Proton Radiation Therapy for the Treatment of Patients With High Risk Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial investigates whether proton radiation therapy directed to the prostate tumor, pelvic, and para-aortic lymph nodes, is an effective way to treat patients with high-risk or lymph node positive prostate cancer who are receiving radiation therapy, and if it will result in fewer gastrointestinal and genitourinary side effects. Proton beam therapy is a new type of radiotherapy that directs multiple beams of protons (positively charged subatomic particles) at the tumor target, where they deposit the bulk of their energy with essentially no residual radiation beyond the tumor. By reducing the exposure of the healthy tissues and organs to radiation in the treatment of prostate cancer, proton therapy has the potential to better spare healthy tissue and reduce the side effects of radiation therapy.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To determine the rate of acute grade 2+ gastrointestinal toxicity compared to historical photon treatments. SECONDARY OBJECTIVES: I. To determine the rate of acute grade 2+ genitourinary toxicity compared to historical photon treatments. II. To assess the feasibility of extended-field proton irradiation of high-risk prostate. III. To demonstrate safety of proton therapy followed by high dose rate (HDR) boost. IV. To determine patient-reported outcomes (PROs) of toxicity. OUTLINE: Patients undergo conventionally fractionated proton beam therapy daily on Monday-Friday. Patients may receive a high-dose rate brachytherapy boost. After completion of study treatment, patients are followed up at 1, 3, 6, 9 and 12 months, and 1.5, 2, 2.5, and 3 years.

Official Title
-----------------
Extended-Field Lymph Node Proton Irradiation for High Risk Prostate Cancer

Conditions
-----------------
Stage III Prostate Cancer AJCC v8, Stage IIIA Prostate Cancer AJCC v8, Stage IIIB Prostate Cancer AJCC v8, Stage IIIC Prostate Cancer AJCC v8

Intervention / Treatment
-----------------
* Radiation: High-Dose Rate Brachytherapy
* Radiation: Proton Beam Radiation Therapy
* Other: Quality-of-Life Assessment
* Other: Survey Administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed high-risk prostate cancer fulfilling any one of the following criteria: Gleason grade 8 or higher cT3b (seminal vesicle involvement) or cT4 Prostate specific antigen [PSA] > 20 (or PSA >10 if on finasteride) Clinically or pathologically positive regional lymph nodes within the inguinal, external iliac, internal iliac, obturator, peri-rectal, pre-sacral, common iliac, or lower para-oaortc (inferior to the L2-L3 interspace) basins Zubrod performance status 0-2 Complete blood cell (CBC)/differential obtained within 90 days prior to registration on study Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 60 days prior to registration on study) Platelets >= 100,000 cells/mm^3 (obtained within 60 days prior to registration on study) Hemoglobin >= 8.0 g/dl (obtained within 60 days prior to registration on study) (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) Patient must be able to provide study specific informed consent Exclusion Criteria: Absence of bone metastasis by bone scan or metabolic imaging (e.g. NaF PET, FACBC PET, PSMA PET, etc.) within 90 days prior to registration. Absence of distant lymph node metastasis by CT and/or MRI within 90 days prior to registration. Previous radical surgery (prostatectomy) or cryosurgery for prostate cancer Prior radiotherapy, including brachytherapy, to the region of the study cancer that would result in overlap of radiation therapy fields Uncontrolled intercurrent illness including, but not limited to, inflammatory bowel disease, human immunodeficiency virus infection, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (proton beam therapy)<br>Patients undergo conventionally fractionated proton beam therapy daily on Monday-Friday directed to the prostate, pelvic lymph nodes, and para-aortic lymph nodes. Patients may receive an optional high-dose rate brachytherapy boost. Androgen deprivation therapy is required. | Radiation: High-Dose Rate Brachytherapy<br>* Receive high-dose rate brachytherapy boost<br>* Other names: Brachytherapy, High Dose;Radiation: Proton Beam Radiation Therapy<br>* Undergo proton beam therapy<br>* Other names: Radiation, Proton Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Survey Administration<br>* Ancillary studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute grade 2+ gastrointestinal (GI) toxicity | The rate of grade 2+ gastrointestinal toxicity within 30 days of receiving radiation therapy (RT) will be measured. It will be compared to the theorized reduction to 24% toxicity using the exact binomial test. Assessments are based on version 5 Common Terminology Criteria for Adverse Events (CTCAE), and the worst severity of GI toxicity will be assessed. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute grade 2+ genitourinary (GU) toxicity rate | The rate of grade 2+ genitourinary toxicity within 30 days of receiving radiation therapy (RT) will be measured. Assessments are based on version 5 CTCAE, and the worst severity of GU toxicity will also be assessed. | Up to 3 years | 
| Optimal frequency of cone beam computed tomography (CT) | Will determine the optimal frequency of cone beam CT during treatment and assess subsequent need for adaptive re-planning. The feasibility of extended-field proton irradiation of high-risk prostate cancer will be estimated using a re-planning rate of less than 10%. The re-planning rate will be estimated as binary variable, yes or no. The exact 95% confidence interval (CI) around the 10 % re-planning count based on the binomial distribution for the estimated 30 patients will be used (0.021-0.265). The study will be deemed feasible if the observed rate is not higher than the upper bound of the estimated 95% CI. | Through study completion, an average of 1 year | 
| Patient reported health related quality of life (QOL) - PRO-CTCAU GI | Assessed using Patient Reported Outcomes-CTCAE GI toxicity | Up to 3 years | 
| Patient reported health related quality of life (QOL) - PRO-CTCAU GU | Assessed using Patient Reported Outcomes-CTCAE GU toxicity | Up to 3 years | 
| Patient reported health related quality of life (QOL) - IPSS | International Prostate Symptom Score (IPSS) | Up to 3 years | 
| Patient reported health related quality of life (QOL) - EPIC-CP | Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) | Up to 3 years | 
| Chronic GI Toxicity | The rate of any grade gastrointestinal toxicity occurring after 90 days from the completion of radiation therapy(RT). Assessments are based on version 5 Common Terminology Criteria for Adverse Events (CTCAE), and the worst severity of GI toxicity will be assessed. | Up to 3 years | 
| Chronic GU Toxicity | The rate of any grade genitourinary toxicity occurring after 90 days from the completion of radiation therapy(RT). Assessments are based on version 5 Common Terminology Criteria for Adverse Events (CTCAE), and the worst severity of GU toxicity will be assessed. | Up to 3 years | 
| Biochemical failure | Assessed by the Phoenix definition (prostate specific antigen [PSA] >= 2 ng/ml over the nadir PSA). | Baseline up to pre-RT |