PROstate Multicentre External beam radioTHErapy Using a Stereotactic boost: the PROMETHEUS study protocol.

BACKGROUND: High Dose Rate Brachytherapy (HDRB) boost is a well-established treatment for prostate cancer (PC). We describe the PROstate Multicentre External beam radioTHErapy Using Stereotactic boost (PROMETHEUS) study. Non-surgical stereotactic techniques are used to deliver similar doses to HDRB boost regimens with a dose escalation sub-study. METHODS: Eligible patients have intermediate or high risk PC. PROMETHEUS explores the safety, efficacy and feasibility of multiple Australian centres cooperating in the delivery of Prostate Stereotactic Body Radiotherapy (SBRT) technology. A SBRT boost component Target Dose (TD) of 19Gy in two fractions is to be delivered, followed by a subsequent EBRT component of 46Gy in 23 fractions. Once accrual triggers have been met, SBRT doses can be escalated in 1 Gy increments to a maximum of 22Gy in two fractions. Patient safety will also be measured with the rate of both acute and late moderate to severe Gastro-Intestinal (GI) and Genito-Urinary (GU) Common Terminology Criteria for Adverse Events (CTCAE) toxicities as well as patient reported quality of life. Efficacy will be assessed via biochemical control after 3 years. DISCUSSION: PROMETHEUS aims to generate evidence for a non-surgical possible future alternative to HDRB boost regimens, and introduce advanced radiotherapy techniques across multiple Australian cancer centres. TRIAL REGISTRATION: The study was retrospectively registered on the ANZCTR (Australian New Zealand Clinical Trials Registry) with trial ID: ACTRN12615000223538 .

Real-time intrafraction prostate motion during linac based stereotactic radiotherapy with rectal displacement.

BACKGROUND: Kilovoltage Intrafraction Monitoring (KIM) is a method which determines the three-dimensional position of the prostate from two-dimensional kilovoltage (kV) projections taken during linac based radiotherapy treatment with real-time feedback. Rectal displacement devices (RDDs) allow for improved rectal dosimetry during prostate cancer treatment. This study used KIM to perform a preliminary investigation of prostate intrafraction motion observed in patients with an RDD in place. METHODS: Ten patients with intermediate to high-risk prostate cancer were treated with a Rectafix RDD in place during two boost fractions of 9.5-10 Gy delivered using volumetric modulated arc therapy (VMAT) on Clinac iX and Truebeam linacs. Two-dimensional kV projections were acquired during treatment. KIM software was used following treatment to determine the displacement of the prostate over time. The displacement results were analyzed to determine the percentage of treatment time the prostate spent within 1 mm, between 1 and 2 mm, between 2 and 3 mm and greater than 3 mm from its initial position. RESULTS: KIM successfully measured displacement for 19 prostate stereotactic boost fractions. The prostate was within 1 mm of its initial position for 84.8%, 1-2 mm for 14%, 2-3 mm 1.2% and ≥3 mm only 0.4% of the treatment time. CONCLUSIONS: In this preliminary study using KIM, KIM was successfully used to measure prostate intrafraction motion, which was found to be small in the presence of a rectal displacement device. TRIAL REGISTRATION: The Hunter New England Human Research Ethics Committee reference number is 14/08/20/3.01.

Prostate Virtual High-dose-rate Brachytherapy Boost: 5-Year Results from the PROMETHEUS Prospective Multicentre Trial.

