Stereotactic Ablative Radiotherapy (SABR) for Low Risk Prostate Cancer With Injectable Rectal Spacer

Study Overview
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Brief Summary
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The purpose is to determine if use of rectal spacers are effective at improving protection of rectum from high dose radiation, using rate of rectal ulceration as a surrogate measure of acute effects. It is also to determine whether it provides sufficient dosimetric benefits to warrant further clinical investigation in future SABR (Stereotactic Ablative Body Radiation) related clinical studies.

Detailed Description
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A phase II study to assess safety and efficacy of the spacer injection process, ability of the spacer to effectively provide the space necessary to reduce acute events in the rectum, and also meet the SABR based rectal constraints, and to monitor stability of this process during SABR. Unlike IMRT, which uses smaller dose/fraction, when using such high dose/fraction, even a few mm of shift in spacer positioning may impact the dose that the rectum receives, and therefore, a rigorous study of stability of material during the SABR treatments will need to be determined. If there is some shift, by doing this study, we may be able to determine the margin of error that will be necessary in considering rectal organ dosimetry, based on the possible shift in positiong that may occur with the spacer over time. As the SABR therapy is strictly local, we will select for patients with prostate cancer locally confined to the prostate gland. As such, we will select eligibility criteria of low risk patients to minimize risk of extraprostatic spread, seminal vesicle invasion, and nodal spread. Hormonal therapy may also be used to shrink prostates that are massively enlarged as this may also help further reduce length of rectum that will be irradiated. As the primary toxicity will likely be mucosal damage, we will avoid enrolling patients with pre-existing mucosal dysfunction (including those with previous radiation, TURP, very large prostate glands, inflammatory bowel disease) and immunosuppressed individuals based on our phase I experience[13]. In this way, patients will be uniformly selected in a fashion that would identify patients likely to receive benefit from the therapy.

Official Title
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Phase II Study of Stereotactic Ablative Radiotherapy (SABR) for Low Risk Prostate Cancer With Injectable Rectal Spacer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Device: Injectable Rectal Spacer (SpaceOAR, Duraseal or equivalent)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must be willing and capable to provide informed consent to participate in the protocol. Eligible patients must have appropriate staging studies identifying them as AJCC stage T1 (a, b, or c) or T2a or T2b adenocarcinoma of the prostate gland. The patient should not have direct evidence of regional or distant metastases after appropriate staging studies. Histologic confirmation of cancer will be required by biopsy performed within 180 days of registration. The patient's Zubrod performance status must be 0-2. The Gleason score should be less than or equal to 6 or 3+4 if < 50% of a 12 core biopsy was involved. The serum PSA should be less than or equal to 10 ng/ml. Study entry PSA must not be obtained during the following time frames: 10 day period following prostate biopsy; following initiation of ADT; within 30 days after discontinuation of finasteride; or within 90 days after discontinuation of dutasteride. Age ≥ 18 years. Patients may have used prior hormonal therapy, but it should be limited to no more than 9 months of therapy prior to enrollment. The ultrasound, or CT based volume estimation of the patient's prostate gland should be ≤ 60 grams. Exclusion Criteria: Subjects who have had previous pelvic radiotherapy or have had chemotherapy or surgery for prostate cancer. Subjects who have plans to receive other concomitant or post treatment adjuvant antineoplastic therapy while on this protocol including surgery, cryotherapy, conventionally fractionated radiotherapy, hormonal therapy, or chemotherapy given as part of the treatment of prostate cancer. Subjects who have undergone previous transurethral resection of the prostate (TURP) or cryotherapy to the prostate. Subjects who have significant urinary obstructive symptoms; AUA score must be ≤15 (alpha blockers allowed). Subjects who have a history of significant psychiatric illness. Men of reproductive potential who do not agree that they or their partner will use an effective contraceptive method such as condom/diaphragm and spermacidal foam, intrauterine device (IUD), or prescription birth control pills. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (e.g., carcinoma in situ of the breast, oral cavity, or cervix are all permissible). Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months. Transmural myocardial infarction within the last 6 months. Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients. Patients with history of inflammatory colitis (including Crohn's Disease and Ulcerative colitis) are not eligible. Subjects with a known allergy to polyethylene glycol hydrogel (spacer material) or contraindication to spacer products (Duraseal or SpaceOAR). Subjects with evidence of extraprostatic extension (T3a) or seminal vesicle involvement (T3b) on clinical evaluation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: No Arm<br>Study did not have Arm(s) | Device: Injectable Rectal Spacer (SpaceOAR, Duraseal or equivalent)<br>* Injectable Rectal Spacer (SpaceOAR, Duraseal or equivalent PEG based product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Reduction in Acute Per-prostatic Rectal Ulcer Events Events From 90%+ to <70% (Particularly in the Anterior Rectum) | The effectiveness of rectal spacer use was measured to determine if they are effective at improving protection of rectum from high dose radiation, using rate of rectal ulceration as a surrogate measure of acute effects | Median 9 months within the end of radiation treatment | 
| Effectiveness of Space Creation of >= 7.5 mm in Protecting Rectum From Toxicity | The effectiveness of rectal spacer use was measured to determine if they are effective at improving protection of rectum from high dose radiation, using rate of rectal ulceration as a surrogate measure of acute effects | Median 9 months within the end of radiation treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Spacer Related Acute Toxicity | Assess spacer related acute toxicity. Spacer related toxicity could be related to the procedure itself (bleeding, infection, pain), or secondary effects of spacer (erectile dysfunction, persistent pain and discomfort). Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and version number 4.0 specified in the protocol. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening; Grade 4: Life threatening consequences; Grade 5: Death related to the adverse event. | 270 days | 
| Determine Spacer's Ability to Change Percent Rectal Circumference (PRC) Receiving 39 Gy | Determine spacer's ability to change percent rectal circumference (PRC) receiving 39 Gy by at least 50%. This will be determined by using CT planning studies for dosimetric analysis before and after spacer placement. | 1 month | 
| Determine Spacer's Ability to Change Percent Rectal Circumference (PRC) Receiving 24 Gy. | Determine spacer's ability to change percent rectal circumference (PRC) receiving 24 and 39 Gy by at least 50%. This will be determined by using CT planning studies for dosimetric analysis before and after spacer placement. | 1 month | 
| Acute (Within 270 Days of Treatment) SABR-related Gastrointestinal (GI) Toxicities | Acute gastrointestinal (GI) toxicity is defined as grade 1-5 toxicity occurring prior to 270 days from the start of protocol treatment. It is graded based on CTCAE v4.0. | 270 days | 
| Acute (Within 270 Days of Treatment) SABR-related Genitourinary (GU) Toxicities | Acute genitourinary (GU)toxicity is defined as grade 1-5 toxicity occurring prior to 270 days from the start of protocol treatment. It is graded based on CTCAE v4.0. | 270 days | 
| Chronic (>270 Days From Treatment) SABR-related Genitourinary (GU) Toxicities | Delayed genitourinary (GU) toxicity is defined as grade 1-5 toxicity occurring after 270 days from the start of protocol treatment. It is graded based on CTCAE v4.0. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and version number 4.0 specified in the protocol. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening; Grade 4: Life threatening consequences; Grade 5: Death related to the adverse event. | From day 271 up to 540 days | 
| Chronic (>270 Days From Treatment) SABR-related Gastrointestinal (GI) Toxicities | Delayed gastrointestinal (GI) toxicity is defined as grade 1-5 toxicity occurring after 270 days from the start of protocol treatment. It is graded based on CTCAE v4.0. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and version number 4.0 specified in the protocol. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening; Grade 4: Life threatening consequences; Grade 5: Death related to the adverse event. | From day 271 up to 540 days | 
| Acute Non-GI (Gastrointestinal) and Non-GU (Genitourinary) Toxicity- Irritative | Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. | 270 days | 
| Acute Non-GI (Gastrointestinal) and Non-GU (Genitourinary) Toxicity-Obstructive | Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. | 270 days | 
| Acute Non-GI (Gastrointestinal) and Non-GU (Genitourinary) Toxicity-Reproductive. | Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. | 270 days | 
| Chronic Non-GI (Gastrointestinal) and Non-GU (Genitourinary) Toxicity-Obstructive. | Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and version number 4.0 specified in the protocol. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening; Grade 4: Life threatening consequences; Grade 5: Death related to the adverse event. | From day 271 up to 540 days | 
