Fatigue was consistently the most-severe symptom over time for both colorectal and esophageal cancer patients treated with CXRT. Symptom severity consistently peaked around the end of treatment, as did serum sTNF-R1 and IL-6 levels. We identified significant temporal associations between the development of fatigue and increases in serum concentrations of sTNF-R1, and between the severity of a fatigue-centered symptom cluster and increased serum IL-6 and sTNF-R1. These effects could not be accounted for by patient and clinical factors, including age, sex, BMI, type of cancer, staging, or previous chemotherapy or statin use.
Our similar study in patients with non-small cell lung cancer receiving CXRT found that sTNF-R1 was associated with fatigue and other major symptoms (Wang et al., 2010
). Another study on radiation alone in breast and prostate cancers found that the downstream markers C-reactive protein and IL-1 receptor antagonist were significantly associated with fatigue (IL-6 and IL-1β were not) (Bower et al., 2009
). Yet another reported that both fatigue and serum IL-1β tended to rise between weeks 1–4 of radiation for prostate cancer (Greenberg et al., 1993
). Although these studies provide no direct evidence of the release of circulating inflammatory markers or angiogenesis with fatigue development, they consistently evidence the temporal association between fatigue and cytokines, receptors, and downstream markers as treatment dose accumulates. These data support our hypothesis that an over-expressed inflammatory response to CXRT may play a critical role in promoting a cluster of fatigue-centered, non-specific symptoms during and after treatment.
As a hypothesis-generating study, our work suggests several possible avenues for future research. First, there is no established animal model of fatigue. This study supports the establishment of an animal model of acute-phase, CXRT-related fatigue to confirm inflammatory mechanisms. A bedside-to-bench approach that utilizes direct evidence from human experience might confirm potential biomarker(s) that are highly relevant to fatigue-centered sickness symptoms.
Second, a causal link between serum inflammatory markers and symptom development cannot be established through discovery studies based on association only; it is possible that inflammation is simply a reflection of other biology that is the primary mechanistic driver of observed symptom and outcome phenomena. Thus, further research is required to explore exactly how inflammation markers may be common denominators mediating the hallmark symptoms of CXRT. Our results support the logical development of clinical trials incorporating concurrent symptom measurement and inflammatory cascade blockade to test pharmacological methods of mitigating symptom burden. In humans, an intervention study using a TNF-α inhibitor was reported to improve tolerability of dose-intensive chemotherapy (Monk et al., 2006
Finally, the longitudinal design and statistical analysis in this study are essential for modeling and interpreting the role of inflammation in dynamic symptom development. CXRT produces a large insult to the patient within an expected time frame, allowing an investigation of changes. Repeated measures allowed us to identify the emergence of fatigue and other symptoms, and that symptom severity peaked around the end of CXRT, after dose accumulation has ended, and returned to baseline by one month post-CXRT. This study illustrates how weekly patient-reported symptom data can quantitatively document treatment-related symptom burden over time. Mixed regression modeling is an appropriate approach for the examination of dynamic changes in multiple cytokine and receptor levels and symptom outcomes, and it effectively handles potential confounding factors and random missing data.
Our study had certain limitations. We designed the study to coincide with patients’ routine weekly blood-draw schedules, so as to reduce patient burden and the likelihood of missing data. Therefore, the timing of the blood draws may not have been optimal for assaying cytokines with a circadian pattern of release. The relatively high missing-data rate at baseline was resulted from limited feasibility of blood collection at enrollment; however, the blood collection rate one week after baseline provided sufficient marker data. Also, the blood draws may not have occurred on the same day as the scheduled weekly MDASI symptom assessment, although 85% of the time the two measures coincided. We also did not measure nuclear factor-kappa B or glucocorticoid signaling axes as potentially important upstream markers that might contribute to parallel mechanisms of fatigue development. Nevertheless, our results show highly consistent patterns over time in symptom development and change in sTNF-R1 and IL-6, with active control of potential covariates between subjects and with known noise from intraday and interday variability (which might explain the wide range in standard deviations on inflammatory markers in ).
In conclusion, the study provided a rationale for further study to confirm the role of sTNF-R1 and IL-6 in the development of chemoradiation-induced, fatigue-centered symptom burden in patients with cancer. These observations argue persuasively for a concerted effort toward reducing the multiple severe symptoms produced by aggressive therapy as an important component of standard care in the oncological management of gastrointestinal cancer, with the ultimate goal of better tolerance of therapy.
Identifying inflammatory markers (here, sTNF-R1 and IL-6) of chemoradiation-induced fatigue is a step toward confirming these biomarkers as a target for mechanism-based symptom management.