BACKGROUND AND OBJECTIVE: Despite the high efficacy of high-dose-rate brachytherapy boost (HDRB) in the management of prostate cancer (PC), use of this approach is declining. Similar dosimetry can be achieved using stereotactic body radiotherapy or "virtual HDRB" (vHDRB). The aim of the multicentre, single-arm, phase 2 PROMETHEUS trial (ACTRN12615000223538) was to evaluate the safety and efficacy of vHDRB in patients with PC. METHODS: Patients with intermediate-risk PC or selected patients with high-risk PC were eligible for inclusion. vHDRB was given as 19-20 Gy in two fractions, delivered 1 wk apart, followed by conventionally fractionated external beam radiotherapy (EBRT) at 46 Gy in 23 fractions or 36 Gy in 12 fractions. The primary endpoint was the biochemical/clinical relapse-free rate (bcRFR). Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and quality of life (QoL) data were collected used the Expanded Prostate Cancer Index Composite-26 questionnaire. KEY FINDINGS AND LIMITATIONS: From March 2014 to December 2018, 151 patients (74% intermediate risk, 26% high risk) with a median age of 69 yr were treated across five centres. Median follow-up was 60 mo. The 5-yr bcRFR was 94.1% (95% confidence interval [CI] 90-98%) and the local control rate was 98.7%. Acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity occurred in 6.6% and 23.2% of patients, respectively, with no acute grade 3 toxicity. At 60 mo after treatment, the prevalence of late grade ≥2 GI toxicity was 1.7% (95% CI 0.3-6.5%) and the prevalence of late grade ≥2 GU toxicity was 3.3% (95% CI 1.1-8.8%). Between baseline and 60 mo, QoL improved for urinary obstructive and hormonal domains, was stable for the bowel domain, and deteriorated slightly for the sexual and urinary incontinence domains. CONCLUSIONS: Delivery of gantry-based vHDRB followed by conventionally fractionated EBRT is feasible in a multicentre setting, with high 5-yr bcRFR and low toxicity. This approach is being compared with prostate ultrahypofractionated radiotherapy in the TROG 18.01 NINJA randomised trial (ACTRN12618001806257). PATIENT SUMMARY: The PROMETHEUS trial investigated noninvasive high-dose precision radiotherapy combined with conventional radiotherapy in patients with prostate cancer. We found that this new technique was well tolerated and resulted in better cancer control outcomes than historically reported.

Visualising the urethra for prostate radiotherapy planning.

INTRODUCTION: The prostatic urethra is an organ at risk for prostate radiotherapy with genitourinary toxicities a common side effect. Many external beam radiation therapy protocols call for urethral sparing, and with modulated radiotherapy techniques, the radiation dose distribution can be controlled so that maximum doses do not fall within the prostatic urethral volume. Whilst traditional diagnostic MRI sequences provide excellent delineation of the prostate, uncertainty often remains as to the true path of the urethra within the gland. This study aims to assess if a high-resolution isotropic 3D T2 MRI series can reduce inter-observer variability in urethral delineation for radiotherapy planning. METHODS: Five independent observers contoured the prostatic urethra for ten patients on three data sets; a 2 mm axial CT, a diagnostic 3 mm axial T2 TSE MRI and a 0.9 mm isotropic 3D T2 SPACE MRI. The observers were blinded from each other's contours. A Dice Similarity Coefficient (DSC) score was calculated using the intersection and union of the five observer contours vs an expert reference contour for each data set. RESULTS: The mean DSC of the observer vs reference contours was 0.47 for CT, 0.62 for T2 TSE and 0.78 for T2 SPACE (P < 0.001). CONCLUSIONS: The introduction of a 0.9 mm isotropic 3D T2 SPACE MRI for treatment planning provides improved urethral visualisation and can lead to a significant reduction in inter-observer variation in prostatic urethral contouring.

Real-Time Image Guided Ablative Prostate Cancer Radiation Therapy: Results From the TROG 15.01 SPARK Trial.

