Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.

CCR-08-2584

Imaging, Diagnosis, Prognosis

Inflammatory Biomarkers and Fatigue during Radiation Therapy for

Breast and Prostate Cancer
Julienne E. Bower,1,2,3,4 Patricia A. Ganz,4,5 May Lin Tao,9 Wenhua Hu,10 Thomas R. Belin,8
Saviz Sepah,1 Steve Cole,3,6 and Najib Aziz7

Abstract Purpose: Biomarkers of radiation-induced behavioral symptoms, such as fatigue, have not
been identified. Studies linking inflammatory processes to fatigue in cancer survivors led
us to test the hypothesis that activation of the proinflammatory cytokine network is asso-
ciated with fatigue symptoms during radiation therapy for breast and prostate cancer.
Experimental Design: Individuals with early-stage breast (n = 28) and prostate cancer
(n = 20) completed questionnaires and provided blood samples for determination of
serum levels of interleukin 1β (IL-1β) and IL-6 at assessments conducted before, during,
and after a course of radiation therapy. Serum markers of proinflammatory cytokine
activity, including IL-1 receptor antagonist and C-reactive protein, were examined in
a subset of participants. Random coefficient models were used to evaluate the associ-
ation between changes in cytokine levels and fatigue.
Results: As expected, there was a significant increase in fatigue during radiation treat-
ment. Changes in serum levels of inflammatory markers C-reactive protein and IL-1 recep-
tor antagonist were positively associated with increases in fatigue symptoms (Ps < 0.05),
although serum levels of IL-1β and IL-6 were not associated with fatigue. These effects
remained significant (Ps < 0.05) in analyses controlling for potential biobehavioral con-
founding factors, including age, body mass index, hormone therapy, depression, and
sleep disturbance.
Conclusions: Results suggest that activation of the proinflammatory cytokine network
and associated increases in downstream biomarkers of proinflammatory cytokine activ-
ity are associated with fatigue during radiation therapy for breast and prostate cancer.
(Clin Cancer Res 2009;15(17):5534–40)

There is considerable interest in the identification of clinical repair, which includes induction of nuclear factor κB activity
biomarkers associated with radiation therapy and their role and up-regulation of proinflammatory cytokines (2–4). Clinical
in clinical outcomes (1). Exposure to radiation initiates a reports have shown elevations in circulating levels of proin-
programmed molecular and cellular response to promote tissue flammatory cytokines during radiation therapy; in some cases,
these are associated with treatment-related toxicities such as ra-
diation pneumonitis in lung cancer (5) and acute proctitis in
Authors' Affiliations: 1 Department of Psychology; 2 Department of prostate cancer (6). However, the role of proinflammatory cy-
Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine; tokines in behavioral toxicities associated with radiation thera-
3
Cousins Center for Psychoneuroimmunology, Semel Institute for py has not been determined.
Neuroscience; 4 Division of Cancer Prevention and Control Research, Fatigue is increasingly recognized as one of the most com-
Jonsson Comprehensive Cancer Center; 5Schools of Medicine and Public
Health; 6 Department of Medicine; 7 Department of Pathology and
mon and disabling side effects of radiation and other cancer
Laboratory Medicine; 8Department of Biostatistics, University of California treatments (7). However, the etiology of cancer-related fatigue
at Los Angeles, Los Angeles, California; 9Epic Care, Pleasant Hill, California; is poorly understood. Although biological [e.g., hemoglobin,
and 10Bristol Myers-Squibb, Wellingford, Connecticut albumin (8, 9) and psychological (e.g., depression (10)] cor-
Received 10/6/08; revised 5/7/09; accepted 6/8/09; published OnlineFirst
relates of fatigue have been identified, these factors are not
8/25/09.
Grant support: Supported by Public Health Service grant K07-CA90407 consistently associated with fatigue and do not fully explain
from the National Cancer Institute, NIH, Department of Health and Human the occurrence of fatigue in cancer populations. Basic research
Services; the California Breast Cancer Research Program; and an American on neuroimmune interactions has shown that proinflammatory
Cancer Society Clinical Research Professorship (P.A. Ganz). cytokines can signal the central nervous system to generate
The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement
fatigue and other behavioral changes (11). In cross-sectional
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. studies conducted with breast cancer survivors, we have shown
Requests for reprints: Julienne E. Bower, Department of Psychology, that persistent posttreatment fatigue is associated with
University of California at Los Angeles, Box 951563, 1285 Franz Hall, Los elevations in markers of proinflammatory cytokine activity
Angeles, CA 90095-1563. Phone: 310-825-3004; Fax: 310-206-5895; E-mail:
[email protected].
and alterations in the cellular immune system, suggesting a
F 2009 American Association for Cancer Research. chronic inflammatory process (12–14). Of note, most women
doi:10.1158/1078-0432.CCR-08-2584 in these studies received radiation therapy, often combined

