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1.  A Dosimetric Analysis of Radiation Therapy Oncology Group (RTOG) 0321: the Importance of Urethral Dose 
Practical radiation oncology  2013;4(1):27-34.
RTOG 0321 is the first multi-institutional cooperative group HDR prostate brachytherapy trial with complete digital brachytherapy dosimetry data. This is a descriptive report of the data and an analysis of toxicity.
Methods and Materials
Patients are treated with EBRT 45 Gy and one HDR implant with 19 Gy in 2 fractions. Implants are done with TRUS guidance, and CT-compatible non-metallic catheters. HDR planning is done on ≤ 3 mm-thick CT slices. The “mean DVH” of the PTV, implanted volume (IP), and organs at risk are calculated. This includes the mean and standard deviation of the volume at ten-percentage-point intervals from 10%–200% of the prescribed dose. The conformal index (COIN), homogeneity index (HI), catheters/implant, and patients/institution are calculated. Multivariate analysis and Hazard Ratios calculation of all the variables against reported Grade ≥ 2 (G2+) GU adverse events (CTCAEv3) are performed.
Dosimetry data is based on 122 eligible patients from 14 institutions. The mean of PTV, IP, catheters/implant, and patients/institution are: 54 cc, 63 cc, 19 and 9. The mean of %V100PTV, V80Bladder, V80Rectum, and V120Urethra were: 94%, 0.40cc, 0.15cc, and 0.25cc. There are too few G2+ GI AE for correlative analysis, thus the analysis has been performed on the more common G2+ GU AE. There are positive correlations noted between both acute and late G2+ GU AE and urethral dose at multiple levels. Positive correlations with late AE are seen with PTV and IP at high-dose levels. A negative correlation is seen between HI and acute AE. A higher patient accrual rate is associated with a lower rate of G2+ acute and late AE.
Higher urethral dose, larger high dose volumes and lower dose homogeneity are associated with greater toxicities. A mean DVH comparison at all dose levels should be used for quality control and future research comparison.
PMCID: PMC4000550  PMID: 24621420
Prostate cancer; High Dose Rate; Brachytherapy; RTOG; Multi-institutional clinical trial
2.  Cold spot mapping inferred from MRI at time of failure predicts biopsy-proven local failure after permanent seed brachytherapy in prostate cancer patients: Implications for focal salvage brachytherapy 
Background and purpose
To establish a method to evaluate dosimetry at the time of primary prostate permanent implant (pPPI) using MRI of the shrunken prostate at the time of failure (tf).
To compare cold spot mapping with sextant-biopsy mapping at tf.
Material and methods
Twenty-four patients were referred for biopsy-proven local failure (LF) after pPPI. Multiparametric MRI and combined-sextant biopsy with a central review of the pathology at tf were systematically performed.
A model of the shrinking pattern was defined as a Volumetric Change Factor (VCF) as a function of time from time of pPPI (t0). An isotropic expansion to both prostate volume (PV) and seed position (SP) coordinates determined at tf was performed using a validated algorithm using the VCF.
pPPI CT-based evaluation (at 4 weeks) vs. MR-based evaluation: Mean D90% was 145.23 ± 19.16 Gy [100.0–167.5] vs. 85.28 ± 27.36 Gy [39–139] (p = 0.001), respectively. Mean V100% was 91.6 ± 7.9% [70–100%] vs. 73.1 ± 13.8% [55–98%] (p = 0.0006), respectively. Seventy-seven per cent of the pathologically positive sextants were classified as cold.
Patients with biopsy-proven LF had poorer implantation quality when evaluated by MRI several years after implantation. There is a strong relationship between microscopic involvement at tf and cold spots.