PURPOSE: Kilovoltage intrafraction monitoring (KIM) is a novel software platform implemented on standard radiation therapy systems and enabling real-time image guided radiation therapy (IGRT). In a multi-institutional prospective trial, we investigated whether real-time IGRT improved the accuracy of the dose patients with prostate cancer received during radiation therapy. METHODS AND MATERIALS: Forty-eight patients with prostate cancer were treated with KIM-guided SABR with 36.25 Gy in 5 fractions. During KIM-guided treatment, the prostate motion was corrected for by either beam gating with couch shifts or multileaf collimator tracking. A dose reconstruction method was used to evaluate the dose delivered to the target and organs at risk with and without real-time IGRT. Primary outcome was the effect of real-time IGRT on dose distributions. Secondary outcomes included patient-reported outcomes and toxicity. RESULTS: Motion correction occurred in ≥1 treatment for 88% of patients (42 of 48) and 51% of treatments (121 of 235). With real-time IGRT, no treatments had prostate clinical target volume (CTV) D98% dose 5% less than planned. Without real-time IGRT, 13 treatments (5.5%) had prostate CTV D98% doses 5% less than planned. The prostate CTV D98% dose with real-time IGRT was closer to the plan by an average of 1.0% (range, -2.8% to 20.3%). Patient outcomes showed no change in the 12-month patient-reported outcomes compared with baseline and no grade ≥3 genitourinary or gastrointestinal toxicities. CONCLUSIONS: Real-time IGRT is clinically effective for prostate cancer SABR.

Reduced motion and improved rectal dosimetry through endorectal immobilization for prostate stereotactic body radiotherapy.

OBJECTIVE: PROMETHEUS (ACTRN12615000223538) is a multicentre clinical trial investigating the feasibility of 19 Gy in 2 fractions of stereotactic body radiotherapy (SBRT) as a boost technique for prostate cancer. The objective of this substudy was to evaluate intrafraction motion using cine MRI and assess the dosimetric impact of using a rectal displacement device (RDD). METHODS: The initial 10 patients recruited underwent planning CT and MRI, with and without a RDD. Cine MRI images were captured using an interleaved T2 HASTE sequence in sagittal and axial planes with a temporal resolution of 5.2 s acquired over 4.3 min. Points of interest (POIs) were defined and a validated tracking algorithm measured displacement of these points over the 4.3 min in the anteroposterior, superior-inferior and left-right directions. Plans were generated with and without a RDD to examine the impact on dosimetry. RESULTS: There was an overall trend for increasing displacement in all directions as time progressed when no RDD was in situ . points of interest remained comparatively stable with the RDD. In the sagittal plane, the RDD resulted in statistically significant improvement in the range of anteroposterior displacement for the rectal wall, anterior prostate, prostate apex and base. Dosimetrically, the use of a RDD significantly reduced rectal V16, V14 and Dmax, as well as the percentage of posterior rectal wall receiving 8.5 Gy. CONCLUSION: The RDD used in stereotactic prostate radiotherapy leads to reduced intrafraction motion of the prostate and rectum, with increasing improvement with time. It also results in significant improvement in rectal wall dosimetry. ADVANCES IN KNOWLEDGE: It was found that the rectal displacement device improved prostate stabilization significantly, improved rectum stabilization and dosimetry significantly. The rectal displacement device did not improve target volume dosimetry.

Phase 2 Multicenter Study of Gantry-Based Stereotactic Radiotherapy Boost for Intermediate and High Risk Prostate Cancer (PROMETHEUS).

