Molecular-Genetic Correlates of Fatigue in Cancer Patients Receiving Localized External Beam Radiation Therapy

Although the underlying mechanisms of fatigue have been studied in several disease conditions
the data are not conclusive, and this symptom remains poorly managed at present. Longitudinal
studies related to treatment-related fatigue in prostate cancer patients have been conducted,
but there are limited studies exploring the changes in physiologic mechanisms before and
after radiotherapy which can identify individuals who are at risk for enduring fatigue during
and after therapy. Fatigue is conceptualized as a multidimensional symptom which incorporates
temporal, sensory, cognitive/mental, affective/emotional, behavioral, and physiological
dimensions. This prospective, observational study is the first study to explore the
molecular-genetic mechanisms underlying fatigue and the cluster of symptoms (urinary, sexual,
gastrointestinal, psychiatric) experienced by prostate cancer patients undergoing External
Beam Radiation Therapy (EBRT).

The primary objective of the study is to describe the changes in the self-reported fatigue;
urinary, sexual, and gastrointestinal symptoms; depression; fatigue catastrophizing; and
health-related quality of life (HRQOL) experienced by patients with and without prostate
surgery before, during, and after EBRT completion. The secondary objectives of this study are
to investigate the pro-inflammatory cytokine profile of EBRT-related fatigue (TNF alpha,
IGF-I, IL-6, IL-8, TGF alpha and beta), determine changes in white blood cell gene
expression, determine levels of oxidative stress and changes in potential biomarkers
influencing oxidative stress from blood and buccal and after EBRT completion and to relate
these changes in the levels of these biological markers to self-reported fatigue; urinary,
sexual, and gastrointestinal symptoms; depression; fatigue catastrophizing; and HRQOL scores.
This study also aims to measure the skeletal muscle strength, activity/fitness levels,
cognitive function and energy expenditure of patients before, at completion of EBRT, and at
least 6 months post EBRT and relate these findings with self-reported fatigue, physical
symptoms (e.g. urinary, gastrointestinal, and sexual functioning), depression, and HRQOL
scores before and after an exercise training program. The study also aims to describe changes
in chemical profile in the brain that are associated with changes in fatigue symptoms using
magnetic resonance spectroscopy before and after EBRT.

- INCLUSION CRITERIA:

To be included, patients must meet all of the following criteria:

- Clinically localized prostate cancer with or without prior prostatectomy;

- Scheduled to receive EBRT either by 3D conformal or IMRT techniques that is not
anticipated to change during the course of the study, with or without ADT;

- No known medical history of tuberculosis (TB);

- Able to provide written informed consent by passing at least 80% of the consent quiz;

- Men greater than or equal to18 years of age;

The control group must meet all the inclusion criteria mentioned above except for number 2.
The control group must not be receiving any form of treatment for their prostate cancer to
include hormone, immune, radiation, or chemotherapy.

EXCLUSION CRITERIA:

All participants with any one of the following criteria will be excluded:

Progressive or unstable disease of any body system causing clinically significant fatigue,
including cardiovascular, pulmonary, gastrointestinal, central nervous system, psychiatric,
endocrine, hematologic, renal, or immunologic disorders, and including patients with any of
the following broad disease categories:

- Systemic infections (e.g., human immunodeficiency virus (HIV), active hepatitis);

- Documented history of major depression, bipolar disease, psychosis, or alcohol
dependence/abuse within the past 5 years;

- Uncorrected hypothyroidism and anemia;

- Chronic inflammatory disease that may be anticipated to alter the proinflammatory
cytokine profile (i.e. rheumatoid arthritis, systemic lupus erythematosus, and
cirrhosis).

Patients taking tranquilizers, steroids, and nonsteroidal anti-inflammatory agents because
these medications are known to affect cytokine production;

Patients who have second malignancies or those receiving chemotherapy with their EBRT.

In addition to the above criteria, participants with the following conditions will be
excluded from participating in the exercise interventions:

1. Significant Restrictive or Obstructive Lung Disease

2. Ischemic heart disease

3. Left ventricular dysfunction with the ejection fraction less than 40 or a documented
pulmonary capillary wedge pressure greater than or equal to 18mmHg.

4. Acute corpulmonale

5. Cardiomyopathy (dilated, hypertrophic, or non-idiopathic)

6. Significant renal or hepatic dysfunction

7. Disabling stroke

8. Uncontrolled diabetes mellitus with a history of diabetic ketoacidosis

9. Mitochondrial disease

Participants unable to pass the English comprehension test will be unable to take the
Computer Assessment of Mild Cognitive Impairement (CAMCT) test but will be asked to
complete the other outcome measures of the study.

Self report of color-blindness, verified by taking the Ishihara card test and scoring
greater than 14 (more or less than 10 minutes), will exclude a participant from taking the
STROOP test, but will be asked to complete the other outcome measures of the study. This
card test will be administered only if the patient states they are color blind.