Official Title
Optimizing the Management of High-risk and Unfavorable Intermediate-risk Disease: the Use of Advanced Imaging, Trans-perineal Mapping Biopsies, and Dual-strength Brachytherapy Sources to Minimize Radiation Dose to Normal Tissues
Summary:
Multi-modality therapy that includes a brachytherapy implant improves outcomes in locally
advanced prostate cancer when compared to other radiation-based treatments, but is also
associated with more adverse side effects. The goal of the OPTiMAL trial is to reduce these
side effects by using advanced imaging and biopsy techniques to locate cancer and deliver
precision radiation therapy, while not compromising the unprecedented high cure rates
obtained for the brachytherapy arm of the Androgen Suppression Combined with Elective Nodal
and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized control trial.
Additionally, some applied research in genetics, pathology and medical imaging is included.
Novel medical imaging methods, namely, multi-parametric magnetic resonance imaging (MRI),
multi-parametric trans-rectal ultrasound (TRUS), prostate-specific membrane antigen (PSMA)
positron emission tomography/computed tomography (PET/CT) are used for re-staging of prostate
cancer. This is followed by trans-perineal biopsy to locate cancerous areas of the prostate
with greater precision compared to conventional biopsy. Results from imaging are compared to
those from biopsy to develop image-based cancer detection methods.
Trial Description
Primary Outcome:
- Frequency of treatment-related GU adverse effects
Secondary Outcome:
- Trans-perineal biopsy and imaging correlation
Purpose:
The purpose of OPTiMAL is to combine new imaging and treatment methods to reduce the
incidence and severity of the genito-urinary (GU) side effects associated with
radiation-based, multimodality treatment for men with locally advanced prostate cancer (PCa).
OPTiMAL was inspired by the highly successful Androgen Suppression Combined with Elective
Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized control trial, in which
men who were randomized to a low-dose-rate brachytherapy (LDR-PB) boost experienced
unprecedented high cure rates, but also had more side effects and a slightly greater decrease
in quality-of-life (QoL) scores when compared to the standard arm which used a dose-escalated
external beam (DE-EBRT) boost.
Hypothesis:
By allowing a higher radiation dose to the cancer while delivering lower dose to healthy
tissue, more accurate cancer localization will result in a decrease in adverse effects and
better QoL, when compared to the men in the experimental arm of ASCENDE-RT.
Justification:
About 1 in 4 newly diagnosed PCa patients will be found to have unfavorable disease , either
National Comprehensive Cancer Network (NCCN) high-risk or intermediate-risk with multiple
adverse features; such men carry a 40% to 80% chance of biochemical recurrence within 5 years
of radical prostatectomy (RP) or conventional external beam radiation therapy (EBRT) alone.
With some exceptions, such men generally require multi-modality treatment to provide the best
chance of long-term disease-free survival.
In the ASCENDE-RT randomized control trial, led by investigators at BCCANCER, an LDR-PB boost
established unprecedented new standards for biochemical (PSA) progression free survival
(b-PFS); however, a higher incidence of adverse GU side effects was also observed. Despite
the increase in adverse effects, most men were symptom-free at 5 years and more than 80% had
minimal or no adverse effects left over from treatment.
Objectives:
Primary objective:
OPTiMAL is powered to determine if combining improved techniques for delivering combined
pelvic EBRT and LDR-PB boost will lead to a reduction in grade 2 and above,
physician-reported GU adverse effects when compared to the ASCENDE-RT trial while not
compromising the high rates of biochemical progression free survival survival (b-PFS)
observed in ASCENDE-RT.
Secondary Objectives:
1. Trans-perineal, template-guided mapping biopsy (TTMB) is the gold standard for locating
the extent of intra-prostatic disease, but it is an invasive procedure. Therefore,
another objective of this trial is to establish and investigate correlations between
TTMB and multi-modality, multi-parametric imaging provided by trans-rectal ultrasound
(TRUS), MRI and PET/CT.
2. To further develop the use of dual air kerma strength sources in a single LDR-PB
implant, which the investigators have shown can improve the planning target volume (PTV)
dose coverage while reducing dose to sensitive normal tissues.
3. Finally, the TTMB biopsy material will also be used to compare computer-based digital
pathology to conventional pathology as read by human pathologists.
Research design:
Eligible patients will undergo a series of re-staging investigations, which includes multiple
advanced imaging: PSMA PET/CT, Multi-parametric MRI and TRUS and trans-perineal biopsy.
Re-staging will be used to determine which components of multi-modality therapy are
appropriate for each individual patient.
Treatment includes a combination of 125 iodine LDR-PB, followed by EBRT. Based on the results
from the re-staging phase and baseline patient diagnosis, in some cases androgen deprivation
therapy will be prescribed for a total duration of at least one year with at least 6 months
being neoadjuvant.
125 Iodine LDR-PB implant will be designed to deliver a minimum peripheral dose (MPD) of 100
Gy to the entire gland and a boost of 150-200 Gy either to the entire peripheral zone, or in
cases with well-localized intra-prostatic disease on the basis of TTMB, to regions of known
disease only. For all trial subjects the use of dual strength source may be used if their use
results in superior coverage and/or protection of normal tissues
Shortly after the completion of the LDR-PB implant, all patients will receive supplemental
pelvic EBRT using Volumetric Modulated Radiation Therapy (VMAT) intensity modulated radiation
therapy (IMRT).
Statistical Analysis:
The study will include a total of 105 enrolled patients who will receive multi-parametric
imaging and TTMB over 4 years. Based on the investigators' experience at the BCCANCER, it is
estimated that 75 patients will receive focal LDR-PB boost.
Assuming that the 2-year cumulative incidence rate of grade 2 or above toxicity is similar to
the DE-EBRT arm of the ASCENDE-RT trial (10%), a study exposing 75 subjects to focal LDR-PB
boost is sufficient to demonstrate a cumulative incidence significantly lower than the 26% in
the LDR-PB boost arm of ASCENDE-RT with 96% power based on a two-sided 95% confidence
interval of the Kalbfleisch-Prentice incidence estimator. Enrolling 75 subjects over 4 years
with 2 years of follow-up and assuming the 2-year rate of grade 3 or above toxicity is 3.4%,
the 95% confidence interval for 2-year incidence will exclude 7.7% with more than 81% power.
View this trial on ClinicalTrials.gov
