A Phase I Trial of MRI-Guided Lattice Extreme Ablative Dose Radiotherapy For Prostate Cancer

• Number of Patients with Adverse Events in a Phase 1 LEAD RT Clinical Trial [ Time Frame: 5.25 years ] [ Designated as safety issue: Yes ]
  To determine the number of patients with and severity of adverse events in a Phase 1 LEAD RT clinical trial.
• The proportion of enrolled patients for whom LEAD RT dose can be successfully administered following MRI-guided planning. [ Time Frame: 5.25 years ] [ Designated as safety issue: No ]
  The proportion of enrolled patients for whom LEAD RT dose can be successfully administered following MRI-guided planning.

• Measuring Risk of leaving tumor cells in prostate after LEAD RT [ Time Frame: 5.25 years ] [ Designated as safety issue: Yes ]
  To measure the risk of leaving tumor cells in the prostate after LEAD RT by obtaining serial post-RT MRI's (3 months and 9 months, and within 2 months of the post-treatment prostate biopsy).
• Biomarker Expression in different prostate tumor regions [ Time Frame: 5.25 years ] [ Designated as safety issue: No ]
  To quantify biomarker expression in different prostate tumor regions, comparing specifically the DCE-MRI enhancing and non-enhancing regions.
• Proportion of Study patients with positive prostate biopsies [ Time Frame: 2.5 years ] [ Designated as safety issue: No ]
  To determine the proportion of study patients with positive prostate biopsies at 2-2.5 years after completion of therapy as a preliminary indication of the efficacy.
• Failure-free and Overall Progression [ Time Frame: 5.25 years ] [ Designated as safety issue: No ]
  To report failure-free (biochemical and clinical progression) and overall survival.
• Assessment of Health-Related Quality of Life [ Time Frame: 5.25 years ] [ Designated as safety issue: No ]
  To assess Health-Related Quality of Life (HRQOL) in the study patients.

The hypotheses of this study are:

1. Delivery of single fraction Lattice Extreme Ablative Dose (LEAD) radiotherapy (RT) to the dominant tumor lesion(s) in the prostate as identified by Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) is safe and feasible.
2. Biomarker expression levels differ in the DCE-MRI enhancing and non-enhancing tumor regions. The investigators hypothesize that a significant source of variation in biomarker levels is due to tumor heterogeneity and that it is molecular abnormalities in the dominant tumor areas that are angiogenic and determine outcome.

The investigators propose to use a novel method for delivery of ablative spatially fractionated radiation to the DCE-MRI defined tumor volume in the framework of a single-arm phase I clinical trial. The technique, deemed Lattice Extreme Ablative Dose (LEAD) RT, involves the creation of high doses shaped in cylinders through the DCE-MRI defined region(s) and adjacent apparently normal prostate in a lattice framework. The LEAD RT delivery will be in a single fraction of 12-14 Gy prior to standard fractions (2.0 Gy per day) for an additional 76 Gy (total dose for all treatments of 88-90 Gy and 149 Gy3.0 in 2.0 Gy equivalents).

In this protocol the investigators also aim to examine biomarkers obtained from ultrasound-guided biopsies. Emphasis will be placed on biopsying regions in which the DCE-MRI shows enhancement. The DCE-MRI will be viewed on a separate monitor during the ultrasound-guided biopsies to enhance the probability of obtained biomarkers more representative of patient outcome. Biomarkers from biopsies from the index lesion(s) will be compared to those from tumor in other areas of the prostate. Biopsy tissues will be collected pre- and post-treatment and analyzed by immunohistochemistry (IHC) for biomarker quantification.

• Prostate Cancer
• Prostate Adenocarcinoma

• Radiation: Lattice Extreme Ablative Dose (LEAD) Radiation Therapy
  12 - 14 Gy dose pipes in 1 fraction to DCE-MRI on Day 1.
  Other Name: LEAD RT
• Radiation: Standard IMRT
  76 Gy in 38 fractions (2 Gy daily) of Standard IMRT starting on Day 2.
  Other Name: IMRT
• Behavioral: EPIC SF-12 Questionnaire
  Expanded Prostate Cancer Index Composite-SF12 (EPIC-SF12) quality of life questionnaire prior to radiation therapy, last week of radiation therapy, 6 weeks, 3 months, 9 months, 15 months and yearly thereafter up to 5.25 years.
• Behavioral: MAX-PC Questionnaire
  Memorial Anxiety Scale for Prostate Cancer patients (MAX-PC) prior to radiation therapy, last week of radiation therapy, 6 weeks, 3 months, 9 months, 15 months and yearly thereafter up to 5.25 years.
• Behavioral: IPSS Questionnaire
  International Prostate Symptom Score (IPSS) prior to radiation therapy, last week of radiation therapy, 6 weeks, 3 months, 9 months, 15 months and every 6 months thereafter up to 5.25 years.
• Procedure: Blood Sample Collection
  Plasma and Serum collection prior to radiation therapy, 24 hours post-LEAD RT, last week of radiation therapy, 6 weeks, 3 months, within 2 months of 2 year biopsy
• Procedure: Urine Sample Collection
  Urine sample collection prior to radiation therapy, 24 hours post-LEAD RT, last week of radiation therapy, 6 weeks, 3 months, within 2 months of 2 year biopsy
• Procedure: Prostate Biopsy
  Prostate biopsy prior to radiation therapy and 2 - 2.5 years post-completion of radiation therapy.
• Procedure: CT Simulation
  Prior to radiation therapy.
• Procedure: MRI Simulation
  Prior to radiation therapy
• Procedure: Fiducial Gold Marker Placement
  Four (4) gold markers will be implanted in the prostate gland during prostate biopsy prior to radiation therapy.

