Optimizing Prostate Cancer Treatment in Men With Advanced Local Disease (OPTiMAL)

Description

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.

Details