Understanding Post-Chemotherapy Fatigue and the Role of Anti-Inflammatory Treatment
Understanding Post-Chemotherapy Fatigue and the Role of Anti-Inflammatory Treatment
Abstracts & Commentary
By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: Fatigue occurs commonly in patients with cancer, particularly when receiving chemotherapy or radiation. Furthermore, in long term survivors, persistent fatigue occurs in up to one third. Although anemia is one contributing factor, fatigue certainly occurs in its absence as well. Two recent reports are reviewed, one addressing the mechanisms and biochemical markers of persistent fatigue, and the other introducing a novel therapeutic approach directed at chemotherapy-associated fatigue are reviewed. It is quite apparent that dysregulation of inflammatory mechanisms accounts for some component of fatigue and anti-inflammatory treatments may be of great value.
Sources: Collado-Hidalgo A, et al. Inflammatory biomarkers for persistent fatigue in breast cancer survivors. Clin Cancer Res. 2006;12:2759-2766; Monk JP, et al. Assessment of Tumor Necrosis Factor Alpha as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol. 2006;24:1852-1859.
Fatigue, both associated with chemotherapy administration and persistent thereafter has become a major concern for cancer patients. In fact, for breast cancer survivors it may occur in as many as 30% for as long as 5 years.1 Anemia is one major factor, particularly during treatment, but fatigue is also common in patients with normal hemoglobin levels, and for patients with anemia, it may persist after raising hemoglobin to normal or near normal levels. Thus, there has been an increased emphasis on understanding the cancer-fatigue syndrome and recent reports have shed some light.
Collado-Hidalgo and colleagues from UCLA have found elevated serum markers of proinflammatory cytokine activity in breast cancer survivors 3 to 5 years after completion therapy and in the absence of detectable residual disease.2,3 This group has gone on to describe biomarkers of dysregulated inflammation that may prove useful in both understanding the pathogenesis of persistent fatigue in cancer survivors and as a marker for which patients are likely to experience it. In the current report, leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and non-fatigued breast cancer survivors recruited > 2 years after successful primary therapy. Fatigued survivors were distinguished from non-fatigued survivors by increased monocyte production of IL-6 and TNF following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor, decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in the peripheral blood (all P < 0.05). Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69 + T lymphocytes as diagnostic of fatigue (P = 0.0005) with cross validation estimates indicating 87% classification accuracy (sensitivity = 83%, specificity = 83%).
In a separate report, Monk and colleagues from Ohio State University describe a pilot trial of etanercept (a TNF-decoy receptor) to combat the fatigue associated with dose-intensive chemotherapy. Initially, 12 patients with advanced malignancies were randomly assigned to docetaxel at 43 mg/m2 weekly (cohort A) or the same docetaxel dose plus added etanercept (25 mg subcutaneously, twice weekly) (cohort B). Subsequently, higher doses of docetaxel in combination with etanercept were evaluated. For those receiving added etanercept, escalation of docetaxel to 52 mg/m2 weekly resulted in neutropenia, not fatigue, as the limiting adverse effect and the addition of filgrastim permitted the maintenance of dose-intensity. Patients randomly assigned to receive etanercept/docetaxel self-reported less fatigue (P < 0.001), and the added etanercept was shown to have no influence on docetaxel pharmacokinetics.
Commentary
Dysregulated proinflammatory factors have been implicated in a wide range of clinical disorders and many of which are characterized by fatigue. During acute inflammation, cytokines such as IL-6, TNF and interferon have all been associated with constitutional symptoms including fever, malaise, cachexia, and profound fatigue. Cancer patients, by virtue of the inflammatory nature of the underlying disease, or by the pro-inflammatory consequences of chemotherapy and radiation, are particularly susceptible to cytokine dysregulation and its consequences. The interventional study of TNF blockade (by etanercept) as an adjunct to weekly docetaxel therapy is intriguing. Not only was fatigue less, but patients were able to tolerate higher doses and thereby, theoretically achieve more optimal responses.
Although it is unclear that persistent fatigue existent in cancer survivors long after completion of therapy (as many as 30% of breast cancer survivors) is of the same mechanism as that occurring in patients with active disease under treatment, it would seem probable that inflammatory mechanisms are also involved. Thus, long-term anti-inflammatory treatment (possibly with non-steroidal anti-inflammatory drugs, or even with parenteral more specific modulators such as etanercept) would seem worthy of clinical investigation in this setting.
References
1. Bower JE, et al. Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life. J Clin Oncol. 2000;18:743-753.
2. Bower JE, et al. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med. 2002;64:604-611.
3. Bower JE, et al. T-cell homeostasis in breast cancer survivors with persistent fatigue. J Natl Cancer Inst. 2003;95:1165-1168.
Fatigue occurs commonly in patients with cancer, particularly when receiving chemotherapy or radiation.Subscribe Now for Access
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