Inclusion Criteria:

• Biopsy confirmed adenocarcinoma of the prostate.

• T1-T2 disease based on digital rectal exam.

  • T3a disease based on MRI only is acceptable.
• Gleason score 6-8.

• Patients with Gleason score 8 must be offered long term androgen deprivation therapy (ADT) and refuse such treatment because only 6 months (short term ADT) is permitted on this protocol. All Gleason score 8 patients must receive 6 months of ADT. The ADT should begin after fiducial marker placement.

  • Gleason 8 must have <20% of the tissue involved with Gleason 8 in the biopsy specimen.
  • Patients with Gleason score ≤7 may be treated with 4-6 months of ADT. The ADT should begin after fiducial marker placement.
• Prostate-specific antigen (PSA) ≤20 ng/mL within 8 weeks of enrollment.
• No previous pelvic radiotherapy.
• No previous history of radical/total prostatectomy (suprapubic prostatectomy is acceptable).
• No concurrent, active malignancy, other than nonmetastatic skin cancer or early stage chronic lymphocytic leukemia (well-differentiated small cell lymphocytic lymphoma). If a prior malignancy is in remission for > 5 years then the patient is eligible.

• Identifiable DCE-MRI tumor lesion or lesions, that total in volume <33% of the prostate

  • DCE-MRI of prostate and pelvis required prior to protocol consideration.
• Ability to understand and the willingness to sign a written informed consent document.
• Zubrod performance status <2.
• Willingness to fill out quality of life forms.
• Bone scan negative if PSA >10 ng/mL or Gleason ≥7 disease. A questionable bone scan is acceptable if plain x-rays and/or MRI are negative for metastasis.
• Serum testosterone is within 40% of normal assay limits and taken within 4 months of enrollment.
• Serum liver function tests (LFT) are within 40% of normal assay limits and taken within 8 weeks of enrollment.
• Complete blood counts are within 40% of normal assay limits, taken within 8 weeks of enrollment.
• Age ≥35 and ≤85 years.

Exclusion Criteria:

• >T2 disease on digital rectal exam unless T3a disease is identified by MRI.
• Gleason score <6 and >8.
• ≥20% Gleason 8 tumor, over the total tissue including other tumor and normal tissue. For example: (Gleason 8 tumor length/other biopsy tissue length)*100 = ≥20%.
• Patients are not eligible if they have been started on androgen deprivation therapy prior to enrollment.
• Androgen deprivation therapy longer than 6 months. Androgen deprivation timing is for the Luteinizing hormone-releasing hormone (LHRH) agonist portion only and not when anti-androgen is started beforehand.
• PSA >20 ng/mL within 8 weeks of enrollment.
• Unable to obtain a 3T MRI of the pelvis and prostate with contrast prior to randomization.
• Unidentifiable DCE-MRI tumor lesion.
• Identifiable DCE-MRI tumor lesions, that total in volume ≥33% of the prostate.
• Previous pelvic radiotherapy.
• Previous history of radical prostatectomy.
• Concurrent, active malignancy, which is not nonmetastatic skin cancer or early stage chronic lymphocytic leukemia (well-differentiated small cell lymphocytic lymphoma). If a prior malignancy is in remission for < 5 years then the patient is not eligible.
• Zubrod performance status ≥ 2.
• Inability to understand or unwilling to sign a written informed consent document
• Unwilling to fill out quality of life/psychosocial forms.
• Bone scan is positive if PSA >10 ng/mL or Gleason ≥7 disease.
• Serum testosterone is not within 40% of normal assay limits taken within 4 months of enrollment.
• Serum liver function tests (LFTs) are not within 40% of normal assay limits taken within 8 weeks of enrollment.
• Complete blood counts are not within 40% of normal assay limits taken within 8 weeks of enrollment.
• Age <35 and >85 years.