This phase II/III trial studies how well methylphenidate and exercise work in reducing cancer-related fatigue in patients with prostate cancer. Methylphenidate is a type of central nervous system stimulant that can improve cognitive ability, mainly in memory and cognitive function. Exercise can improve mood and the physical aspects of cancer-related fatigue. Giving methylphenidate in combination with exercise may work better in reducing cancer-related fatigue in patients with prostate cancer.

PRIMARY OBJECTIVE:

I. To determine if the combination of exercise (EX) plus methylphenidate (MP) is superior to exercise plus placebo in the treatment of cancer-related fatigue (CRF) in patients with prostate cancer scheduled to receive radiotherapy with androgen deprivation therapy for 12 weeks.

SECONDARY OBJECTIVE:

I. To determine the effects of combined exercise plus methylphenidate on quality-of-life, mood, physical, and cognitive measures.

EXPLORATORY OBJECTIVES:

I. To identify potential synergistic effects of exercise and methylphenidate in improvement of CRF.

II. To explore changes in brain activity by electroencephalography (EEG) in responders (with 4 point or greater change in Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] scores) versus (vs) non-responders to the intervention.

OUTLINE: Patients are randomized to 1 of 4 groups.

GROUP I: Patients receive methylphenidate orally (PO) twice daily (BID) and undergo exercise program consisting of resistance training twice weekly (BIW) and walking 15- 40 minutes a day 4 days a week for 12 weeks.

GROUP II: Patients receive a placebo PO BID and undergo exercise program consisting of resistance training BIW and walking 15-40 minutes a day for 4 days a week for 12 weeks.

GROUP III: Patients receive methylphenidate PO BID and undergo stretching for 4 days a week for 12 weeks.

GROUP IV: Patients receive a placebo PO BID and undergo stretching for 4 days a week for 12 weeks.

After completion of study treatment, patients are followed up at 3 months.

Inclusion Criteria:

• Have a diagnosis of prostate cancer and be scheduled to receive radiotherapy with concurrent androgen deprivation therapy, and presence of fatigue with severity of 1/10, on a 0-10 scale for at least 2 weeks
• Patient not regularly engaging in moderate aerobic exercise for >90 minutes/week and/or vigorous aerobic exercise for >30 minutes/week, and/ or strength training for >/= 1 day/week
• Have no clinical evidence of cognitive failure as evidenced by Memorial Delirium Assessment Scale score of </=13 at baseline
• Be aged 18 years or older
• Be willing to engage in follow-up telephone calls with a research staff
• Be willing to participate in the exercise programs
• Have telephone access so they can be contacted by the research staff
• Have a hemoglobin level of >/= 10 g/dL within 2 weeks of enrollment
• Be able to understand the description of the study and give written informed consent
• Have a Zubrod performance status score of 0 to 2
• Seen at an outpatient clinic at MD Anderson Cancer Center, its Houston Area Locations (HALs) or Smith Radiation Oncology Clinic (HHS)

Exclusion Criteria:

• Have a major contraindication to MethylphenidateMP) (e.g., allergy/hypersensitivity to study medications or their constituents), exercise (e.g., cardiac disease), or conditions making adherence difficult as determined by the attending physician
• Be currently taking MP, or have taken it within the previous 10 days
• Be unable to complete the baseline assessment forms (e.g., due to language or sensory barriers) or to understand the recommendations for participation in the study
• Need monoamine oxidase inhibitors, tricyclic antidepressants, or clonidine
• Have glaucoma
• Have severe cardiac disease (New York Heart Association functional class III or IV)
• Have tachycardia and/or uncontrolled hypertension
• Be currently receiving anticoagulants, anticonvulsants (phenobarbital, diphenylhydantone, primidone), phenylbutazone, and/or tricyclic drugs (imipramine, clomipramine, or desipramine).