Radiation Therapy–Induced Fatigue Linked to Inflammation

Roxanne Nelson

September 18, 2010

August 18, 2009 — Fatigue is one of the most common and disabling adverse effects of cancer treatment, but exactly why it occurs has not been well understood. Now, preliminary data suggest that activation of the proinflammatory cytokine network may be largely responsible for fatigue that is experienced during radiotherapy.

According to a report in Clinical Cancer Research, there is an association between fatigue and downstream biomarkers of cytokine activity. In particular, increased levels of the interleukin (IL) 6 cumulative exposure biomarker C-reactive protein and the IL-1β cumulative exposure biomarker IL-1 receptor antagonist were associated with a higher frequency and severity of fatigue.

The authors note that these effects could not be accounted for by other variables, including age, body mass index, depressed mood, or sleep disturbance.

This research provides insight into the biological mechanisms underlying radiation-induced fatigue and is an important step forward, commented Stephen Hahn, MD, chair of the Department of Radiation Oncology at the Abramson Cancer Center at the University of Pennsylvania, Philadelphia.

Dr. Hahn, who was not involved in the study, explained that the study suggests one possible mechanism for radiation therapy–associated fatigue as well as an avenue for treatment. "There are compounds under development that may block these inflammatory substances," he told Medscape Oncology. "As those compounds come into clinical use, it would be useful to study them as measures to counteract radiation fatigue."

Although these agents have not yet been studied in patients undergoing radiotherapy, initial trials with cytokine antagonists have demonstrated a beneficial effect on fatigue. This includes studies with cancer patients that were designed to improve the tolerability of chemotherapy. However, lead author Julie Bower, PhD, an associate professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California–Los Angeles, feels that that it is too early to recommend the use of cytokine antagonists, "given the potential for negative side effects."

"We need better evidence that radiation-induced inflammation causes fatigue, and a serious consideration of the risks and benefits of blocking cytokine activity," she told Medscape Oncology.

Underlying Causes Poorly Understood

The underlying causes of cancer-related fatigue remain poorly understood, and even though biological and psychological factors have been identified, they are not consistently associated with fatigue, nor do they fully explain the occurrence of fatigue in cancer patients. The authors point out that basic research involving neuroimmune interactions demonstrated that proinflammatory cytokines can signal the central nervous system to generate fatigue, along with other behavioral changes.

Studies with breast cancer survivors have also shown that persistent posttreatment fatigue is associated with elevated markers of proinflammatory cytokine activity, along with observed alterations in the cellular immune system. This suggests a chronic inflammatory process, say the authors.

In this study, Dr. Bower and colleagues tested the hypothesis that activation of the proinflammatory cytokine network is associated with the fatigue experienced by patients with early-stage breast and prostate cancers who are undergoing radiation therapy.

Might Be Applicable to Other Cancers

The observational study included 28 patients with breast cancer and 20 patients with prostate cancer, and all participants completed questionnaires and provided blood samples to determine serum levels of IL-1β and IL-6 at assessments conducted before, during, and after a course of radiation therapy.

In a subset of patients, the researchers evaluated serum markers of proinflammatory cytokine activity, including IL-1 receptor antagonist and C-reactive protein.

As they anticipated, a strong link between radiotherapy treatment and fatigue was observed. There were also changes in serum levels of inflammatory markers C-reactive protein and IL-1 receptor antagonist, which were positively associated with increases in symptoms of fatigue (Ps < .05). However, no association between serum levels of IL-1β and IL-6 and fatigue was seen. These associations remained significant (Ps < .05), even after the researchers controlled for potential biobehavioral confounding factors such as sleep and depressive symptoms.

Although the cohort in this study was limited to patients with early-stage breast and prostate cancers, these findings could be applicable to other types of malignancies. "Inflammation is a non-specific response to radiation exposure, so it is very possible that the findings we observed in breast and prostate cancer patients might also apply to patients with other types of cancer undergoing radiation therapy," said Dr. Bower.

The study was supported by a Public Health Service from the National Cancer Institute, the California Breast Cancer Research Program, and an American Cancer Society Clinical Research Professorship to co-author Patricia A. Ganz. The authors have disclosed no relevant financial relationships.

Clin Cancer Res. 2009;15(17):OF1–7.

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