaires and give blood for immunological analysis. All appointments will be scheduled to coincide with clinic visits to minimize any extra burden for them, and participants will receive a small payment ($50) to partly compensate them for their time.

To date, there has been minimal research attention focused specifically on side effects of breast cancer treatment, including symptoms of fatigue. Women who experience problems with fatigue during and after treatment have few resources to help them manage this symptom, and may even be reluctant to mention the problem to their physicians. This project will help to advance our understanding of radiation-induced fatigue, paving the way for the development of interventions to reduce this symptom and the disruption it causes during the treatment process. In addition, information gained from this project will help to identify women who are at risk for enduring fatigue and allow us to intervene at an earlier stage to improve long-term quality of life.


Final Report (2004)
Fatigue is one of the most common side effects of radiation treatment and causes significant disruption in the lives of breast cancer patients receiving radiation therapy. Despite its prevalence, the mechanisms underlying the occurrence of radiation-induced fatigue are unknown. The primary goal of this study was to identify factors that contribute to fatigue in breast cancer patients undergoing radiation treatment. We were particularly interested in biological factors that may impact fatigue, specifically changes in the immune system induced by radiation. We hypothesized that activation of proinflammatory cytokines, which mediate communication between the peripheral immune system and the brain, would influence symptoms of fatigue during treatment. In addition, we examined psychological and behavioral responses to breast cancer that might contribute to fatigue, focusing on symptoms of depression.

Study participants included 33 women diagnosed with early-stage breast cancer who were scheduled to receive radiation therapy at the UCLA Radiation Oncology Clinic. Participants were assessed before treatment onset, at four time points during treatment, and at three follow-up appointments. At each of these assessments, women completed self-report questionnaires to assess fatigue and other symptoms and provided blood for immune analyses. Examination of fatigue scores over time demonstrated a significant increase in fatigue levels during radiation therapy, peaking in the final week of treatment. Fatigue levels then declined to pre-treatment levels by the 6 month follow-up. Levels of proinflammatory cytokines IL-1ß and IL-6 showed significant variability over the study period, although there was some evidence of increased levels during radiation therapy.

Study Aim #1 focused on the association between changes in the immune system and changes in fatigue during radiation therapy. Hierarchical linear modeling was used to probe the association between these variables. Consistent with hypotheses, results showed that fatigue was positively associated with cumulative levels of IL-1ß and IL-6. As cumulative levels of cytokines increased, number of days fatigued also increased. This effect remained significant in analyses controlling for relevant demographic and biobehavioral confounds.

Study Aim #2 focused on the role of psychosocial factors as predictors and correlates of radiation-induced fatigue. As expected, we found a strong and significant association between fatigue and depression; as depressed mood increased, fatigue also increased. Analyses revealed that women’s cognitive appraisals were also strong predictors of fatigue. In particular, women who perceived that they had more control over their health reported significantly less fatigue during treatment. In contrast, women who had more negative expectations about their health and response to treatment reported significantly higher levels of fatigue. Coping by behavioral disengagement was not associated with fatigue severity.

Study Aim #3 focused on identifying women whose fatigue did not remit following treatment and determining the predictors of persistent fatigue. Of the 33 women assessed, 10 (30%) reported significant fatigue at the 6 month follow-up. Using logistic regression, we examined whether any of the variables that were associated with fatigue during treatment predicted fatigue status 6 months later. No significant predictors were identified in this analysis; however, correlation analyses indicated that pre-treatment fatigue levels were associated with fatigue at 6 months post-treatment.

To date, there has been minimal research attention focused specifically on side effects of breast cancer treatment, including symptoms of fatigue. Women who experience problems with fatigue during and after treatment have few resources to help them manage this symptom, and may even be reluctant to mention the problem to their physicians. Our findings indicate that fatigue is driven by both biological and psychological factors. This is the first study to show that changes in proinflammatory cytokines are associated with fatigue in women undergoing radiation therapy for breast cancer; of note, the use of hierarchical linear modeling may have enabled us to identify a relationship that has not been seen in research using traditional regression techniques. In addition, this is the first study to show that cognitive responses to cancer diagnosis, particularly perceptions of control over one’s health and response to treatment, have a significant influence on fatigue.

Based on this data, our group has begun a more intensive examination of women undergoing radiation therapy for breast cancer designed to specify the immune disturbances associated with radiation and to examine the role of other physiological systems (i.e., hypothalamic-pituitary-adrenal axis, autonomic nervous system) in fatigue and immune alterations. To further investigate the association between fatigue and other behavioral symptoms associated with cancer treatment, we are conducting a study examining fatigue, sleep, depression, and cognitive function in women who have completed treatment for breast cancer. Finally, we have initiated two trials designed to improve energy in breast cancer patients with persistent fatigue. In line with our finding that cancer-related fatigue may be influenced by both biological and psychological factors, one of these trials utilizes a behavioral intervention while the other utilizes a pharmacological intervention designed to reduce proinflammatory cytokine levels.


Symposium Abstract (2003)
Fatigue is one of the most common side effects of radiation therapy and causes significant disruption in the lives of breast cancer patients receiving this treatment. Despite its prevalence, the mechanisms underlying the occurrence of radiation-induced fatigue are unknown. The current study was designed to elucidate biological and psychological mechanisms of fatigue in women undergoing radiation therapy for early-stage breast cancer. We focus on changes in the immune system induced by irradiation, specifically increases in proinflammatory cytokines, which we hypothesize to be key mediators of radiation-induced fatigue. We also examine psychological and physical factors that may influence fatigue.

Study participants are assessed before treatment onset, at four time points during treatment (1, 2, 4, and 6 weeks into treatment) and at three longer-term follow-ups (2 weeks, 2 months, and 6 months post-treatment). At each assessment point, they complete self-report questionnaires assessing fatigue and other behavioral and psychological symptoms (e.g., sleep disturbance, depressed mood). Psychological responses to cancer diagnosis and treatment are also assessed. Blood samples are drawn at each assessment for determination of serum cytokines interleukin 1 (IL-1) and interleukin 6 (IL-6). Basic lymphocyte subsets are also assessed.

To date, a total of 33 women have been recruited into the study; all have completed their 2 month follow-up, and 28 have completed their 6 month follow-up. Preliminary examination of fatigue scores indicates that mean fatigue levels increase from baseline to treatment week 4 then decline following treatment completion, as predicted. However, there is considerable individual variability in fatigue trajectories. Preliminary examination of cytokine data suggests elevations in serum cytokines for selected participants. Results linking fatigue, cytokines, and other factors (stress/depression, physical symptoms) will be presented at the meeting.

This project is important as it will advance our understanding of the basic mechanisms underlying radiation-induced fatigue, thereby paving the way for the development of interventions to help manage and reduce this problem among women receiving radiation therapy. In addition, the study will elucidate factors that contribute to persistent fatigue, a significant problem for many breast cancer survivors following completion of successful therapy.

T-cell homeostasis in breast cancer survivors with persistent fatigue.
Periodical:Journal of the National Cancer Institute
Index Medicus: J Natl Cancer Inst
Authors: Bower JE, Ganz PA, Aziz N, Fahey JL, Cole SW
Yr: 2003 Vol: 95 Nbr: 15 Abs: Pg:1165-1168