PMCID: PMC4081029  PMID: 24231238
Prostate cancer; Prostate permanent implant; Seeds; Local failure; MR-based dosimetry
3.  Catheter-based ultrasound hyperthermia with HDR brachytherapy for treatment of locally advanced cancer of the prostate and cervix 
A clinical treatment delivery platform has been developed and is being evaluated in a clinical pilot study for providing 3D controlled hyperthermia with catheter-based ultrasound applicators in conjunction with high dose rate (HDR) brachytherapy. Catheter-based ultrasound applicators are capable of 3D spatial control of heating in both angle and length of the devices, with enhanced radial penetration of heating compared to other hyperthermia technologies. Interstitial and endocavity ultrasound devices have been developed specifically for applying hyperthermia within HDR brachytherapy implants during radiation therapy in the treatment of cervix and prostate. A pilot study of the combination of catheter based ultrasound with HDR brachytherapy for locally advanced prostate and cervical cancer has been initiated, and preliminary results of the performance and heating distributions are reported herein. The treatment delivery platform consists of a 32 channel RF amplifier and a 48 channel thermocouple monitoring system. Controlling software can monitor and regulate frequency and power to each transducer section as required during the procedure. Interstitial applicators consist of multiple transducer sections of 2–4 cm length × 180 deg and 3–4 cm × 360 deg. heating patterns to be inserted in specific placed 13g implant catheters. The endocavity device, designed to be inserted within a 6 mm OD plastic tandem catheter within the cervix, consists of 2–3 transducers × dual 180 or 360 deg sectors. 3D temperature based treatment planning and optimization is dovetailed to the HDR optimization based planning to best configure and position the applicators within the catheters, and to determine optimal base power levels to each transducer section. To date we have treated eight cervix implants and six prostate implants. 100 % of treatments achieved a goal of >60 min duration, with therapeutic temperatures achieved in all cases. Thermal dosimetry within the hyperthermia target volume (HTV) and clinical target volume (CTV) are reported. Catheter-based ultrasound hyperthermia with HDR appears feasible with therapeutic temperature coverage of the target volume within the prostate or cervix while sparing surrounding more sensitive regions. (NIHR01CA122276).
PMCID: PMC4112774  PMID: 25076820
Ultrasound; Hyperthermia; Thermal Therapy; Interstitial; Endocavity
4.  Interactive, multi-modality image registrations for combined MRI/MRSI-planned HDR prostate brachytherapy 
This study presents the steps and criteria involved in the series of image registrations used clinically during the planning and dose delivery of focal high dose-rate (HDR) brachytherapy of the prostate.
Material and methods
Three imaging modalities – Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopic Imaging (MRSI), and Computed Tomography (CT) – were used at different steps during the process. MRSI is used for identification of dominant intraprosatic lesions (DIL). A series of rigid and nonrigid transformations were applied to the data to correct for endorectal-coil-induced deformations and for alignment with the planning CT. Mutual information was calculated as a morphing metric. An inverse planning optimization algorithm was applied to boost dose to the DIL while providing protection to the urethra, penile bulb, rectum, and bladder. Six prostate cancer patients were treated using this protocol.
The morphing algorithm successfully modeled the probe-induced prostatic distortion. Mutual information calculated between the morphed images and images acquired without the endorectal probe showed a significant (p = 0.0071) increase to that calculated between the unmorphed images and images acquired without the endorectal probe. Both mutual information and visual inspection serve as effective diagnostics of image morphing. The entire procedure adds less than thirty minutes to the treatment planning.
This work demonstrates the utility of image transformations and registrations to HDR brachytherapy of prostate cancer.
PMCID: PMC3627724  PMID: 23606866
MRSI; HDR; prostate; image registration
5.  Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiotherapy for Adenocarcinoma of the Prostate: Preliminary Results of RTOG 0321 
To estimate the rate of late grade 3 or greater genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) following treatment with external beam radiation therapy and prostate high dose rate (HDR) brachytherapy.
Methods and Materials
Each participating institution submitted CT based HDR brachytherapy dosimetry data electronically for credentialing and for each study patient. Patients with locally confined T1c-T3b prostate cancer were eligible for this study. All patients were treated with 45 Gy in 25 fractions from external beam radiotherapy and one HDR implant delivering 19 Gy in 2 fractions. All AEs were graded according to CTCAEv3.0. Late GU/ GI AEs were defined as those occurring more than nine months from the start of the protocol treatment, in patients with at least 18 months of potential follow-up.