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 Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-08-2584

Inflammation and Fatigue during Radiation Therapy

because of concerns about blood draws, time demands, or general lack

Translational Relevance of interest, and three withdrew within 2 wk after treatment onset. Thus,
the final sample for these analyses included 48 patients (n = 28 breast
Behavioral symptoms are increasingly recognized cancer patients, n = 20 prostate cancer patients). The University of
as a common and disabling side effect of cancer California at Los Angeles Institutional Review Board approved the
treatment. Understanding the etiology of these study procedures, and written informed consent was obtained from
all participants.
symptoms and developing targeted therapies is crit-
Procedures. Potential participants were screened for eligibility dur-
ical for improving treatment adherence and overall ing initial consultations at the University of California at Los Angeles
quality of life. This work provides insight into the Radiation Oncology Clinic. After determination of eligibility, subjects
biological mechanisms underlying radiation-induced completed a baseline assessment before treatment onset. Patients with
fatigue and suggests potential avenues for treat- localized breast and prostate cancer typically receive radiation therapy
ment, including use of cytokine antagonists. 5 d per week, Monday through Friday, for a 6- to 8-wk course of treat-
ment. Study assessments were conducted at specific points in the treat-
ment trajectory: after 5 d of treatment, after 10 d of treatment, after 20 d
of treatment, during the final week of treatment, and at two regularly
with chemotherapy or endocrine therapy. Similar findings have scheduled follow-up visits targeted at 2 wk and 2 mo after treatment
been observed by other investigators (15, 16). These studies completion. This intensive assessment schedule was designed to capture
provide preliminary evidence for a role of proinflammatory the initial increase and peak in fatigue symptoms that have been ob-
cytokines in cancer-related fatigue, but the role of cancer served in previous research (21–24), as well as the initial inflammatory
treatment in initiating these dynamics remains unclear. response to treatment and the more persistent effects of daily radiation
To determine whether radiation-induced inflammation therapy on inflammatory markers.
might contribute to cancer-related fatigue, this study tested Assessments were scheduled to coincide with treatment appoint-
ments and thus did not occur at the same time of day for all partici-
the hypothesis that elevations in circulating levels of proin-
pants; however, appointments for individual participants typically did
flammatory cytokines would be associated with fatigue symp-
occur at the same time of day. At each assessment, subjects completed
toms during radiation treatment for breast and prostate
self-report questionnaires and provided blood samples for immune
cancer. A handful of previous reports on this topic have analysis. Assessments were not conducted on weeks when participants
yielded mixed results (17–20), possibly because of constraints reported an active illness or infection.
of the respective study designs (e.g., small sample sizes, use of Measures. Fatigue was assessed using the Fatigue Symptom Inven-
nonstandard measures to detect cytokine levels) and the focus tory, a 14-item measure that assesses fatigue frequency, severity, and in-
on cross-sectional associations between cytokine levels and terference with daily functioning during the past week (25). The Fatigue
fatigue, which may not adequately capture the dynamic Symptom Inventory was specifically designed to assess fatigue in cancer
changes that occur in these systems over the course of treat- populations, has acceptable psychometric properties, and is responsive
