Accelerated Hypofractionation Radiotherapy for prostate cancer of 36.25 Gy delivered in 5 fractions will not be inferior to the standard treatment of 70.2 Gy given in 26 fractions with respect to four-year biochemical failure (PSA failure) by Phoenix definition post-treatment completion.

Inclusion Criteria:

1. Histologically proven prostate adenocarcinoma.

   • Gleason score 2-7 (reviewed by reference lab at UM).
   • Biopsy within one year of date of enrollment.

2. Clinical stage ≤ T2 based on DRE and/or ≤ T3a based on MRI (if done); N0-Nx; M0-Mx (AJCC 7th Edition)

   • T-stage and N-stage determined by physical exam and available imaging studies (CT, and/or MRI of the pelvis; see section 4.5). For MRI, questionable extracapsular extension is permitted. To distinguish blood from tumor the ideal study would be to acquire T2, T1 noncontrast and T1 dynamic contrast enhanced sequence, although this is not required. A small amount of extracapsular extension is permitted, as long as it can be included in the clinical target volume (CTV) and the constraints are met.
   • M-stage determined by physical exam, CT or MRI. Bone scan not required unless clinical findings suggest possible osseous metastases.

3. Prostate-Specific Antigen (PSA) < 20 ng/ml, obtained no greater than 3 months prior to enrollment.

4. Patients belonging in one of the following risk groups:

   • Low:

     • Clinical stage* T1-T2; Gleason ≤ 6, PSA ≤ 10 & <50% biopsy cores positive.

   • Intermediate:

     • Clinical stage T2b-T2c; Gleason ≤ 6, PSA ≤ 10 & <50% biopsy cores positive.
     • Clinical stage T1-T2; Gleason ≤ 6, PSA ≤ 10 & ≥50% biopsy cores positive.
     • Clinical stage T1-T2; Gleason = 7, PSA ≤ 10 & <50% biopsy cores positive or T1-T2; Gleason ≤ 6 & PSA >10 and < 20 & < 50% biopsy cores positive.
     • MRI stage T3a with evidence of extraprostatic extension is allowed.
     • Clinical stage is based on digital rectal exam (DRE). Seminal vesicle invasion on MRI is not eligible. T1a should be permitted if subsequent peripheral zone biopsies show tumor.

5. Prostate volume: ≤ 80 cc.

   • Determined using: volume = π/6 x length x height x width.
   • Measured from CT or MRI ≤90 days prior to enrollment.

6. Zubrod performance status 0-1.

7. No prior total prostatectomy or cryotherapy of the prostate.

   • Prior suprapubic prostatectomy, transurethral resection and laser ablation are permitted.

8. No prior radiotherapy to the prostate or lower pelvis.

9. No implanted hardware or other material that would prohibit appropriate treatment planning or treatment delivery, in the investigator's opinion.

10. No chemotherapy for a malignancy in the last 5 years.

11. No history of an invasive malignancy (other than this prostate cancer, or nonmetastatic basal or squamous skin cancers) in the last 5 years.

12. 4-6 months of androgen deprivation therapy (ADT) are allowed for intermediate risk patients. This must be declared prior to randomization. This may not have been started more than 2 months prior to randomization.

13. Patient must be able to have gold fiducial markers placed in the prostate (if on anticoagulants, must be cleared by a primary care physician or cardiologist), or if patient already has fiducial marker placed, they must be in accordance with the protocol specifications. Note: If a method of intrafraction prostate tracking is available which does not require fiducial markers, this will be adequate for this trial (i.e. fourth dimensional (4D) transperitoneal ultrasound, onboard MRI guidance).

14. Ability to understand and the willingness to sign a written informed consent document.

15. Willingness to fill out quality of life/psychosocial forms.

16. Age >= 35 and =< 85 years.

17. International Prostate Symptom Index (IPSS) (AUA) score ≤12

Exclusion Criteria:

1. Does not have a diagnosis of prostate adenocarcinoma.
2. Patient has clinical T3a or any evidence of T3b disease.
3. Patient has stage N1 or M1 disease.
4. Patients has a PSA of greater than 20 ng/ml, obtained no greater than 3 months prior to randomization.
5. Patient does not meet any of the risk groups outlined in section 3.1.4.
6. Prostate volume greater than 80 cc.
7. Zubrod performance status 2 or greater.
8. Prior total prostatectomy.
9. Prior radiation therapy to the prostate or lower pelvis.
10. Implanted hardware which limits treatment planning or delivery (determined by the investigator).
11. Chemotherapy within the past 5 years.
12. Diagnosis of an invasive malignancy within 5 years (other than current prostate cancer or non-metastatic basal or squamous skin cancers or non-metastatic curatively treated papillary thyroid carcinoma).
13. The use of more than 2 months of androgen deprivation therapy (ADT) prior to randomization, or plans for ADT to be continued for greater than 6 months.
14. Inability to have gold fiducial markers placed in the prostate, or fiducial markers already placed that are not in accordance with the protocol (Section 4.2.2). Note: If a method of intrafraction prostate tracking is available which does not require fiducial markers, this will be adequate for this trial (i.e. 4D transperitoneal ultrasound, onboard MRI guidance).
15. Unwilling or inability to give informed consent.
16. Not willing to fill out quality of life/psychosocial questionnaires.
17. IPSS score > to 12.
18. Age < 35 and > 85 years.