This longitudinal study demonstrated, in response to accumulating combined radiation and chemotherapy in patients with NSCLC, (1) a significant worsening of symptom burden during CXRT that peaked at week 8; (2) a significant increase in serum IL-6, sTNF-R1, and IL-10 during 8 weeks of CXRT, perhaps as a result of tissue destruction; and (3) association between over-expressed serum concentrations pro-inflammatory cytokines (primarily sTNF-R1 and IL-6) and worsening treatment-related symptoms.
CXRT with systemic chemotherapy and a sufficient dose and volume of radiotherapy can control tumor recurrence and the spread to nearby lymph nodes in locally advanced NSCLC. Although many therapeutic strategies to relieve the acute complications of CXRT have been integrated into patient care (eg, anti-inflammatory agents, analgesics, hydration, nutrition) (Bradley et al., 2004
), we observed increase in both non-specific symptoms and treatment-related toxicities (Hickok et al., 2005
) during therapy for this cohort of patients with NSCLC. This was especially true for the most severe physical symptoms (pain, fatigue, lack of appetite, disturbed sleep, sore throat). The component score for total symptom burden (all 15 MDASI symptoms) increased gradually during CXRT, reached significant difference from baseline at week 4, peaked in severity after completion of therapy at week 8, and remained high for several more weeks, not returning to baseline severity until week 13. The results showing that symptoms peaked after treatment had ended could help to establish expectations of post-treatment symptom burden and highlight the need for more effective post-treatment symptom control.
Patients entering the study may already have been experiencing NSCLC-related symptoms; therefore, using their baseline symptom and cytokine assessments as the control for the study was an appropriate way to measure the effect of time (measured in weeks), and therefore the effect of accumulating chemoradiation dose, on the dynamic changes in patients’ CXRT-related symptom profiles. The results of this study add to the knowledge of aggressive therapy-induced dynamic changes in the quantitative relationship between symptom severity and inflammatory cytokines. Tests of the hypothesis that sickness behavior is induced by cytokine dysregulation have shown evidence of IL-6, IL-1RA, IL-1, TNF-α (Rube et al., 2002
), albumin (Meyers et al., 2005
; Schubert et al., 2007
), and neopterin (Bower et al., 2002
) in patients and survivors with cancer-related fatigue and in depressed patients (Miller et al., 2008
). The use of a TNF-α inhibitor has been reported to improve tolerability of dose-intensive chemotherapy in patients with cancer (Graham et al., 1999
Serum TNF-α was undetectable in this patient cohort. However, the serum concentrations of sTNF-R1 (which as a TNF-α receptor reflects serum TNF-α activity) were normally distributed and sufficiently robust to detect a significant week-by-week change, as shown in . There are several possible reasons that TNF-α was not detectable. First, TNF-α levels may have been affected by the prolonged hours associated with the sampling process in human cytokine studies (Schubert et al., 2007
), as TNF-α is known to be highly sensitive to sampling conditions (Thavasu et al., 1992
), Second, it is possible that the concentration of measurable free TNF-α in this cohort of patients actually was very low.
IL-6 was significantly associated with the most severe physical symptoms, but not all 15 symptoms, in this cohort of patients. This is consistent with another symptom study showing that serum IL-6 was highly correlated with a rapid increase in severe physical symptoms at white blood count nadir among cancer patients undergoing allogeneic stem cell transplantation (Wang et al., 2008
).Together, these studies further confirm the preliminary impression of the significant positive effect of IL-6 on cancer-related fatigue discussed in the quantitative review by Schubert and colleagues (Schubert et al., 2007
Disease-driven cytokine dysregulation has been recognized (Germano et al., 2008
), and reported as prognostic biomarker for poor clinical outcomes in cancer. In our study, baseline (pre-CXRT) serum concentrations of both IL-6 and sTNF-R1 were already higher than previously reported normal concentrations (Miles et al., 1992
; Preti et al., 1997
; Trikha et al., 2003
). Accordingly, the over-expression of serum cytokines during CXRT appears to have been induced by both cancer and aggressive cancer therapy. The cytokines selected for this study were common pro-inflammatory and anti-inflammatory cytokines that have been reported in animal sickness behaviors, such as IL-6, IL-1RA, TNF-α, and sTNF-R1. We also included IL-8, IL-10, and IL-12p40p70 because they have been investigated for predicting the effect and acute complications of radiation therapy in humans.
The therapeutic radiation dose to tumor was a relatively fixed factor in this study. However, the volume of tissue (including normal lung tissue) irradiated by at least 20 Gy (V20) varied by individual patient. A larger V20 score was associated with increased serum levels of sTNF-R1, and both a larger V20 score and an increased serum level of sTNF-R1 were associated with an increased risk for moderate to severe overall symptoms in these NSCLC patients undergoing CXRT.
The homogeneous sample, validated patient-reported outcome measure (MDASI), longitudinal design with both symptom and cytokine data collection, and mixed-effects statistical analysis in this study were essential for modeling and interpreting the role of cytokines in dynamic symptom development due to CXRT. Given the complexity of the role of inflammatory cytokines in both disease and symptom outcomes in cancer patients, we believe that mixed modeling, a statistical method that provides standardized coefficients (estimate scores), is an appropriate approach for the examination of dynamic changes in multiple cytokine levels and symptom outcomes. This method effectively handles missing data and controls for potential confounding (Fairclough and Wang, 2005
Our study had certain limitations. We designed our study to coincide with patients’ routine 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 and could have missed peak levels of cytokines with a circadian pattern of release, such as IL-6 and TNF-α. Also, the blood draws may not have occurred on the same day as the scheduled weekly symptom assessment, and a few samples, although kept on ice, were delayed up to 24 hours before being delivered to the research lab for processing; either of these situations could have introduced noise into the data. Further, because it was not feasible to require patients to return to the clinic for a research blood draw upon completion of therapy, we did not collect serum samples for cytokine analysis during the CXRT recovery phase. With 15 weeks of symptom data but only eight weeks of serum samples per patient, we could not establish whether serum levels of inflammatory cytokines declined after cessation of therapy (as did symptom severity) or model the association between multiple symptom burden and cytokine levels for the post-treatment period. Finally, we used sTNF-R1 as a substitute marker for TNF-α, which was our original target but was not detectible in our study. It is possible that a high-sensitivity TNF-α assay could have detected this cytokine without our having to resort to a substitute. Nonetheless, we are satisfied that measuring sTNF-R1 was an appropriate method for assessing the significant effect of tumor necrosis factor.
In conclusion, the current study provides evidence that over-expressed sTNF-R1 is positively associated with the amount of lung tissue irradiated (indicated by V20) and with a rapid increase in overall symptom burden, and that over-expressed IL-6 is associated with increase in the most severe physical symptoms in response to accumulated radiation plus chemotherapy, an aggressive cancer treatment for NSCLC. This inflammatory response may underlie the development of multiple co-occurring CXRT-induced sickness symptoms and, if so, it could provide a target for effective symptom management that focuses on the inflammation pathway to help patients with NSCLC better tolerate their curative therapy.