The objective of this phase I/II trial is to prospectively evaluate the toxicity and therapeutic efficacy of Stereostatic Body Radiation Therapy (SBRT) to prostate and pelvic lymph nodes in combination with high-dose-rate (HDR) brachytherapy to the prostate in patients with localized unfavorable-intermediate risk or higher disease.

Currently the practice of minimizing monetary and human costs of therapy in the field of oncology is in vogue. As such, there has been heightened interest in the ability to decrease the total number and duration of radiation therapy treatments via brachytherapy and stereotactic body radiation therapy (SBRT). With this, the use of SBRT has been increasingly utilized for elective nodal irradiation (ENI) to treat patients with intermediate-risk prostate cancer or higher to improve biochemical progression free survival (bPFS). However, there is a dearth of studies assessing the efficacy and toxicity profile of these two modalities in combination. The objective of this phase I/II trial is to prospectively evaluate the toxicity and therapeutic efficacy of SBRT to prostate and pelvic lymph nodes in combination with high-dose-rate (HDR) brachytherapy to the prostate in patients with localized unfavorable-intermediate risk or higher disease. We hypothesize that this combination therapy will have an acceptable toxicity profile and that ENI via SBRT will provide improved bPFS compared to no nodal treatment and synonymous with conventional fractionation. The sample size will be 53 patients, with biopsy confirmed unfavorable-intermediate or higher risk prostate cancer and ≥ 15% probability of nodal involvement as determined by publicly available nomograms. Eligible patients will undergo ultrasound-guided HDR brachytherapy to the whole prostate to a dose of 15 Gy in 1 fractions followed by SBRT to a dose of 25 Gy in 5 fractions given every other day. Follow-up will assess toxicity and biochemical progression-free survival and subsequent comparison to historical results.

Inclusion Criteria:

1. Histopathologically proven diagnosis of local unfavorable intermediate or higher risk prostate cancer as defined by NCCN risk group criteria. Biopsies will be confirmed by UNMC pathology review if collected outside our institution.
2. No prior definitive treatment or intervention received.
3. Life expectancy of more than 10 years as estimated by the treating physician.
4. Negative evaluation lymph node involvement or distant metastatic disease on abdominopelvic CT, prostate MRI, and/or PSMA PET.
5. Negative evaluation of osseous metastatic disease via bone scan or PSMA PET scan.
6. Greater than or equal to 15% nodal involvement risk predicated on publicly available MSKCC pre-prostatectomy nomogram.
7. Karnofsky performance status ≥ 80 within 30 days prior to registration.
8. Age ≥ 19 years.
9. Clinically determined to be a candidate for HDR brachytherapy.
10. Patient must be able to provide study-specific informed consent prior to study entry.

Exclusion Criteria:

1. American Urological Association Urinary Symptom Score (AUA score) ≥ 15.
2. Large prostate volume relative to pelvic arch width that can hinder proper placement of applicator insertion. To be done by MRI, TRUS, and/or physical exam for size, by CT A/P or MRI for arch interference. Specifically, prostates must be no greater than 75 cc in size as decerned by MRI, TRUS, or physical exam. Potential for pubic arch interference will be decerned by the treating radiation oncologist based on MRI and/or CT imaging.
3. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
4. Relative or absolute contraindications to radiation therapy as determined by the treating physician. These include, but not limited to, inflammatory bowel disease, connective tissue disorders (systemic lupus erythematosus, scleroderma, etc.), genetic disorders that risk increase sensitivity to radiation therapy.
5. Medical conditions that, in the opinion of the investigator could compromise patient safety.
6. Prior invasive malignancy other than prostate cancer (except non-melanomatous skin cancer) unless disease free for a minimum of 1 year.
7. History of rectal surgeries.
8. Recent major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to registration.
9. History of Urolift.
10. Contraindications to general anesthesia.
11. Preexisting rectal fistula.