Phase I/II Hypofractionated Radiotherapy for Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to examine the clinical feasibility of using Intensity-modulated radiation therapy (IMRT) combined with daily pretreatment prostate localization to deliver increasingly hypofractionated treatment courses. Progressively larger fraction sizes will be delivered in a phase I design based on both acute and long-term tolerances to the treatment. The dose-per-fraction escalation design utilizes schemas that maintain an isoeffective dose for late effects, while predicting that tumor control will actually improve. The delivery of fewer, larger fractions of radiation, if proven effective and safe, would result in significant cost saving and more efficient use of resources. Phase II will commence with Maximum Tolerated Dose (MTD) finding with up to 200 additional patients being enrolled during this phase of the study.

Official Title
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Phase I/II Trial Examining Dose-per-Fraction Escalation Using Intensity Modulated Radiation Therapy in the Treatment of Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven adenocarcinoma of the prostate. Stage ≤ T2b disease, as defined by 1997 American Joint Committee on Cancer (AJCC) classification Predicted risk of lymph node involvement (by standard nomograms) of 15% or less (24), OR histologically negative pelvic nodes Gleason score ≤ 7 No evidence of distant metastasis Age 18+ Informed consent signed in accordance with institutional protocol Pretreatment evaluations must be completed as specified in Section 7.0. ECOG performance status 0-1 No previous or concurrent cancers, other than localized basal cell or squamous cell skin carcinoma, unless continually disease free for at least 5 years No prior pelvic irradiation, prostate brachytherapy, or bilateral orchiectomy Gonadotropin-releasing hormone agonist (GnRH-a) use permitted (maximum of 6 months duration). Anti-androgen therapy permitted concurrently with GnRH-a. No previous or concurrent cytotoxic chemotherapy No radical surgery or cryosurgery for prostate cancer The absence of any co-morbid medical condition which would constitute a contraindication for radical radiotherapy The absence of serious concurrent illness of psychological, familial, sociological, geographical or other concomitant conditions which do not permit adequate follow-up and compliance with the study protocol. No current use of anticoagulation therapy, other than aspirin.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: dose escalation, 3 possible dose groups, with one Phase II group based on MTD. Per protocol, while waiting for safety data to mature for escalation, protocol permitted enrollment to continue on last dose that was already proven safe. Thus Arms one and two have more than 50 subjects each.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Level 1<br>64.7 Gy/22 fractions of 2.94 Gy | Radiation: Radiotherapy<br>* Daily radiation to prescribed dose<br>|
| Experimental: Level 2<br>58.08 Gy/16 fractions of 3.63 Gy | Radiation: Radiotherapy<br>* Daily radiation to prescribed dose<br>|
| Experimental: Level 3<br>51.6 Gy/12 fractions of 4.3 Gy | Radiation: Radiotherapy<br>* Daily radiation to prescribed dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience Grade 3 or Higher Acute Toxicities | To evaluate acute tolerances to dose-per-fraction escalation in the treatment of prostate cancer using optimized treatment of Intensity-modulated radiation therapy (IMRT), daily rectal balloon displacement, and transabdominal ultrasound localization of the prostate. For toxicities observed within the first 10 patients at each hypofractionation level, ≥20% acute grade 3 or higher GI or genitourinary (GU) toxicity will constitute a threshold toxicity level and will dictate a decrease in frequency of treatment by one treatment per week. Maximum tolerated dose is reached if 20% of participants experience acute toxicities grade 3 or higher. | 90 days post radiation treatment | 
| Number of Subjects Experiencing Grade 2 or Higher Late Rectal Toxicities at Any Time During Follow Up | To evaluate late radiation toxicities to dose-per fraction escalation in the treatment of prostate | from 90 days post XRT through last follow-up visit (up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Progression-free Survival Based on PSA Surveillance | Patients will be considered to be without biochemical recurrence if either the Prostate-specific antigen (PSA) is still declining or the PSA nadir has been reached and is below 1.0ng/ml | up to 15 years from enrollment | 
| Fox Chase Bowel Survey at Baseline and 3 Years | The Fox Chase Bowel/Bladder survey was divided into two sections: Bowel (questions 1 to 14, N=14) and Bladder (questions 19, and 21 to 30, N=11). To facilitate analysis, Bowel and Bladder scores for each section were rescaled to a total score of between 0 - 100, where higher scores indicated better Quality of Life (QoL). Results for the Bowel Section are reported here. | Baseline and 3 years | 
| Fox Chase Bladder Survey at Baseline and 3 Years | The Fox Chase Bowel/Bladder survey was divided into two sections: Bowel (questions 1 to 14, N=14) and Bladder (questions 19, and 21 to 30, N=11). To facilitate analysis, Bowel and Bladder scores for each section were rescaled to a total score of between 0 - 100, where higher scores indicated better Quality of Life. Results for the Bladder Section are reported here. | Baseline and 3 years | 
| International Index of Erectile Function (IIEF) Score at Baseline and 3 Years | The IIEF is a 15-item survey where 9-items are scored 0-5 and 6-items are scored 1-5 with a total range of 6-75. The standard scoring mechanism was used for IIEF, where the QoL items corresponded to the following domains: erectile function (score range 1-30), orgasmic function (score range 1-10), sexual desire (score range 2-10), intercourse satisfaction (score range 0-15), and overall satisfaction (score range 2-10). Higher numbers indicate increased QoL. | Baseline and 3 years | 
| Spritzer Quality of Life Index (SQLI) at Baseline and 3 Years | The SQLI is composed of five items (activity, daily living, health, support, outlook) scored utilizing a numerical scale of 0-2. Standard scoring was also used for the SQLI survey (total score range 0-10) where higher score indicate increased QoL. | Baseline and 3 years |