Objectives: To report feasibility, early toxicity, and PSA kinetics following gantry-based, stereotactic radiotherapy (SBRT) boost within a prospective, phase 2, multicenter study (PROMETHEUS: ACTRN12615000223538). Methods: Patients were treated with gantry-based SBRT, 19-20 Gy in two fractions delivered 1 week apart, followed by conventionally fractionated IMRT (46 Gy in 23 fractions). The study mandated MRI fusion for RT planning, rectal displacement, and intrafraction image guidance. Toxicity was prospectively graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4). Results: Between March 2014 and July 2018, 135 patients (76% intermediate, 24% high-risk) with a median age of 70 years (range 53-81) were treated across five centers. Short course (≤6 months) androgen deprivation therapy (ADT) was used in 36% and long course in 18%. Rectal displacement method was SpaceOAR in 59% and Rectafix in 41%. Forty-two and ninety-three patients were treated at the 19 Gy and 20 Gy dose levels, respectively. Median follow-up was 24 months. Acute grade 2 gastrointestinal (GI) and urinary toxicity occurred in 4.4 and 26.6% with no acute grade 3 toxicity. At 6, 12, 18, 24, and 36 months post-treatment the prevalence of late grade ≥2 gastrointestinal toxicity was 1.6, 3.7, 2.2, 0, and 0%, respectively, and the prevalence of late grade ≥2 urinary toxicity was 0.8, 11, 12, 7.1, and 6.3%, respectively. Three patients experienced grade 3 late toxicity at 12 to 18 months which subsequently resolved to grade 2 or less. For patients not receiving ADT the median PSA value pre-treatment was 7.6 ug/L (1.1-20) and at 12, 24, and 36 months post-treatment was 0.86, 0.36, and 0.20 ug/L. Conclusions: Delivery of a gantry-based SBRT boost is feasible in a multicenter setting, is well-tolerated with low rates of early toxicity and is associated with promising PSA responses. A second transient peak in urinary toxicity was observed at 18 months which subsequently resolved. Follow-up is ongoing to document late toxicity, long-term patient reported outcomes, and tumor control with this approach.

Moderate hypofractionation for prostate cancer: A user's guide.

Three large randomised controlled trials have been published in the last year demonstrating the non-inferiority of moderate hypofractionation compared to conventional fractionation for localised prostate cancer with respect to both disease control and late toxicity at 5 years. Furthermore, no clinically significant differences in patient-reported outcomes have emerged. More mature follow-up data are now also available from phase 2 studies confirming that moderate hypofractionation is associated with low rates of significant toxicity at 10 years. Moving forward it is likely that appropriate patient selection, integration of androgen deprivation and attention to optimising technique will play a more important role than modest differences in dose-fractionation schedules. Here we briefly review the evidence, discuss issues of patient selection and provide an approach to implementing moderately hypofractionated radiation therapy for prostate cancer in clinical practice.

Rectal protection in prostate stereotactic radiotherapy: a retrospective exploratory analysis of two rectal displacement devices.

INTRODUCTION: High rectal doses are associated with increased toxicity. A rectal displacement device (RDD) reduces rectal dose in prostate stereotactic body radiation therapy (SBRT). This study investigates any dosimetric difference between two methods of rectal displacement (Rectafix and SpaceOAR) for prostate SBRT. METHODS: Rectal dosimetry of 45 men who received SBRT within the PROMETHEUS trial was retrospectively examined, across two radiation therapy centres using the two RDD's. Men received a total dose (TD) of 19 or 20 Gy in two fractions followed by 46 Gy in 23 fractions. Centre 1 contributed 16 Rectafix and 10 SpaceOAR patients. Centre 2 contributed 19 Rectafix patients. Rectal dose volume histogram (DVH) data were recorded as a TD percentage at the following volume intervals; V1%, V2%, V5%, V10% and then 10% increments to V80%. As only one centre employed both RDD's, three sequential rectal dosimetry comparisons were performed; (1) centre 1 Rectafix versus centre 1 SpaceOAR; (2) centre 1 Rectafix versus centre 2 Rectafix and (3) centre 1+ centre 2 Rectafix versus centre 1 SpaceOAR. RESULTS: In comparison (1) Rectafix demonstrated lower mean doses at 9 out of 11 measured intervals (P = 0.0012). Comparison (2) demonstrated a moderate difference with centre 2 plans producing slightly lower rectal doses (P = 0.013). Comparison (3) further demonstrated that Rectafix returned lower mean doses than SpaceOAR (P < 0.001). Although all dose levels were in favour of Rectafix, in absolute terms differences were small (2.6-9.0%). CONCLUSIONS: In well-selected prostate SBRT patients, Rectafix and SpaceOAR RDD's provide approximately equivalent rectal sparing.

