MRI-Guided Lattice Extreme Ablative Dose Radiotherapy For Prostate Cancer

The investigators propose to use a novel method for delivery of ablative spatially
fractionated radiation to the multiparametric functional 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
dynamic contrast-enhanced MRI (DCE-MRI) and/or diffusion-weighted MRI (DWI-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 Gy 3.0 in 2.0
Gy equivalents).

In this protocol the investigators also aim to examine biomarkers obtained from
ultrasound-guided prostate biopsies. The patients will have the option of refusing the pre-RT
prostate biopsies that are planned to be done when the patient has fiducial markers placed.
Emphasis will be placed on biopsying regions in which the multiparametric MRI shows
enhancement with or without DWI indicated water restriction. The preferred method of protocol
research biopsies will involve the Eigen Artemis® system, which allows for fusion of the MRI
images to ultrasound in real time. The Artemis® system is an FDA approved transrectal
ultrasound prostate biopsy device. At the present time, Eigen has made available to us the
MRI-ultrasound (MRIus) fusion software, which is in beta testing. The Eigen Artemis® system
fusion software (not FDA approved) may be used to fine-tune the location of the tumor and
biopsies by fusion of the previously obtained multiparametric MRI to the transrectal
ultrasound in real time. The ultrasound is the true guidance imaging parameter that
identifies the prostate boundaries and other nearby structures. The MRI is fused to the
ultrasound such that the biopsies may be directed to a region in the ultrasound space.

The Eigen Artemis® system software will be used as a means of better targeting tumor regions,
which are poorly seen on ultrasound alone. Recently, Natarajan et al (24) described the
University of California Los Angeles (UCLA) experience, demonstrating that the proportion of
positive biopsies was much higher using the MRIus fusion software, as compared to ultrasound
alone. In this protocol, the MRIus fusion software may be used to obtain research biopsies
and the results of the biopsies (e.g., in terms of Gleason score) will not be used for
diagnosis (the patients already have a diagnosis) or influence treatment in any way. The
patient is free to withdraw from the protocol at any time, including upon learning the
results of the biopsies.

If the Eigen Artemis system® is unavailable, ultrasound biopsies may be performed while
viewing the functional MRI images on a separate monitor during the ultrasound-guided biopsies
to enhance the probability of obtained biomarkers more representative of patient outcome. A
third option that will become available in 2012 is to perform MRI-guided biopsies directly on
the MRI scanner using a commercially available approach.. 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.

Inclusion Criteria:

- A. Biopsy confirmed adenocarcinoma of the prostate.

- B. T1-T3a disease based on digital rectal exam (DRE).

- T3a disease based on MRI is acceptable (no evidence of frank (clear cut) seminal
vesicle (SV) involvement or invasion of bladder or rectum).

- C. Gleason score 6-10.

- D. Patients with Gleason score ≥8 must be offered long term androgen deprivation
therapy (ADT) and refuse such treatment because only 4-6 months (+/- 2 months) (short
term ADT) is permitted (not required) on this protocol. The ADT is recommended to
begin after fiducial marker placement; however, ADT is permitted to have been started
up to two months prior to the signing of consent. All patients in this protocol may
(not required) be treated with 4-6 months (+/- 2 months) of ADT, at the discretion of
the treating physician.

- Gleason ≥8 must have < 40% of the tissue involved with Gleason 8 in the biopsy
specimen.

- E. Prostate-specific antigen (PSA) ≤ 30 ng/mL within 3 months of enrollment. If PSA
was above 30 and dropped to ≤30 with antibiotics, this is acceptable for enrollment.

- F. No previous pelvic radiotherapy.

- G. No previous history of radical/total prostatectomy (suprapubic prostatectomy is
acceptable).

- H. 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.

- I. Identifiable multiparametric-MRI tumor lesion or lesions, that total in volume <
33% of the prostate

- Multiparametric MRI of prostate and pelvis is required prior to protocol
consideration.

- If contrast not given, the point dose on the apparent diffusion coefficient (ADC)
map should be < 1000.

- J. Ability to understand and the willingness to sign a written informed consent
document.

- K. Zubrod performance status < 2.

- L. Willingness to fill out quality of life forms.

- M. Bone scan negative if PSA > 15 ng/mL or Gleason ≥ 8 disease. A questionable bone
scan is acceptable if other imaging tests are negative for metastasis.

- N. Serum testosterone is within 40% of normal assay limits (e.g., x=0.4*lower assay
limit and x=.04*upper assay limit + upper assay limit), and taken within 4 months of
enrollment. Patients who have been started on ADT prior to signing consent are not
required to have a serum testosterone at this level prior to signing consent; but, a
serum testosterone prior to fiducial marker placement is recommended.

- O. Serum liver function tests (LFT) are taken within 3 months of enrollment.

- P. Complete blood counts are taken within 3 months of enrollment.

- Q. Age ≥ 35 and ≤ 85 years.

Exclusion Criteria:

- A. > T3a disease on digital rectal exam or >T3a disease clearly identified by MRI.

- B. Gleason score < 6.

- C. >= 40% Gleason 8-10 tumor, over the total tissue including other tumor and normal
tissue. For example: (Gleason 8-10 tumor length/other biopsy tissue length)*100 = >=
40%.

- D. Androgen deprivation therapy longer than 8 months. Androgen deprivation timing is
for the Luteinizing hormone-releasing hormone (LHRH) agonist portion only and not when
anti-androgen is started beforehand with the purpose of counteracting the surge in
testosterone from the LHRH agonist - PSA > 30 ng/mL within 3 months of enrollment.

- E. PSA > 30 ng/mL within 3 months of enrollment

- F. Unable to obtain a 1.5T or 3.0T multiparametric MRI of the pelvis and prostate with
contrast.

- G. Unidentifiable multiparametric MRI tumor lesion.

- H. Identifiable multiparametric-MRI tumor lesions, that total in volume ≥ 33% of the
prostate.

- I. Previous pelvic radiotherapy.

- J. Previous history of radical prostatectomy.

- K. 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.

- L. Zubrod performance status ≥ 2.

- M. Inability to understand or unwilling to sign a written informed consent document

- N. Unwilling to fill out quality of life/psychosocial forms.

- O. Bone scan is positive and other imaging tests confirm a suspicion of metastasis
from prostate cancer.

- P. Serum testosterone is not within 40% of normal assay limits taken within 4 months
of enrollment (only applicable to patients not started on ADT prior to signing
consent).

- Q. Serum liver function tests (LFTs) are not taen within 3 months of enrollment.

- R. Complete blood counts are not taken within 3 months of enrollment.

- S. Age < 35 and > 85 years.