Relationship Between Mitochondrial Dysfunction and Fatique in Cancer Patients Following External Beam Radiation Therapy
Condition: Cancer; Fatigue
MeSH terms: Fatigue
Study type: Observational

Summary: 
      Background:

      - Fatigue is a very common early and late side effect of cancer treatment, including
      radiation therapy. The cause of fatigue is poorly understood, making it hard to diagnose and
      treat. More research is necessary to understand why patients receiving cancer treatment
      experience fatigue. Changes in mitochondria, parts of body cells that help provide energy to
      the cell, may contribute to fatigue. Researchers are interested in looking at blood chemicals
      and mitochondrial genes of cancer patients to study those associated with fatigue.

      Objectives:

      - To study the relationship between fatigue and the effects of cancer treatment.

      Eligibility:

        -  Men at least 18 years of age who have been diagnosed with localized prostate cancer and
           are scheduled to receive external beam radiation therapy.

        -  Participants on study 09-NR-0088, Molecular-Genetic Correlates of Fatigue in Cancer
           Patients Receiving External Beam Radiation Therapy, are also eligible.

      Design:

        -  This study requires three outpatient visits to the NIH Clinical Center.

        -  Participants will be seen before they start radiation treatment, at the middle of
           treatment, and at the end of treatment. Each visit will take less than 30 minutes to
           complete.

        -  Participants will complete questionnaires that ask about fatigue and depression.

        -  Participants will provide blood samples for research testing and potential HIV testing.

        -  No treatment will be provided as part of this protocol.
    

Detailed description: 
      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.
    

Time perspective: Prospective
Keywords: Fatigue; Mitochondria; Mitochondrial Abnormality; Oxidative Stress; Gene Expression; Prostate Cancer