ment. In the current study, random coefficient models were to cancer treatments, including radiation therapy (21). We focused on
used to examine within-subject relationships between inflam- two dimensions of fatigue: severity and duration. Fatigue severity is mea-
sured by the item “Rate your level of fatigue on the day you felt most
matory markers and fatigue assessed at multiple times before,
fatigued in the last week,” scored on a 11-point scale ranging from “not
during, and after treatment. We focused on changes in two at all fatigued” to “as fatigued as I could be.” Fatigue duration is mea-
proinflammatory cytokines, interleukin 1β (IL-1β) and IL-6, sured by the item “Indicate how many days in the last week you felt fa-
which have been identified as key mediators of neuroimmune tigued for any part of the day,” scored on an eight-point scale ranging
interactions. In addition, we examined changes in IL-1 recep- from 0 to 7 d. Higher scores on both dimensions indicate greater fatigue.
tor antagonist and C-reactive protein (CRP) in a subset of Two other cancer-related behavioral comorbidities were assessed that
study participants as a secondary study aim. These markers may confound associations between inflammatory markers and fatigue.
were of interest because they provide a measure of the cumu- Sleep problems were assessed using the Medical Outcomes Study Sleep
lative activity of IL-1β and IL-6, respectively, and have been Scale, a 12-item measure that assesses important dimensions of sleep,
correlated with posttreatment fatigue in our research with including sleep initiation, maintenance, and quantity; perceived ade-
quacy of sleep; respiratory problems; and somnolence (26). This scale
cancer survivors (12).
has been validated in the general U.S. population and among chroni-
cally ill individuals (26), and has also used in our previous research
Materials and Methods with cancer patients (27). Depressed mood was assessed using the Cen-
ter for Epidemiologic Studies–Depression scale, a 20-item measure with
Participants. Patients with breast or prostate cancer who were excellent reliability and validity designed to assess depressive symptom-
scheduled to receive external beam radiation therapy were recruited atology in the general population (28). Demographic and medical vari-
from the University of California at Los Angeles Radiation Oncology ables were assessed by self-report questionnaire and validated by review
Clinic. Patients were eligible for study participation if they met the fol- of medical records.
lowing criteria: (a) age of 25 to 75 y, (b) newly diagnosed with local- Inflammatory markers. Serum samples were separated according to
ized breast cancer (stage 0, I, or II) or prostate cancer (T1-T3, N0, M0), standard procedures and stored at -70°C for subsequent batch testing.
(c) external beam radiation therapy as part of the primary treatment Serum levels of IL-1β and IL-6 cytokines were measured using Quanti-
plan, (d) completion of definitive primary surgery (for breast cancer kine High Sensitivity Immunoassay kits (R&D Systems). Serum levels of
patients), and (e) ability to read and write English. Exclusion criteria IL-1 receptor antagonist and CRP were measured in a subset of study
included (a) recurrent cancer, (b) previous or planned treatment with participants (n = 12 breast cancer patients, n = 10 prostate cancer pa-
chemotherapy, and (c) regular use of immunosuppressive medication tients) with Quantikine Immunoassay kits for IL-1 receptor antagonist
or tobacco. (R&D Systems) and high sensitivity Immunodiagnostik kits for CRP
Of the 107 patients screened for study eligibility, 41 were not eligible (ALPCO Diagnostics). These assays were conducted as part of an initial
because of medical conditions (e.g., previous cancer treatment) or use validation study designed to identify inflammatory responses to treat-
of tobacco. Fifteen patients were eligible but refused participation ment. The measurement of cytokine levels was done according to the