Real-time in vivo rectal wall dosimetry using MOSkin detectors during linac based stereotactic radiotherapy with rectal displacement.

BACKGROUND: MOSFET dosimetry is a method that has been used to measure in-vivo doses during brachytherapy treatments and during linac based radiotherapy treatment. Rectal displacement devices (RDDs) allow for safe dose escalation for prostate cancer treatment. This study used dual MOSkin detectors to assess real-time in vivo rectal wall dose in patients with an RDD in place during a high dose prostate stereotactic body radiation therapy (SBRT) boost trial. METHODS: The PROMETHEUS study commenced in 2014 and provides a prostate SBRT boost dose with a RDD in place. Twelve patients received two boost fractions of 9.5-10 Gy each delivered to the prostate with a dual arc volumetric modulated arc therapy (VMAT) technique. Two MOSkins in a face-to-face arrangement (dual MOSkin) were used to decrease angular dependence. A dual MOSkin was attached to the anterior surface of the Rectafix and read out at 1 Hz during each treatment. The planned dose at each measurement point was exported from the planning system and compared with the measured dose. The root mean square error normalised to the total planned dose was calculated for each measurement point and treatment arc for the entire course of treatment. RESULTS: The average difference between the measured and planned doses over the whole course of treatment for all arcs measured was 9.7% with a standard deviation of 3.6%. The cumulative MOSkin reading was lower than the total planned dose for 64% of the arcs measured. The average difference between the final measured and final planned doses for all arcs measured was 3.4% of the final planned dose, with a standard deviation of 10.3%. CONCLUSIONS: MOSkin detectors were an effective tool for measuring dose delivered to the anterior rectal wall in real time during prostate SBRT boost treatments for the purpose of both ensuring the rectal doses remain within acceptable limits during the treatment and for the verification of final rectal doses.

The first clinical implementation of a real-time six degree of freedom target tracking system during radiation therapy based on Kilovoltage Intrafraction Monitoring (KIM).

PURPOSE: We present the first clinical implementation of a real-time six-degree of freedom (6DoF) Kilovoltage Intrafraction Monitoring (KIM) system which tracks the cancer target translational and rotational motions during treatment. The method was applied to measure and correct for target motion during stereotactic body radiotherapy (SBRT) for prostate cancer. METHODS: Patient: A patient with prostate adenocarcinoma undergoing SBRT with 36.25Gy, delivered in 5 fractions was enrolled in the study. 6DoF KIM technology: 2D positions of three implanted gold markers in each of the kV images (125kV, 10mA at 11Hz) were acquired continuously during treatment. The 2D→3D target position estimation was based on a probability distribution function. The 3D→6DoF target rotation was calculated using an iterative closest point algorithm. The accuracy and precision of the KIM method was measured by comparing the real-time results with kV-MV triangulation. RESULTS: Of the five treatment fractions, KIM was utilised successfully in four fractions. The intrafraction prostate motion resulted in three couch shifts in two fractions when the prostate motion exceeded the pre-set action threshold of 2mm for more than 5s. KIM translational accuracy and precision were 0.3±0.6mm, -0.2±0.3mm and 0.2±0.7mm in the Left-Right (LR), Superior-Inferior (SI) and Anterior-Posterior (AP) directions, respectively. The KIM rotational accuracy and precision were 0.8°±2.0°, -0.5°±3.3° and 0.3°±1.6° in the roll, pitch and yaw directions, respectively. CONCLUSION: This treatment represents, to the best of our knowledge, the first time a cancer patient's tumour position and rotation have been monitored in real-time during treatment. The 6 DoF KIM system has sub-millimetre accuracy and precision in all three translational axes, and less than 1° accuracy and 4° precision in all three rotational axes.