| Chronic Non-GI (Gastrointestinal) and Non-GU (Genitourinary) Toxicity-Reproductive. | Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and version number 4.0 specified in the protocol. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening; Grade 4: Life threatening consequences; Grade 5: Death related to the adverse event. | From day 271 up to 540 days | 
| Chronic Non-GI (Gastrointestinal) and Non-GU (Genitourinary) Toxicity-Irritative. | Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE V4.0) and version number 4.0 specified in the protocol. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life threatening; Grade 4: Life threatening consequences; Grade 5: Death related to the adverse event. | From day 271 up to 540 days | 
| Freedom From Biochemical Recurrence | Biochemical failure RTOG-ASTRO definition (also known as Phoenix definition) - Thus, when the PSA rises by more than 2 ng/ml above the lowest level (nadir) achieved after treatment, biochemical failure has occurred and the date of the failure is recorded at the time the nadir plus 2 ng/ml level is reached | 4 year | 
| Overall Survival | Overall survival as measured by percentage of participants who survived at 5 years. The survival time will be measured from the date of accession to the date of death. | 5 year | 
| Disease-specific Survival | Percentage of patients who did not die from prostate cancer at 5 years. | 5 year | 
| Local Relapse | Percentage of patients without local relapse at 3 years. Local relapse will be measured from the date of study entry to the date of documented local relapse as determined by clinical exam. | 3 year | 
| Regional Relapse | Percentage of patients without regional relapse at 3 years. Regional relapse will be measured from the date of study entry to the date of documented regional nodal recurrence or distant disease relapse. | 3 years | 
| Distant Relapse | Percentage of patients without distant relapse at 3 years. Distant relapse will be measured from the date of study entry to the date of documented regional nodal recurrence or distant disease relapse. | 3 years | 
| EPIC (Expanded Prostate Cancer Index Composite) Bowel Function | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0 (worst) -100 (best)). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Bowel Frequency | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0-100). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Bloody Stools | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0-100). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Bowel Habits | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0-100). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Bowel Urgency | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0-100). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Bowel Leakage/Fecal Incontinence | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0-100). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Bowel Pelvic/Rectal Pain | Outcomes for bowel function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) bowel function score (range, 0-100). EPIC bowel urgency (percentages are for men reporting more than a small problem). EPIC bowel frequency (percentages are for men reporting more than a small problem). EPIC bowel leakage or fecal incontinence (percentages are for men having fecal incontinence at least once per week). EPIC bloody stools (percentages are for men having bloody stools half the time or more). EPIC bowel, pelvic, or rectal pain (percentages are for men reporting more than a small problem). EPIC bowel habits (percentages are for men reporting more than a small problem). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Urinary Function | Outcomes for urinary function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) urinary function score (range, 0 (worst)-100 (best)). EPIC urinary irritation or obstruction (range, 0-100).EPIC urinary incontinence (range, 0-100). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Urinary Irritative/Obstructive | Outcomes for urinary function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) urinary function score (range, 0-100). EPIC urinary irritation or obstruction (range, 0 (worst)-100 (best)).EPIC urinary incontinence (range, 0-100). | 18 months | 
| EPIC (Expanded Prostate Cancer Index Composite) Urinary Incontinence | Outcomes for urinary function and effect on quality of life. Expanded Prostate Cancer Index Composite (EPIC) urinary function score (range, 0-100). EPIC urinary irritation or obstruction (range, 0-100).EPIC urinary incontinence (range, 0 (worst)-100 (best)). | 18 months | 
| AUA (American Urological Association) Quality of Life Questionnaire | AUA Questionnaire is used to measure urinary symptoms. AUA uses a 7-item self-report measure used to assess urinary urgency, frequency, and voiding symptoms. SYMPTOM SCORE: 0-7 (Mild) 8-19 (Moderate) 20-35 (Severe) | 18 months |