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 Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-08-2584

Imaging, Diagnosis, Prognosis

Table 1. Demographic characteristics of study participants

Characteristic Breast cancer (n = 28) Prostate cancer (n= 20)

Mean age, y (range) 57.1 (29-75) 70.6 (54-79)

Ethnicity
White 20 12
Hispanic 1 2
African American 2 4
Asian 3 2
Other 2 0
Married/committed relationship
Yes 16 16
No 12 4
Education status
High school graduate 9 8
College graduate 11 7
Graduate degree 8 5
Employment status
Employed full or part time 15 8
Homemaker or student 4 0
Retired 7 11
Unemployed or medical leave 2 1
Yearly income*
≤$45,000 4 4
$45,000-$100,000 8 8
≥$100,000 14 7
Mean radiation dose, Gy (range) 5796 (5040-6640) 7165 (4500-7560)

*Numbers based on available data.

manufacturer's instructions. Quality control procedures for our labora- Complete data for the primary study variables (i.e., fatigue, IL-1β,
tory were conducted in the manner reported by Aziz et al. (29, 30). The IL6) were available for all 48 participants at baseline and week 1, for
intra-assay precision of all tests was ≤15% for in-house quality control 46 participants at weeks 2 and 4, for 45 participants at week 3 and 2
samples. All samples for a given participant were run in parallel to min- weeks post-tx, and for 41 participants at 2 months post-tx. Missing va-
imize interassay variability. lues were primarily due to problems with blood draws, participant ill-
The lower limit of assay detection in our laboratory is 0.02 pg/mL for ness, or scheduling difficulties (e.g., subject changed appointment time
IL-1β, 0.025 pg/mL for IL-6, 0.20 mg/L for CRP, and 14 pg/mL for IL-1 without notifying research assistant). In addition, three of the prostate
receptor antagonist. Of the 319 samples collected for IL-1β and IL-6, cancer patients began brachytherapy after their first posttreatment
25 (13%) were undetectable for IL-1β and assigned a score of 0. None
of the samples were below the lower limit of detection for IL-6. Of the
143 samples collected for IL-1 receptor antagonist and CRP, none were
below the lower limit of detection.
Statistical analyses. Analyses were conducted using random coeffi-
cient models (Hierarchical Linear Modeling 6.04; ref. 31) to account for
correlated measures on individuals over time. To evaluate changes over
time in fatigue and inflammatory markers, we first fit models testing
linear (days since treatment start) and quadratic (days since treatment
start squared) trends. Next, we fit models to test the hypothesis that
increases in proinflammatory cytokines and markers of inflammatory
cytokine activity would be associated with increases in fatigue during
treatment. The study was conceived as a two-level nested design, with
time (level 1) nested within subjects (level 2). Fatigue and inflamma-
tory markers were measured at level 1. Demographic and biobehavioral
variables that may impact inflammation and fatigue were examined as
potential confounding factors. These included depressive symptoms
and sleep disturbance (measured at level 1), as well as age, body mass
index, and use of hormone therapy (measured at level 2). Breast and
prostate cancer patients were combined in analyses, with preliminary
analyses incorporating a moderating effect of gender (level 2) that
was omitted from final models because of lack of significance. Predictor
variables were grand-mean centered, which enabled us to determine
how deviations from the average score on a particular predictor variable
were associated with changes in the outcome variable. Because their dis-
Fig. 1. Fatigue symptoms during radiation therapy. There was a significant
tributions were clearly nonnormal and highly skewed, all inflammatory increase in number of days fatigued in breast and prostate cancer
marker measures were transformed before analyses using a log transfor- patients during treatment, followed by a decrease in fatigue after treatment
mation. All tests of statistical significance were two sided. completion.

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Inflammation and Fatigue during Radiation Therapy

follow-up appointment and were withdrawn from the study before the an inverted-U shape consistent with the negative quadratic co-
second follow-up. efficient. These results indicate an increase in fatigue over the
course of treatment, followed by a decline in the posttreat-
Results ment period, consistent with previous research (22, 23).
For the inflammatory markers, there was a significant qua-
Demographic characteristics of study participants are re- dratic trend for IL-1β (β = -0.002; SE = 0.001; P = 0.034),
ported in Table 1. Twenty-six women in the current sample significant linear (β = 0.11; SE = 0.04; P = 0.007) and quadratic
had undergone lumpectomy before study enrollment, and (β = -0.006; SE = 0.002; P = 0.003) trends for IL-6, and a mar-
two women had undergone mastectomy with immediate recon- ginally significant quadratic trend for CRP (β = -0.004; SE =
struction. Nine of the prostate cancer patients were treated with 0.002; P = 0.079); see Fig. 2 for box plots of cytokine responses
hormone therapy, and one breast cancer patient was treated to treatment on the untransformed scales of the original mea-
with tamoxifen during radiation therapy. surements. These results indicate an increase in IL-6 levels dur-
Changes in fatigue and proinflammatory cytokines during ing treatment, with a decline by 2 months posttreatment, and
treatment. Random coefficient models were used to evaluate a plateau in levels of IL-1β and CRP, followed by a general
changes in fatigue and serum inflammatory markers over the decrease over time. There were no significant time trends for
course of radiation treatment. There was a significant linear IL-1 receptor antagonist. Unlike the relatively stable plasma
(β = 0.24; SE = 0.07; P = 0.001) and quadratic (β = -0.013; biomarkers of cumulative cytokine activity (IL-1 receptor antag-
SE = 0.004; P = 0.001) trend for fatigue duration and a signif- onist and CRP), instantaneous levels of IL-1β and IL-6 showed
icant quadratic trend for fatigue severity (β = -0.008; SE = substantial intraindividual fluctuation.
0.003; P = 0.024). Figure 1 plots the number of days fatigued Although this was a relatively homogenous patient popula-
in breast and prostate cancer patients, both of which exhibit tion, there was variability in the total dose of radiation received

