Relationship Between Mitochondrial Dysfunction and Fatique in Cancer Patients Following External Beam Radiation Therapy

Fatigue is a common early and chronic adverse effect of radiation but its correlates and
prevalence are poorly understood. Over 40% of cancer patients receive radiation therapy
during the management of their disease. While external beam intensity modulated radiation
therapy (EBRT/IMRT) successfully increases disease-free survival rates and life expectancy,
ionizing radiation leads to increased treatment-related adverse effects including fatigue.
Multidimensional causes and mechanisms of cancer-related fatigue remain unclear, and early
biomarkers prognostic for radiation-induced fatigue have not been identified.

There is evidence that an increase in reactive oxygen species (ROS) formation will cause
cellular damage resulting in dysfunction to mitochondria. ROS are considered one of the major
direct causes of ionizing radiation-induced damage, resulting in a number of adverse effects
(e.g. fatigue, nausea, vomiting, diarrhea, peripheral neuropathy, and cognitive function
impairment) that reduce the efficacy of treatment. Mitochondrial dysfunction is involved in
all clinical conditions including fatigue which are associated with the deficient energy
metabolism of oxidative phosphorylation. Mitochondria are vulnerable to ROS which are
generated endogenously (e.g. mitochondrial superoxide) and exogenously (e.g. ionizing
radiation, inflammation). Once mitochondrial proteins are damaged, the affinity of substrates
or enzymes is decreased resulting in mitochondrial dysfunction including reduced ATP
production, increased ROS generation, and initiated apoptosis signaling. While mitochondrial
dysfunction has been implicated in a variety of clinical fatigue states, the physiological
pathways and pathophysiological mechanisms are complicated and remain unclear.

The primary purpose of this study is to explore the relationships between mitochondrial
dysfunction and fatigue in prostate cancer patients receiving EBRT. Specific aims include:
(1) identify mitochondrial-related gene expression profile changes over time; (2) quantify
the severity of perceived fatigue before, during and at the end of radiation therapy; (3)
determine possible pathways and early biomarkers of mitochondrial dysfunction related to
fatigue in patients with prostate cancer receiving EBR. Blood samples and self-administrated
questionnaires are collected at baseline, midpoint and the end of EBRT. Human mitochondrial
PCR array will be utilized to identify differential regulation of genes involved in
mitochondrial dysfunction at the different time points compared with gene expression from the
baseline samples.

- INCLUSION CRITERIA:

1. Clinically localized prostate cancer;

2. 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 Androgen
Deprivation Therapy (ADT);

3. Able to provide written informed consent;

4. Men greater than or equal to 18 years of age;

5. Have enrolled in the study of molecular-genetic correlates of fatigue in cancer
patients receiving localized radiation therapy (09-NR-0088).

EXCLUSION CRITERIA:

A. Any condition other than prostate cancer able to cause 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:

1. Systemic infections (e.g., human immunodeficiency virus [HIV], active hepatitis);

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

3. Uncorrected hypothyroidism and anemia;

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

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

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