A total of 129 patients from 14 institutions were enrolled in this study. 125 patients were eligible and AE data was available for 112 patients. The pretreatment characteristics of the patients were as follows: T1c-T2c 91%, T3a-T3b 9%, PSA ≤ 10 70%, PSA >10-≤20 30%, GS 2-6 10%, GS 7 72%, and GS 8-10 18%. At a median follow-up time of 29.6 months, 3 acute and 4 late grade 3 GU/GI AEs were reported. The estimated rate of late grade 3-5 GU and GI AE at 18 months was 2.56%.
This is the first prospective, multi-institutional trial of CT based HDR brachytherapy and external beam radiotherapy. The technique and doses used in this study resulted in acceptable levels of adverse events.
PMCID: PMC2946454  PMID: 20207506
Prostate cancer; High Dose Rate; Brachytherapy; Prospective multi-institutional clinical trial
6.  Toward adaptive stereotactic robotic brachytherapy for prostate cancer: Demonstration of an adaptive workflow incorporating inverse planning and an MR stealth robot 
To translate any robot into a clinical environment, it is critical that the robot can seamlessly integrate with all the technology of a modern clinic. MRBot, an MR-stealth brachytherapy delivery device, was used in a closed-bore 3T MRI and a clinical brachytherapy cone beam CT suite. Targets included ceramic dummy seeds, MR-Spectroscopy-sensitive metabolite, and a prostate phantom. Acquired DICOM images were exported to planning software to register the robot coordinates in the imager’s frame, contour and verify target locations, create dose plans, and export needle and seed positions to the robot. The coordination of each system element (imaging device, brachytherapy planning system, robot control, robot) was validated with a seed delivery accuracy of within 2 mm in both a phantom and soft tissue. An adaptive workflow was demonstrated by acquiring images after needle insertion and prior to seed deposition. This allows for adjustment if the needle is in the wrong position. Inverse planning (IPSA) was used to generate a seed placement plan and coordinates for ten needles and 29 seeds were transferred to the robot. After every two needles placed, an image was acquired. The placed seeds were identified and validated prior to placing the seeds in the next two needles. The ability to robotically deliver seeds to locations determined by IPSA and the ability of the system to incorporate novel needle patterns were demonstrated. Shown here is the ability to overcome this critical step. An adaptive brachytherapy workflow is demonstrated which integrates a clinical anatomy-based seed location optimization engine and a robotic brachytherapy device. Demonstration of this workflow is a key element of a successful translation to the clinic of the MRI stealth robotic delivery system, MRBot.
PMCID: PMC3108452  PMID: 20642386
Robotic brachytherapy; prostate cancer; adaptive workflow; seed location
7.  Sensorless Motion Planning for Medical Needle Insertion in Deformable Tissues 
Minimally invasive medical procedures such as biopsies, anesthesia drug injections, and brachytherapy cancer treatments require inserting a needle to a specific target inside soft tissues. This is difficult because needle insertion displaces and deforms the surrounding soft tissues causing the target to move during the procedure. To facilitate physician training and preoperative planning for these procedures, we develop a needle insertion motion planning system based on an interactive simulation of needle insertion in deformable tissues and numerical optimization to reduce placement error. We describe a 2-D physically based, dynamic simulation of needle insertion that uses a finite-element model of deformable soft tissues and models needle cutting and frictional forces along the needle shaft. The simulation offers guarantees on simulation stability for mesh modications and achieves interactive, real-time performance on a standard PC. Using texture mapping, the simulation provides visualization comparable to ultrasound images that the physician would see during the procedure. We use the simulation as a component of a sensorless planning algorithm that uses numerical optimization to compute needle insertion offsets that compensate for tissue deformations. We apply the method to radioactive seed implantation during permanent seed prostate brachytherapy to minimize seed placement error.
PMCID: PMC2822650  PMID: 19126473
Brachytherapy; medical robotics; motion planning; needle insertion; physically based simulation; sensorless planning
Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard “closed-bore” 1.5T scanner.
Methods and Materials:
Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T2-weighted MRI.
Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V125 ranged from 0% to 18% (median, 5%), and the rectal V75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients.
High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.
PMCID: PMC2396328  PMID: 15275727
Prostate cancer; Brachytherapy; MRI; Image guidance

Results 1-8 (8)