Fig. 2. Circulating inflammatory markers during radiation therapy. Box-and-whisker plots represent data with boxes ranging from the 25th to the 75th
percentile of the observed distribution of values. Horizontal lines, the median value for serum levels of IL-1B (A), IL-6 (B), CRP (C), and IL-1 receptor
antagonist (D). Whiskers span minimum to maximum observed values, with algorithm-defined outliers identified by open circles and stars.

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Imaging, Diagnosis, Prognosis

tigue on weeks when CRP was elevated. This association is illus-

trated in Fig. 3, which shows fatigue and CRP data from two
representative study participants. The association between
CRP and number of days fatigued remained significant in anal-
yses controlling for sleep disturbance and depressive symp-
toms, although each of these variables was independently
associated with fatigue (for Center for Epidemiologic Studies–
Depression, P < 0.0001; for Medical Outcomes Study sleep, P =
0.093). In addition, this association remained significant in
analyses controlling for age, body mass index, and hormone
therapy.
Increases in circulating levels of the IL-1β exposure bio-
marker IL-1 receptor antagonist were associated with increases
in fatigue severity (β = 0.63; SE = 0.26; P = 0.016.). Partici-
pants reported experiencing more severe fatigue on weeks
when IL-1 receptor antagonist was elevated. This association
remained significant after controlling for sleep and depressive
symptoms, both of which were associated with fatigue (for
Center for Epidemiologic Studies–Depression, P = 0.001; for
Medical Outcomes Study sleep, P < 0.0001), and after control-
ling for age, body mass index, and hormone therapy. Of note,
neither IL-1 receptor antagonist nor CRP was independently
associated with depressive symptoms, although increases in
circulating levels of IL-1 receptor antagonist were associated
with greater sleep disturbance.

Discussion
This study was designed to identify mechanisms of fatigue in
cancer patients undergoing radiation therapy, focusing on in-
flammatory processes. Although there was no evidence for an
association between fatigue and the proinflammatory cytokines
IL-1β and IL-6, results did support an association between fa-
tigue and downstream biomarkers of cytokine activity. In par-
ticular, increases in circulating levels of the IL-6 cumulative
exposure biomarker CRP and the IL-1β cumulative exposure
Fig. 3. Association between CRP and fatigue symptoms. Representative biomarker IL-1 receptor antagonist were associated with in-
data from two participants showing that, on weeks when serum levels of creased frequency and severity of fatigue symptoms. These ef-
CRP were elevated, there was a corresponding elevation in the number of
days fatigued.
fects could not be accounted for by other variables, including
age, body mass index, depressed mood, or sleep disturbance.
As noted above, circulating levels of IL-1β and IL-6 were not
associated with fatigue in this sample. Proinflammatory cyto-
(see Table 1). A higher dose of radiation was associated with kines are typically produced locally and in small quantities,
significantly higher levels of IL-6 and CRP over the assessment and can be difficult to detect in serum. In contrast, CRP and
period (Ps < 0.05), consistent with a causal effect of radiation IL-1 receptor antagonist are produced in larger quantities as
exposure on production of IL-6 and associated markers. Treat- acute phase proteins by the liver and can often be quantified
ment dose was not associated with levels of IL-1β or IL-1 recep- more reliably than the cytokines that induce their production;
tor antagonist. they may also provide a more accurate reflection of cytokine
Association between fatigue and proinflammatory cytokines. activity (32). Thus, downstream markers such as CRP and
Random coefficient models were used to examine the associa- IL-1 receptor antagonist may be more reliable and sensitive in-
tion between proinflammatory cytokines and fatigue. There was dicators of systemic inflammation, facilitating the detection of
no evidence that changes in serum levels of IL-1β or IL-6 were relationships with behavioral states. Indeed, our research with
associated with changes in fatigue severity or duration over the breast cancer survivors has shown elevations in stable plasma
assessment period (all Ps > 0.30). markers of cumulative cytokine activity (e.g., IL-1 receptor antag-
Association between fatigue and markers of proinflammatory onist) among patients with posttreatment fatigue but no differ-
cytokine activity. As a secondary study aim, we examined the ences in noisier instantaneous plasma cytokine levels (e.g., IL-1β
association between serum markers of cytokine activity and fa- and IL-6; refs. 12, 13). Of note, inflammatory biomarkers were
tigue in a subset of study participants. Increases in circulating assessed in a subset of participants in the current study; thus,
levels of the stable IL-6 biomarker CRP were significantly asso- our significant results should be viewed as having been derived
ciated with increases in fatigue duration (β = 0.32; SE = 0.14; from secondary data analysis and as such would benefit from
P = 0.022). Participants reported experiencing more days of fa- confirmation in other settings.

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Inflammation and Fatigue during Radiation Therapy

Previous studies investigating the association between fatigue; for example, we have shown an association between cy-
proinflammatory cytokines and fatigue in cancer patients dur- tokine gene polymorphisms and persistent fatigue in breast
ing radiation therapy have yielded mixed results (17–20). Our cancer survivors (37), and between neuroendocrine function
trial differs from earlier research because we included more and fatigue in this population (38–40). Identifying risk factors
frequent assessments, used random coefficient models to ex- for cytokine-induced fatigue and determining the neural sub-
amine within-subject associations between cytokines and fa- strates of this symptom are important topics for future research.
tigue, and assayed markers of inflammatory activity in In addition, insight into the mechanisms responsible for inducing
addition to proinflammatory cytokines. This more intensive fatigue would benefit from further research wherein exposures af-
approach to intraindividual measurement and analysis may fecting inflammatory processes are under experimental control.
provide greater resolution of relationships between inflamma- The identification of inflammatory processes as potential
tion and fatigue. Future research may benefit from inclusion mediators of radiation-induced fatigue has important treatment
of systemic markers of inflammatory activity and use of statis- implications for cancer patients. Initial trials with cytokine an-
tical methods that account for correlated measures on indivi- tagonists have shown beneficial effects on fatigue (41), includ-
duals over time. In addition, if the goal is to capture the ing trials conducted with cancer patients designed to improve
dynamic response of the immune system to radiation, it the tolerability of chemotherapy (41, 42). Although these
may be necessary to conduct even more frequent blood draws agents have not yet been investigated in patients undergoing ra-
(e.g., daily blood sampling). diation therapy, they may be indicated if fatigue is of sufficient
The pattern of results observed in this study suggests that in- severity to merit discontinuation of treatment, leads to signifi-
flammatory processes play a role in radiation-induced fatigue, cant decrements in quality of life, and/or persists for months or
although the observational nature of the study design precludes years after treatment completion.
conclusions about the causal nature of this association. Induc-
tion of proinflammatory cytokines in the periphery is known to Disclosure of Potential Conflicts of Interest
induce production and release of cytokines in the central ner-
vous system (33), which have a host of effects on brain func- No potential conflicts of interest were disclosed.
tion. Persistent exposure to cytokines can produce changes in
neural activity (34, 35), similar to effects seen with glucocorti- Acknowledgments
coids (36); if these neural changes persist, they might account
for the chronic posttreatment fatigue observed in a subgroup of We thank Drs. William McBride, Mark Litwin, Tony Butch, and John L.
Fahey for their contributions to this study, Dr. Michael Irwin for his com-
cancer survivors (27). Host factors may also play an important ments on an earlier draft of this manuscript, and Dr. Guy Juilliard and other
role in determining the extent and duration of inflammatory physicians and staff at the Radiation Oncology Clinic for their assistance
processes in cancer patients and associated symptoms of with patient recruitment and data collection.

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Inflammatory Biomarkers and Fatigue during Radiation

Therapy for Breast and Prostate Cancer
Julienne E. Bower, Patricia A. Ganz, May Lin Tao, et al.

Clin Cancer Res 2009;15:5534-5540. Published OnlineFirst August 25, 2009.

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